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Global developmental delay(DD)

MedGen UID:
107838
Concept ID:
C0557874
Finding; Mental or Behavioral Dysfunction
Synonyms: Cognitive delay; DD; Delayed cognitive development; Delayed development; Delayed developmental milestones; Delayed intellectual development; Delayed milestones; Delayed psychomotor development; Developmental delay; Developmental delay in early childhood; Developmental retardation; Lack of psychomotor development; Mental and motor retardation; Motor and developmental delay; Psychomotor delay; Psychomotor development deficiency; Psychomotor development failure; Psychomotor developmental delay; Psychomotor retardation; Retarded development; Retarded mental development; Retarded psychomotor development
SNOMED CT: Global developmental delay (224958001)
 
HPO: HP:0001263

Definition

A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age. [from HPO]

Conditions with this feature

DiGeorge sequence
MedGen UID:
4297
Concept ID:
C0012236
Disease or Syndrome
Individuals with 22q11.2 deletion syndrome (22q11.2DS) have a range of findings including the following: Congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus). Palatal abnormalities (69%), particularly velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate. Characteristic facial features (present in the majority of individuals of northern European heritage). Learning difficulties (70%-90%). An immune deficiency (regardless of the clinical presentation) (77%). Additional findings include the following: Hypocalcemia (50%). Significant feeding and swallowing problems; constipation with or without structural gastrointestinal anomalies (intestinal malrotation, imperforate anus, and Hirschsprung disease). Renal anomalies (31%). Hearing loss (both conductive and sensorineural). Laryngotracheoesophageal anomalies. Growth hormone deficiency. Autoimmune disorders. Seizures (idiopathic or associated with hypocalcemia). CNS anomalies including tethered cord. Skeletal abnormalities (scoliosis with or without vertebral anomalies, clubbed feet, polydactyly, and craniosynostosis). Ophthalmologic abnormalities (strabismus, posterior embryotoxon, tortuous retinal vessels, scleracornea, and anophthalmia). Enamel hypoplasia. Malignancies (rare). Developmental delay (in particular delays in emergence of language), intellectual disability, and learning differences (non-verbal learning disability where the verbal IQ is significantly greater than the performance IQ) are common. Autism or autistic spectrum disorder is found in approximately 20% of children and psychiatric illness (specifically schizophrenia) is present in 25% of adults; however, attention deficit disorder, anxiety, perseveration, and difficulty with social interactions are also common.
Pigmentary pallidal degeneration
MedGen UID:
6708
Concept ID:
C0018523
Disease or Syndrome
Pantothenate kinase-associated neurodegeneration (PKAN) is a type of neurodegeneration with brain iron accumulation (NBIA). The phenotypic spectrum of PKAN includes classic PKAN and atypical PKAN. Classic PKAN is characterized by early childhood onset of progressive dystonia, dysarthria, rigidity, and choreoathetosis. Pigmentary retinal degeneration is common. Atypical PKAN is characterized by later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease.
Cowden syndrome
MedGen UID:
5420
Concept ID:
C0018553
Neoplastic Process
Cowden syndrome-1 is a hamartomatous disorder characterized by macrocephaly, facial trichilemmomas, acral keratoses, papillomatous papules, and an increased risk for the development of breast, thyroid, and endometrial carcinoma. Bannayan-Riley-Ruvalcaba syndrome (BRRS), previously thought be distinct, shared clinical characteristics with Cowden syndrome, such as hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, and increased risk of developing neoplasms, but had the additional features of developmental delay, macrocephaly, lipomas, hemangiomas, and pigmented speckled macules of the glans penis in males. Because features of BRRS and Cowden syndrome have been found in individuals within the same family with the same PTEN mutation, Cowden syndrome-1 and BRRS are considered to be the same disorder with variable expression and age-related penetrance (summary by Marsh et al., 1999, Lachlan et al., 2007, and Blumenthal and Dennis, 2008). Approximately 80% of patients reported with Cowden syndrome and 60% with BRSS have PTEN mutations (Blumenthal and Dennis, 2008). Some patients with Cowden syndrome may have immune system defects resulting in increased susceptibility to infections (summary by Browning et al., 2015).
Neutral 1 amino acid transport defect
MedGen UID:
6723
Concept ID:
C0018609
Disease or Syndrome
Hartnup disease is a condition caused by the body's inability to absorb certain protein building blocks (amino acids) from the diet. As a result, affected individuals are not able to use these amino acids to produce other substances, such as vitamins and proteins. Most people with Hartnup disease are able to get the vitamins and other substances they need with a well-balanced diet.People with Hartnup disease have high levels of various amino acids in their urine (aminoaciduria). For most affected individuals, this is the only sign of the condition. However, some people with Hartnup disease have episodes during which they exhibit other signs, which can include skin rashes; difficulty coordinating movements (cerebellar ataxia); and psychiatric symptoms, such as depression or psychosis. These episodes are typically temporary and are often triggered by illness, stress, nutrient-poor diet, or fever. These features tend to go away once the trigger is remedied, although the aminoaciduria remains. In affected individuals, signs and symptoms most commonly occur in childhood.
Hepatitis B surface antigen
MedGen UID:
9219
Concept ID:
C0019168
Immunologic Factor
Any one of the hepatitis B antigens found on the surface of the Dane particle and on the 20 nm spherical and tubular particles. Several subspecificities of the surface antigen are known. These were formerly called the Australia antigen.
Hereditary insensitivity to pain with anhidrosis
MedGen UID:
6915
Concept ID:
C0020074
Disease or Syndrome
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain) is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often the initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common.
Normal pressure hydrocephalus
MedGen UID:
42526
Concept ID:
C0020258
Disease or Syndrome
A form of compensated hydrocephalus characterized clinically by a slowly progressive gait disorder (see GAIT DISORDERS, NEUROLOGIC), progressive intellectual decline, and URINARY INCONTINENCE. Spinal fluid pressure tends to be in the high normal range. This condition may result from processes which interfere with the absorption of CSF including SUBARACHNOID HEMORRHAGE, chronic MENINGITIS, and other conditions. (From Adams et al., Principles of Neurology, 6th ed, pp631-3)
Leigh syndrome
MedGen UID:
44095
Concept ID:
C0023264
Disease or Syndrome
Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation. Thus, Leigh syndrome may be a clinical feature of a primary deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (see 252010), complex II deficiency (see 252011), complex III deficiency (see 124000), complex IV deficiency (cytochrome c oxidase; see 220110), or complex V deficiency (see 604273) (summary by Lake et al., 2015). Genetic Heterogeneity of Leigh Syndrome Mutations in complex I genes include mitochondrial-encoded MTND2 (516001), MTND3 (516002), MTND5 (516005), and MTND6 (516006), the nuclear-encoded NDUFS1 (157655), NDUFS3 (603846), NDUFS4 (602694), NDUFS7 (601825), NDUFS8 (602141), NDUFA2 (602137), NDUFA9 (603834), NDUFA10 (603835), NDUFA12 (614530), NDUFAF6 (612392), and NDUFAF5 (612360). Mutation in the MTFMT gene (611766), which is involved in mitochondrial translation, has also been reported with complex I deficiency. A mutation has been found in a complex III gene: BCS1L (603647), which is involved in the assembly of complex III. Mutations in complex IV genes include mitochondrial-encoded MTCO3 (516050) and nuclear-encoded COX10 (602125), COX15 (603646), SCO2 (604272), SURF1 (185620), which is involved in the assembly of complex IV, TACO1 (612958), and PET100 (614770). A mutation has been found in a complex V gene: the mitochondrial-encoded MTATP6 (516060). Mutations in genes encoding mitochondrial tRNA proteins have also been identified in patients with Leigh syndrome: see MTTV (590105), MTTK (590060), MTTW (590095), and MTTL1 (590050). Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, 238331 and PDHA1, 300502). The French Canadian (or Saguenay-Lac-Saint-Jean) type of Leigh syndrome with COX deficiency (LSFC; 220111) is caused by mutation in the LRPPRC gene (607544). Deficiency of coenzyme Q10 (607426) can present as Leigh syndrome.
Deficiency of alpha-mannosidase
MedGen UID:
7467
Concept ID:
C0024748
Disease or Syndrome
Alpha-mannosidosis encompasses a continuum of clinical findings from mild to severe. Three major clinical subtypes have been suggested: A mild form recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression (type 1). A moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression (type 2). A severe form manifested as prenatal loss or early death from progressive central nervous system involvement or infection (type 3). Individuals with a milder phenotype have mild-to-moderate intellectual disability, impaired hearing, characteristic coarse features, clinical or radiographic skeletal abnormalities, immunodeficiency, and primary central nervous system disease – mainly cerebellar involvement causing ataxia. Periods of psychiatric symptoms are common. Associated medical problems can include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alpha-mannosidosis is insidiously progressive; some individuals may live into the sixth decade.
Marinesco-Sjögren syndrome
MedGen UID:
6222
Concept ID:
C0024814
Disease or Syndrome
Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia with cerebellar atrophy, dysarthria, nystagmus, early-onset (not necessarily congenital) cataracts, myopathy, muscle weakness, and hypotonia. Additional features may include psychomotor delay, hypergonadotropic hypogonadism, short stature, and various skeletal abnormalities. Children with MSS usually present with muscular hypotonia in early infancy; distal and proximal muscular weakness is noticed during the first decade of life. Later, cerebellar findings of truncal ataxia, dysdiadochokinesia, nystagmus, and dysarthria become apparent. Motor function worsens progressively for some years, then stabilizes at an unpredictable age and degree of severity. Cataracts can develop rapidly and typically require lens extraction in the first decade of life. Although many adults have severe disabilities, life span in MSS appears to be near normal.
Multiple endocrine neoplasia, type 2b
MedGen UID:
9959
Concept ID:
C0025269
Neoplastic Process
Multiple endocrine neoplasia type 2 (MEN 2) includes the following phenotypes: MEN 2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN 2A), and MEN 2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN 2A and MEN 2B involve an increased risk for pheochromocytoma; MEN 2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC.
Pelger-Huët anomaly
MedGen UID:
10617
Concept ID:
C0030779
Disease or Syndrome
An autosomal dominant inherited condition caused by mutations in the lamin B receptor gene. It is characterized by defects in the neutrophil lobulation, resulting in the presence of dumbbell-shaped neutrophils with bilobed nuclei in the peripheral blood smear.
Prader-Willi syndrome
MedGen UID:
46057
Concept ID:
C0032897
Disease or Syndrome
Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present.
Pyruvate carboxylase deficiency
MedGen UID:
18801
Concept ID:
C0034341
Disease or Syndrome
Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Three clinical types are recognized: Type A (infantile form), in which most affected children die in infancy or early childhood. Type B (severe neonatal form), in which affected infants have hepatomegaly, pyramidal tract signs, and abnormal movement and die within the first three months of life. Type C (intermittent/benign form), in which affected individuals have normal or mildly delayed neurologic development and episodic metabolic acidosis.
Pyruvate dehydrogenase complex deficiency
MedGen UID:
19610
Concept ID:
C0034345
Disease or Syndrome
A genetic disorder caused by mutations in the genes that are responsible for production of protein components of the pyruvate dehydrogenase complex. It may present with lactic acidosis. Signs and symptoms include developmental delays, seizures and hypotonia.
Holoprosencephaly sequence
MedGen UID:
38214
Concept ID:
C0079541
Congenital Abnormality
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Dysostosis multiplex
MedGen UID:
39698
Concept ID:
C0086795
Disease or Syndrome
Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap; thus, affected individuals are best described as having either severe or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory-tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal. By age three years, linear growth decreases. Intellectual disability is progressive and profound. Hearing loss is common. Death, typically caused by cardiorespiratory failure, usually occurs within the first ten years of life. Attenuated MPS I. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decades to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities can be present. Clinical onset is usually between ages three and ten years. Hearing loss and cardiac valvular disease are common.
Angelman syndrome
MedGen UID:
58144
Concept ID:
C0162635
Disease or Syndrome
Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious.
Russell-Silver syndrome
MedGen UID:
104492
Concept ID:
C0175693
Disease or Syndrome
Russell-Silver syndrome (RSS) is characterized by intrauterine growth retardation accompanied by postnatal growth deficiency. The birth weight of affected infants is typically two or more SD below the mean, and postnatal growth two or more SD below the mean for length or height. Affected individuals typically have proportionately short stature, normal head circumference, fifth-finger clinodactyly, typical facial features with triangular facies characterized by broad forehead and narrow chin, and limb-length asymmetry that may result from hemihypotrophy with diminished growth of the affected side. Growth velocity is normal in children with RSS. The average adult height of males is 151.2 cm and that of females is 139.9 cm. Evidence exists that children with RSS are at significant risk for developmental delay (both motor and cognitive) and learning disabilities.
Aarskog syndrome
MedGen UID:
61234
Concept ID:
C0175701
Disease or Syndrome
Aarskog-Scott syndrome, also known as faciogenital dysplasia, is an X-linked disorder characterized by short stature, hypertelorism, shawl scrotum, and brachydactyly, although there is wide phenotypic variability and other features, such as joint hyperextensibility, short nose, widow's peak, and inguinal hernia, may also occur. Most patients do not have mental retardation, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature (summary by Orrico et al., 2010).
Radial aplasia-thrombocytopenia syndrome
MedGen UID:
61235
Concept ID:
C0175703
Disease or Syndrome
Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia (<50 platelets/nL) that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur.
Progressive sclerosing poliodystrophy
MedGen UID:
60012
Concept ID:
C0205710
Disease or Syndrome
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
Pelizaeus-Merzbacher disease
MedGen UID:
61440
Concept ID:
C0205711
Disease or Syndrome
PLP1-related disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Female carriers may manifest mild to moderate signs of the disease.
Gordon syndrome
MedGen UID:
66314
Concept ID:
C0220666
Disease or Syndrome
DA3, or Gordon syndrome, is distinguished from other distal arthrogryposes by short stature and cleft palate (summary by Bamshad et al., 2009). There are 2 syndromes with features overlapping those of DA3 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 5 (DA5; 108145) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of ocular abnormalities and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition. For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).
KBG syndrome
MedGen UID:
66317
Concept ID:
C0220687
Disease or Syndrome
KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors), characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip), short stature, developmental delay / intellectual disability, and behavioral issues. Affected individuals may have feeding difficulties (particularly in infancy), skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis), hearing loss (conductive, mixed, and sensorineural), seizure disorder, and brain malformations. There is significant variability in the clinical findings, even between affected members of the same family.
Medium-chain acyl-coenzyme A dehydrogenase deficiency
MedGen UID:
65086
Concept ID:
C0220710
Disease or Syndrome
Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid ß-oxidation. Fatty acid ß-oxidation fuels hepatic ketogenesis, which provides a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. MCAD deficiency is the most common disorder of fatty acid ß-oxidation and one of the most common inborn errors of metabolism. Most children are now diagnosed through newborn screening. Clinical symptoms in a previously apparently healthy child with MCAD deficiency include hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma triggered by a common illness. Hepatomegaly and liver disease are often present during an acute episode. Children appear normal at birth and – if not identified through newborn screening – typically present between age three and 24 months, although presentation even as late as adulthood is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged periods of fasting.
Bixler Christian Gorlin syndrome
MedGen UID:
113104
Concept ID:
C0220742
Disease or Syndrome
A very rare syndrome with characteristics of the combination of hypertelorism, cleft lip and palate and microtia. Nine cases have been reported in the literature in seven families. Some patients have associated cardiac or renal congenital malformations. Short stature and intellectual deficiency are common. The reported cases support autosomal recessive inheritance.
Biotinidase deficiency
MedGen UID:
66323
Concept ID:
C0220754
Disease or Syndrome
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Craniofrontonasal dysplasia
MedGen UID:
65095
Concept ID:
C0220767
Disease or Syndrome
Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism (Twigg et al., 2004; Wieland et al., 2004).
FG syndrome
MedGen UID:
113106
Concept ID:
C0220769
Disease or Syndrome
The phenotypic spectrum of MED12-related disorders, which is still being defined, includes at a minimum the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), and X-linked Ohdo syndrome. FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. X-linked Ohdo syndrome (referred to as XLOS in this GeneReview) is characterized by intellectual disability, blepharophimosis, and facial coarsening. A number of individuals with nonsyndromic intellectual disability – including some affected females – have been described.
Mucolipidosis type IV
MedGen UID:
68663
Concept ID:
C0238286
Disease or Syndrome
Mucolipidosis IV is characterized by severe psychomotor delay evident by the end of the first year of life and slowly progressive visual impairment during the first decade as a result of a combination of corneal clouding and retinal degeneration. By the end of the first decade of life and certainly by their early teens, all individuals with typical mucolipidosis IV have severe visual impairment as a result of retinal degeneration. Neurodegeneration is thought to occur in no more than 15% of individuals. About 5% of individuals have atypical mucolipidosis IV, often manifest as less severe psychomotor retardation and/or eye findings. Although in the past, mucolipidosis IV was considered an Ashkenazi Jewish disease, currently most affected individuals are non-Ashkenazi Jewish.
Weaver syndrome
MedGen UID:
120511
Concept ID:
C0265210
Disease or Syndrome
EZH2-related overgrowth includes EZH2-related Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous EZH2 pathogenic variant have been identified because of a clinical suspicion of Weaver syndrome, a minority have been identified through molecular genetic testing of family members of probands or individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome. Thus, the extent of the phenotypic spectrum associated with a heterozygous EZH2 pathogenic variant is not yet known. Weaver syndrome is characterized by tall stature, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance, and a range of associated clinical features including advanced bone age, poor coordination, soft doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse low cry in infancy. Brain MRI has identified abnormalities in a few individuals with EZH2-related overgrowth. Neuroblastoma occurs at a slightly increased frequency in individuals with a heterozygous EZH2 pathogenic variant but data are insufficient to determine absolute risk. There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency.
Pallister-Hall syndrome
MedGen UID:
120514
Concept ID:
C0265220
Disease or Syndrome
Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.
Netherton syndrome
MedGen UID:
78578
Concept ID:
C0265962
Disease or Syndrome
Netherton syndrome is a rare and severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Generalized scaly erythroderma is apparent at or soon after birth and usually persists. Scalp hair is sparse and brittle with a characteristic 'bamboo' shape under light microscopic examination due to invagination of the distal part of the hair shaft to its proximal part. Atopic manifestations include eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia. Life-threatening complications are frequent during the neonatal period, including hypernatremic dehydration, hypothermia, extreme weight loss, bronchopneumonia, and sepsis. During childhood, failure to thrive is common as a result of malnutrition, metabolic disorders, chronic erythroderma, persistent cutaneous infections, or enteropathy (summary by Bitoun et al., 2002).
Adenylosuccinate lyase deficiency
MedGen UID:
78641
Concept ID:
C0268126
Disease or Syndrome
Adenylosuccinase deficiency is an autosomal recessive inborn error of metabolism caused by an enzymatic defect in de novo purine synthesis (DNPS) pathway. ADSL deficiency leads to the accumulation of toxic intermediates, including succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) in body fluids. There are 3 major phenotypic forms of the disorder that correlate with different values of the S-Ado and SAICAr concentration ratios (S-Ado/SAICAr) in the cerebrospinal fluid. These include the most severe fatal neonatal encephalopathy (S-Ado/SAICAr ratio less than 1); childhood form (type I) with severe psychomotor retardation (S-Ado/SAICAr ratio close to 1), and a milder form (type II) with psychomotor retardation or hypotonia (S-Ado/SAICAr ratio greater than 2) (summary by Baresova et al., 2012).
Orotic aciduria
MedGen UID:
78642
Concept ID:
C0268128
Finding
Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001). Bailey (2009) stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported.
Deficiency of cytochrome-b5 reductase
MedGen UID:
75661
Concept ID:
C0268193
Disease or Syndrome
Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (review by Percy and Lappin, 2008). There are 2 types of methemoglobin reductase deficiency. In type I, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type II, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type II methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979).
Hepatic failure, early-onset, and neurologic disorder due to cytochrome C oxidase deficiency
MedGen UID:
75662
Concept ID:
C0268237
Congenital Abnormality
Leigh syndrome (or subacute necrotizing encephalomyelopathy) is characterized by decompensation (often with elevated lactate levels in blood and/or CSF) during an intercurrent illness. It is typically associated with psychomotor retardation or regression, often followed by transient or prolonged stabilization or even improvement, but inevitably resulting in eventual progressive neurologic decline, typically occurring in stepwise decrements. Neurologic manifestations include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Extraneurologic manifestations may include hypertrophic cardiomyopathy, hypertrichosis, anemia, renal tubulopathy, liver involvement, ptosis, and muscle weakness. Onset is typically between ages three and 12 months; about 50% of affected individuals die by age three years, most often as a result of respiratory or cardiac failure. Later onset (including in adulthood) and long-term survival may occasionally occur.
Niemann-Pick disease, type A
MedGen UID:
78650
Concept ID:
C0268242
Disease or Syndrome
Acid sphingomyelinase (ASM) deficiency has been categorized in the past as either neuronopathic (Niemann-Pick disease type A [NPD-A]), with death in early childhood, or non-neuronopathic (Niemann-Pick disease type B [NPD-B]). While forms intermediate to these two extremes occur, all ASM deficiency that is not NPD-A is designated in this review as NPD-B, despite its wide range of manifestations and severity. The first symptom in NPD-A is hepatosplenomegaly, usually noted by age three months; over time the liver and spleen become massive. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year. NPD type B, later in onset and milder in manifestations than NPD type A, is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, osteopenia, and atherogenic lipid profile. Progressive and/or clinically significant neurologic manifestations occur infrequently. Survival to adulthood can occur.
Acute neuronopathic Gaucher disease
MedGen UID:
78652
Concept ID:
C0268250
Disease or Syndrome
Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute. Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2. Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.
Sphingolipid activator protein 1 deficiency
MedGen UID:
120624
Concept ID:
C0268262
Disease or Syndrome
Metachromatic leukodystrophy is an inherited disorder characterized by the accumulation of fats called sulfatides in cells. This accumulation especially affects cells in the nervous system that produce myelin, the substance that insulates and protects nerves. Nerve cells covered by myelin make up a tissue called white matter. Sulfatide accumulation in myelin-producing cells causes progressive destruction of white matter (leukodystrophy) throughout the nervous system, including in the brain and spinal cord (the central nervous system) and the nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system).In people with metachromatic leukodystrophy, white matter damage causes progressive deterioration of intellectual functions and motor skills, such as the ability to walk. Affected individuals also develop loss of sensation in the extremities (peripheral neuropathy), incontinence, seizures, paralysis, an inability to speak, blindness, and hearing loss. Eventually they lose awareness of their surroundings and become unresponsive. While neurological problems are the primary feature of metachromatic leukodystrophy, effects of sulfatide accumulation on other organs and tissues have been reported, most often involving the gallbladder.The most common form of metachromatic leukodystrophy, affecting about 50 to 60 percent of all individuals with this disorder, is called the late infantile form. This form of the disorder usually appears in the second year of life. Affected children lose any speech they have developed, become weak, and develop problems with walking (gait disturbance). As the disorder worsens, muscle tone generally first decreases, and then increases to the point of rigidity. Individuals with the late infantile form of metachromatic leukodystrophy typically do not survive past childhood.In 20 to 30 percent of individuals with metachromatic leukodystrophy, onset occurs between the age of 4 and adolescence. In this juvenile form, the first signs of the disorder may be behavioral problems and increasing difficulty with schoolwork. Progression of the disorder is slower than in the late infantile form, and affected individuals may survive for about 20 years after diagnosis.The adult form of metachromatic leukodystrophy affects approximately 15 to 20 percent of individuals with the disorder. In this form, the first symptoms appear during the teenage years or later. Often behavioral problems such as alcoholism, drug abuse, or difficulties at school or work are the first symptoms to appear. The affected individual may experience psychiatric symptoms such as delusions or hallucinations. People with the adult form of metachromatic leukodystrophy may survive for 20 to 30 years after diagnosis. During this time there may be some periods of relative stability and other periods of more rapid decline.Metachromatic leukodystrophy gets its name from the way cells with an accumulation of sulfatides appear when viewed under a microscope. The sulfatides form granules that are described as metachromatic, which means they pick up color differently than surrounding cellular material when stained for examination.
Multiple sulfatase deficiency
MedGen UID:
75664
Concept ID:
C0268263
Disease or Syndrome
Initial symptoms of multiple sulfatase deficiency (MSD) can develop from infancy through early childhood, and presentation is widely variable. Some individuals display the multisystemic features characteristic of mucopolysaccharidosis disorders (e.g., developmental regression, organomegaly, skeletal deformities) while other individuals present primarily with neurologic regression (associated with leukodystrophy). Based on age of onset, rate of progression, and disease severity, several different clinical subtypes of MSD have been described: Neonatal MSD is the most severe with presentation in the prenatal period or at birth with rapid progression and death occurring within the first two years of life. Infantile MSD is the most common variant and may be characterized as attenuated (slower clinical course with cognitive disability and neurodegeneration identified in the 2nd year of life) or severe (loss of the majority of developmental milestones by age 5 years). Juvenile MSD is the rarest subtype with later onset of symptoms and subacute clinical presentation. Many of the features found in MSD are progressive, including neurologic deterioration, heart disease, hearing loss, and airway compromise.
Tay-Sachs disease, variant AB
MedGen UID:
78657
Concept ID:
C0268275
Disease or Syndrome
The GM2-gangliosidoses are a group of disorders caused by excessive accumulation of ganglioside GM2 and related glycolipids in the lysosomes, mainly of neuronal cells. GM2-gangliosidosis AB variant is characterized by normal hexosaminidase A (HEXA; 606869) and hexosaminidase B (HEXB; 606873) but the inability to form a functional GM2 activator complex. The clinical and biochemical phenotype of the AB variant is very similar to that of classic Tay-Sachs disease (see 272800) (Gravel et al., 2001).
Cutis laxa-corneal clouding-oligophrenia syndrome
MedGen UID:
82794
Concept ID:
C0268354
Disease or Syndrome
De Barsy syndrome, or autosomal recessive cutis laxa type III (ARCL3), is characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (summary by Kivuva et al., 2008). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see 219100. Genetic Heterogeneity of de Barsy Syndrome Also see ARCL3B (614438), caused by mutation in the PYCR1 gene (179035) on chromosome 17q25.
Deficiency of glycerol kinase
MedGen UID:
82803
Concept ID:
C0268418
Disease or Syndrome
NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD.
Alstrom syndrome
MedGen UID:
78675
Concept ID:
C0268425
Disease or Syndrome
Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family.
Dihydropteridine reductase deficiency
MedGen UID:
75682
Concept ID:
C0268465
Disease or Syndrome
Tetrahydrobiopterin deficiency is a rare disorder characterized by a shortage (deficiency) of a molecule called tetrahydrobiopterin or BH4. This condition alters the levels of several substances in the body, including phenylalanine. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in foods that contain protein and in some artificial sweeteners. High levels of phenylalanine are present from early infancy in people with untreated tetrahydrobiopterin deficiency. This condition also alters the levels of chemicals called neurotransmitters, which transmit signals between nerve cells in the brain.Infants with tetrahydrobiopterin deficiency appear normal at birth, but medical problems ranging from mild to severe become apparent over time. Signs and symptoms of this condition can include intellectual disability, progressive problems with development, movement disorders, difficulty swallowing, seizures, behavioral problems, and an inability to control body temperature.
GTP cyclohydrolase I deficiency
MedGen UID:
75683
Concept ID:
C0268467
Disease or Syndrome
Tetrahydrobiopterin deficiency is a rare disorder characterized by a shortage (deficiency) of a molecule called tetrahydrobiopterin or BH4. This condition alters the levels of several substances in the body, including phenylalanine. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in foods that contain protein and in some artificial sweeteners. High levels of phenylalanine are present from early infancy in people with untreated tetrahydrobiopterin deficiency. This condition also alters the levels of chemicals called neurotransmitters, which transmit signals between nerve cells in the brain.Infants with tetrahydrobiopterin deficiency appear normal at birth, but medical problems ranging from mild to severe become apparent over time. Signs and symptoms of this condition can include intellectual disability, progressive problems with development, movement disorders, difficulty swallowing, seizures, behavioral problems, and an inability to control body temperature.
Sepiapterin reductase deficiency
MedGen UID:
120642
Concept ID:
C0268468
Disease or Syndrome
The phenotypic spectrum of sepiapterin reductase deficiency (SRD), which ranges from significant motor and cognitive deficits to only minimal findings, has not been completely elucidated. Clinical features in the majority of affected individuals include motor and speech delay, axial hypotonia, dystonia, weakness, and oculogyric crises; symptoms show diurnal fluctuation and sleep benefit. Other common features include parkinsonian signs (tremor, bradykinesia, masked facies, rigidity), limb hypertonia, hyperreflexia, intellectual disability, psychiatric and/or behavioral abnormalities, autonomic dysfunction, and sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, and drowsiness). Most affected individuals have nonspecific features in infancy including developmental delays and axial hypotonia; other features develop over time.
Hydroxykynureninuria
MedGen UID:
78681
Concept ID:
C0268474
Disease or Syndrome
Proline dehydrogenase deficiency
MedGen UID:
120645
Concept ID:
C0268529
Disease or Syndrome
Phang et al. (2001) noted that prospective studies of HPI probands identified through newborn screening as well as reports of several families have suggested that it is a metabolic disorder not clearly associated with clinical manifestations. Phang et al. (2001) concluded that HPI is a relatively benign condition in most individuals under most circumstances. However, other reports have suggested that some patients have a severe phenotype with neurologic manifestations, including epilepsy and mental retardation (Jacquet et al., 2003). Genetic Heterogeneity of Hyperprolinemia See also hyperprolinemia type II (HYRPRO2; 239510), which is caused by mutation in the gene encoding pyrroline-5-carboxylate dehydrogenase (P5CDH, ALDH4A1; 606811) on chromosome 1p36.
Prolidase deficiency
MedGen UID:
120647
Concept ID:
C0268532
Disease or Syndrome
Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and hepatomegaly with elevated liver enzymes and splenomegaly. Anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are common. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described.
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
MedGen UID:
82815
Concept ID:
C0268540
Disease or Syndrome
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is characterized by variable clinical presentation and age of onset. Neonatal onset (~12% of affected individuals). Infants are normal for the first 24-48 hours followed by onset of symptoms related to hyperammonemia (poor feeding, vomiting, lethargy, low temperature, rapid breathing). Information on long-term outcome is limited. Infancy, childhood, and adult presentation (~88%). Affected individuals may present with: Chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits and/or unexplained seizures); Acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and Chronic liver dysfunction (unexplained elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance). Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia.
Ornithine carbamoyltransferase deficiency
MedGen UID:
75692
Concept ID:
C0268542
Disease or Syndrome
Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely in females) and as a post-neonatal-onset (partial deficiency) disease in males and females. Males with severe neonatal-onset OTC deficiency are typically normal at birth but become symptomatic from hyperammonemia on day two to three of life and are usually catastrophically ill by the time they come to medical attention. After successful treatment of neonatal hyperammonemic coma these infants can easily become hyperammonemic again despite appropriate treatment; they typically require liver transplant by age six months to improve quality of life. Males and heterozygous females with post-neonatal-onset (partial) OTC deficiency can present from infancy to later childhood, adolescence, or adulthood. No matter how mild the disease, a hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at any age and in any situation in life. For all individuals with OTC deficiency, typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention deficit hyperactivity disorder (ADHD), and executive function deficits.
Argininosuccinate lyase deficiency
MedGen UID:
78687
Concept ID:
C0268547
Disease or Syndrome
Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, may present as a severe neonatal-onset form and a late-onset form: The severe neonatal-onset form is characterized by hyperammonemia within the first few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death. In contrast, the manifestations of late-onset form range from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia. Manifestations of ASL deficiency (ASLD) that appear to be unrelated to the severity or duration of hyperammonemic episodes: Neurocognitive deficiencies (attention-deficit/hyperactivity disorder, developmental delay, seizures, and learning disability). Liver disease (hepatitis, cirrhosis). Trichorrhexis nodosa (coarse brittle hair that breaks easily). Systemic hypertension.
Arginase deficiency
MedGen UID:
78688
Concept ID:
C0268548
Disease or Syndrome
Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily.
Isovaleryl-CoA dehydrogenase deficiency
MedGen UID:
82822
Concept ID:
C0268575
Disease or Syndrome
Isovaleric acidemia is an inborn error of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase. It can present with severe neonatal ketoacidosis leading to death, but in milder cases recurrent episodes of ketoacidosis of varying degree occur later in infancy and childhood (summary by Vockley et al., 1991).
Propionyl-CoA carboxylase deficiency
MedGen UID:
75694
Concept ID:
C0268579
Disease or Syndrome
The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy. Isolated cardiomyopathy can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits. Manifestations of neonatal and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure.
Holocarboxylase synthetase deficiency
MedGen UID:
120653
Concept ID:
C0268581
Disease or Syndrome
Holocarboxylase synthetase deficiency, a biotin-responsive multiple carboxylase deficiency (MCD), is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period (summary by Suzuki et al., 2005). Also see biotinidase deficiency (253260), another form of MCD with a later onset. Care must be taken to differentiate the inherited multiple carboxylase deficiencies from acquired biotin deficiencies, such as those that develop after excessive dietary intake of avidin, an egg-white glycoprotein that binds specifically and essentially irreversibly to biotin (Sweetman et al., 1981) or prolonged parenteral alimentation without supplemental biotin (Mock et al., 1981).
3-MCC Deficiency
MedGen UID:
78691
Concept ID:
C0268600
Disease or Syndrome
3-methylcrotonyl-CoA carboxylase deficiency (also known as 3-MCC deficiency) is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have a shortage of an enzyme that helps break down proteins containing a particular building block (amino acid) called leucine.Infants with 3-MCC deficiency appear normal at birth but usually develop signs and symptoms in infancy or early childhood. The characteristic features of this condition, which can range from mild to life-threatening, include feeding difficulties, recurrent episodes of vomiting and diarrhea, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, this disorder can lead to delayed development, seizures, and coma. Many of these complications can be prevented with early detection and lifelong management with a low-protein diet and appropriate supplements. Some people with gene mutations that cause 3-MCC deficiency never experience any signs or symptoms of the condition.The characteristic features of 3-MCC deficiency are similar to those of Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.
Deficiency of hydroxymethylglutaryl-CoA lyase
MedGen UID:
78692
Concept ID:
C0268601
Disease or Syndrome
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988).
Succinate-semialdehyde dehydrogenase deficiency
MedGen UID:
124340
Concept ID:
C0268631
Disease or Syndrome
Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by infantile-onset hypotonia, developmental delay, cognitive impairment, expressive language deficit, and mild ataxia. Epilepsy is present in about half of affected individuals and is more common in adults. Hyperkinetic behavior, aggression, self-injurious behaviors, hallucinations, and sleep disturbances have been reported in nearly half of all affected individuals, more commonly in those who are older. Basal ganglia signs including choreoathetosis, dystonia, and myoclonus have been reported in a few individuals with earlier-onset, more severe disease. Involvement beyond the central nervous system has not been described. Individuals with SSADH deficiency typically have 4-hydroxybutyric aciduria present on urine organic acid analysis. Head MRI reveals T2 hyperintensities in multiple regions, involving the globus pallidi, cerebellar dentate nuclei, subthalamic nuclei, subcortical white matter, and brain stem, as well as cerebral and sometimes cerebellar atrophy. EEG findings include background slowing and spike discharges that are usually generalized.
Infantile neuroaxonal dystrophy
MedGen UID:
82852
Concept ID:
C0270724
Disease or Syndrome
PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features: Infantile neuroaxonal dystrophy (INAD). Atypical neuroaxonal dystrophy (atypical NAD). PLA2G6-related dystonia-parkinsonism. INAD usually begins between ages six months and three years with psychomotor regression or delay, hypotonia, and progressive spastic tetraparesis. Many affected children never learn to walk or lose the ability shortly after attaining it. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid, resulting in severe spasticity, progressive cognitive decline, and visual impairment. Many affected children do not survive beyond their first decade. Atypical NAD shows more phenotypic variability than INAD. In general, onset is in early childhood but can be as late as the end of the second decade. The presenting signs may be gait instability, ataxia, or speech delay and autistic features, which are sometimes the only evidence of disease for a year or more. Strabismus, nystagmus, and optic atrophy are common. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common. The course is fairly stable during early childhood and resembles static encephalopathy but is followed by neurologic deterioration between ages seven and 12 years. PLA2G6-related dystonia-parkinsonism has a variable age of onset, but most individuals present in early adulthood with gait disturbance or neuropsychiatric changes. Affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties. Dystonia is most common in the hands and feet but may be more generalized. The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability.
Pineal hyperplasia AND diabetes mellitus syndrome
MedGen UID:
78783
Concept ID:
C0271695
Disease or Syndrome
INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.
Glucocorticoid deficiency with achalasia
MedGen UID:
82889
Concept ID:
C0271742
Disease or Syndrome
Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood sugar (hypoglycemia). Addison disease, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of triple A syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two.Many of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. This part of the nervous system controls involuntary body processes such as digestion, blood pressure, and body temperature. People with triple A syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).People with this condition may have other neurological abnormalities, such as developmental delay, intellectual disability, speech problems (dysarthria), and a small head size (microcephaly). In addition, affected individuals commonly experience muscle weakness, movement problems, and nerve abnormalities in their extremities (peripheral neuropathy). Some develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Many of the neurological symptoms of triple A syndrome worsen over time.People with triple A syndrome frequently develop a thickening of the outer layer of skin (hyperkeratosis) on the palms of their hands and the soles of their feet. Other skin abnormalities may also be present in people with this condition.Alacrima is usually the first noticeable sign of triple A syndrome, as it becomes apparent early in life that affected children produce little or no tears while crying. They develop Addison disease and achalasia during childhood or adolescence, and most of the neurologic features of triple A syndrome begin during adulthood. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.
Peroxisome biogenesis disorder 1B
MedGen UID:
79470
Concept ID:
C0282527
Disease or Syndrome
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a PEX gene defect regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Septo-optic dysplasia sequence
MedGen UID:
90926
Concept ID:
C0338503
Disease or Syndrome
Microphthalmia, anophthalmia, and coloboma comprise the MAC spectrum of ocular malformations. Microphthalmia refers to a globe with a total axial length that is at least two standard deviations below the mean for age. Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Coloboma refers to the ocular malformations that result from failure of closure of the optic fissure. Chorioretinal coloboma refers to coloboma of the retina and choroid. Iris coloboma causes the iris to appear keyhole-shaped. Microphthalmia, anophthalmia, and coloboma may be unilateral or bilateral; when bilateral they may occur in any combination.
Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness
MedGen UID:
83338
Concept ID:
C0342287
Congenital Abnormality
Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia occurs between infancy and adolescence. The anemia is corrected with thiamine treatment, but the red cells remain macrocytic, and anemia can recur when treatment is withdrawn. Progressive sensorineural hearing loss has generally been early and can be detected in toddlers; hearing loss is irreversible and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence. Thiamine treatment may delay onset of diabetes in some individuals.
Congenital defect of folate absorption
MedGen UID:
83348
Concept ID:
C0342705
Disease or Syndrome
Hereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system. Findings include poor feeding, failure to thrive, and anemia. There can be leukopenia and thrombocytopenia, diarrhea and/or oral mucositis, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections, most often Pneumocystis jerovicii pneumonia. Neurologic manifestations include developmental delays, cognitive and motor impairment, behavioral disorders and, frequently, seizures.
Gamma-aminobutyric acid transaminase deficiency
MedGen UID:
137977
Concept ID:
C0342708
Disease or Syndrome
GABA-transaminase deficiency is characterized by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. Electroencephalograms show burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Severity varies, but most patients have profound developmental impairment and some patients die in infancy (summary by Koenig et al., 2017).
3-Methylglutaconic aciduria type 1
MedGen UID:
90994
Concept ID:
C0342727
Disease or Syndrome
3-methylglutaconyl-CoA hydratase deficiency is an inherited condition that causes neurological problems. Beginning in infancy to early childhood, children with this condition often have delayed development of mental and motor skills (psychomotor delay), speech delay, involuntary muscle cramping (dystonia), and spasms and weakness of the arms and legs (spastic quadriparesis). Affected individuals can also have optic atrophy, which is the degeneration (atrophy) of nerve cells that carry visual information from the eyes to the brain.In some cases, signs and symptoms of 3-methylglutaconyl-CoA hydratase deficiency begin in adulthood, often in a person's twenties or thirties. These individuals have damage to a type of brain tissue called white matter (leukoencephalopathy), which likely contributes to progressive problems with speech (dysarthria), difficulty coordinating movements (ataxia), stiffness (spasticity), optic atrophy, and a decline in intellectual function (dementia).Affected individuals who show symptoms of 3-methylglutaconyl-CoA hydratase deficiency in childhood often go on to develop leukoencephalopathy and other neurological problems in adulthood.All people with 3-methylglutaconyl-CoA hydratase deficiency accumulate large amounts of a substance called 3-methylglutaconic acid in their body fluids. As a result, they have elevated levels of acid in their blood (metabolic acidosis) and excrete large amounts of acid in their urine (aciduria). 3-methylglutaconyl-CoA hydratase deficiency is one of a group of metabolic disorders that can be diagnosed by the presence of increased levels 3-methylglutaconic acid in urine (3-methylglutaconic aciduria). People with 3-methylglutaconyl-CoA hydratase deficiency also have high urine levels of another acid called 3-methylglutaric acid.
Acetyl-CoA acetyltransferase-2 deficiency
MedGen UID:
90995
Concept ID:
C0342735
Disease or Syndrome
Beta-hydroxyisobutyryl-CoA deacylase deficiency
MedGen UID:
83349
Concept ID:
C0342738
Disease or Syndrome
3-Hydroxyisobutyryl-CoA hydrolase deficiency is an autosomal recessive inborn error of metabolism characterized by severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia (summary by Ferdinandusse et al., 2013).
Fumarase deficiency
MedGen UID:
87458
Concept ID:
C0342770
Disease or Syndrome
Fumarate hydratase deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are non-verbal and non-ambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported.
Deficiency of butyryl-CoA dehydrogenase
MedGen UID:
90998
Concept ID:
C0342783
Disease or Syndrome
Most infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. A broad range of clinical findings was originally reported in those with confirmed SCADD, including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported. In a large series of affected individuals detected on metabolic evaluation for developmental delay, 20% had failure to thrive, feeding difficulties, and hypotonia; 22% had seizures; and 30% had hypotonia without seizures. In contrast, the majority of infants with SCADD have been detected by expanded newborn screening, and the great majority of these infants remain asymptomatic. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness. A diagnosis of SCADD based on clinical findings should not preclude additional testing to look for other causes.
Deficiency of malonyl-CoA decarboxylase
MedGen UID:
91001
Concept ID:
C0342793
Disease or Syndrome
Malonyl-CoA decarboxylase deficiency is an uncommon inherited metabolic disease. The characteristic phenotype is variable, but may include developmental delay in early childhood, seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, ketosis, abnormal urinary compounds, lactic acidemia, and hypertrophic cardiomyopathy (Sweetman and Williams, 2001).
Sialuria
MedGen UID:
137980
Concept ID:
C0342853
Disease or Syndrome
Sialuria is a rare inborn error of metabolism in which excessive free sialic acid is synthesized. Clinical features include hepatosplenomegaly, coarse facial features, and varying degrees of developmental delay (summary by Enns et al., 2001).
Bifunctional peroxisomal enzyme deficiency
MedGen UID:
137982
Concept ID:
C0342870
Pathologic Function
D-bifunctional protein deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also peroxisomal acyl-CoA oxidase deficiency (264470), caused by mutation in the ACOX1 gene (609751) on chromosome 17q25. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including X-linked adrenoleukodystrophy (ALD; 300100), Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (NALD; see 601539) (Watkins et al., 1995). DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. McMillan et al. (2012) proposed a type IV deficiency on the basis of less severe features; these patients have a phenotype reminiscent of Perrault syndrome (PRLTS1; 233400). Pierce et al. (2010) noted that Perrault syndrome and DBP deficiency overlap clinically and suggested that DBP deficiency may be underdiagnosed.
Carbohydrate-deficient glycoprotein syndrome type I
MedGen UID:
138111
Concept ID:
C0349653
Disease or Syndrome
PMM2-CDG (CDG-Ia) (previously known as congenital disorder of glycosylation type 1a), the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three types: infantile multisystem, late-infantile and childhood ataxia-intellectual disability, and adult stable disability. The three types notwithstanding, clinical presentation and course are highly variable, ranging from infants who die in the first year of life to mildly involved adults. Clinical presentations tend to be similar in sibs. In the infantile multisystem type, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, failure to thrive, and impaired growth are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical presentations are observed: (1) a non-fatal neurologic form with strabismus, psychomotor retardation, and cerebellar hypoplasia in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade and (2) a neurologic-multivisceral form with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia-intellectual disability type, with onset between age three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability type, intellectual ability is stable; peripheral neuropathy is variable, thoracic and spinal deformities progress, and premature aging is observed; females lack secondary sexual development and males may exhibit decreased testicular volume. Hyperglycemia-induced growth hormone release, hyperprolactinemia, insulin resistance, and coagulopathy may occur. An increased risk for deep venous thrombosis is present.
Lhermitte-Duclos disease
MedGen UID:
140251
Concept ID:
C0391826
Neoplastic Process
A benign, WHO grade I cerebellar mass, which occurs in young adults and is composed of dysplastic ganglion cells. It is the major CNS manifestation of Cowden disease, an autosomal dominant condition that causes a variety of hamartomas and neoplasms.
Roberts-SC phocomelia syndrome
MedGen UID:
95931
Concept ID:
C0392475
Disease or Syndrome
Roberts syndrome (RBS) is characterized by prenatal growth retardation (ranging from mild to severe), craniofacial findings (including microcephaly and cleft lip and/or palate) and limb malformations (including bilateral symmetric tetraphocomelia or hypomelia caused by mesomelic shortening). Upper limbs are more severely affected than lower limbs. Other limb malformations include oligodactyly with thumb aplasia or hypoplasia, syndactyly, clinodactyly, and elbow and knee flexion contractures. Craniofacial abnormalities include cleft lip and/or cleft palate, premaxillary prominence, micrognathia, microbrachycephaly, malar flattening, downslanted palpebral fissures, widely spaced eyes, exophthalmos resulting from shallow orbits, corneal clouding, underdeveloped ala nasi, beaked nose, and ear malformations. Intellectual disability is reported in the majority of affected individuals. Mortality is high among severely affected pregnancies and newborns. Mildly affected individuals may survive to adulthood.
Troyer syndrome
MedGen UID:
97950
Concept ID:
C0393559
Disease or Syndrome
Troyer syndrome is characterized by progressive spastic paraparesis, dysarthria, pseudobulbar palsy, distal amyotrophy, short stature, and subtle skeletal abnormalities. Most affected children exhibit delays in walking and speech and difficulty in managing oral secretions, followed by increased lower-limb spasticity and slow deterioration in both gait and speech. Mild cerebellar signs are common. The most severely affected individuals have choreoathetosis. Emotional lability / difficulty in controlling emotions and affective disorders, such as inappropriate euphoria and/or crying, are frequently described. Life expectancy is normal.
Congenital disorder of glycosylation type 2C
MedGen UID:
96022
Concept ID:
C0398739
Disease or Syndrome
Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe psychomotor retardation, mild dysmorphism, and impaired neutrophil motility. It is a member of a group of disorders with a defect in the processing of protein-bound glycans. For a general overview of congenital disorders of glycosylation (CDGs), see CDG1A (212065) and CDG2A (212066). The neutrophil defect in CDG2C has been referred to as 'leukocyte adhesion deficiency type II' (LAD2), which is a manifestation of the disorder; there are no cases of 'primary' LAD II (Frydman, 1996). Etzioni and Harlan (1999) provided a comprehensive review of both LAD1 (116920) and LAD2. While the functional neutrophil studies are similar in the 2 LADs, the clinical course is milder in LAD2. Furthermore, patients with LAD2 present other abnormal features, such as growth and mental retardation, which are related to the primary defect in fucose metabolism. Delayed separation of the umbilical cord occurs in LAD1.
Neonatal pseudo-hydrocephalic progeroid syndrome
MedGen UID:
140806
Concept ID:
C0406586
Disease or Syndrome
Wiedemann-Rautenstrauch syndrome (WDRTS) is a rare autosomal recessive neonatal progeroid disorder characterized by intrauterine growth retardation, failure to thrive, short stature, a progeroid appearance, hypotonia, and variable mental impairment (summary by Toriello, 1990). Average survival in WDRTS is 7 months, although survival into the third decade of life has been reported (Akawi et al., 2013).
Encephalocraniocutaneous lipomatosis
MedGen UID:
140807
Concept ID:
C0406612
Congenital Abnormality
Encephalocraniocutaneous lipomatosis (ECCL) is a neurocutaneous disorder characterized by ocular anomalies, skin lesions, and central nervous system (CNS) anomalies (Moog et al., 2007). The malformations in ECCL are patchy and asymmetric. The most characteristic skin anomaly is nevus psiloliparus, a well-demarcated, alopecic fatty tissue nevus on the scalp, seen in 80% of affected individuals. Other dermatologic features include frontotemporal or zygomatic subcutaneous fatty lipomas, nonscarring alopecia, focal dermal hypoplasia or aplasia of the scalp, periocular skin tags, and pigmentary abnormalities following the lines of Blaschko. Choristomas of the eye (epibulbar dermoids or lipodermoids) are also present in 80% of patients, and can be unilateral or bilateral. Characteristic CNS features in ECCL include intracranial and intraspinal lipomas, seen in 61% of patients, and less often cerebral asymmetry, arachnoid cysts, enlarged ventricles, and leptomeningeal angiomatosis. A predisposition to low-grade gliomas has also been observed. Seizures and intellectual disability are common, but one-third of affected individuals have normal intellect. Skeletal manifestations include bone cysts and jaw tumors, such as odontomas, osteomas, and ossifying fibromas (summary by Bennett et al., 2016).
Kohlschutter syndrome
MedGen UID:
98036
Concept ID:
C0406740
Disease or Syndrome
Kohlschutter-Tonz syndrome is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth. Although the phenotype is consistent, there is variability. Intellectual disability is related to the severity of seizures, and the disorder can thus be considered an epileptic encephalopathy. Some infants show normal development until seizure onset, whereas others are delayed from birth. The most severely affected individuals have profound mental retardation, never acquire speech, and become bedridden early in life (summary by Schossig et al., 2012 and Mory et al., 2012).
Lissencephaly 1
MedGen UID:
98463
Concept ID:
C0431375
Disease or Syndrome
PAFAH1B1-associated lissencephaly includes Miller-Dieker syndrome (MDS), isolated lissencephaly sequence (ILS), and (rarely) subcortical band heterotopia (SBH). Lissencephaly and SBH are cortical malformations caused by deficient neuronal migration during embryogenesis. Lissencephaly refers to a "smooth brain" with absent gyri (agyria) or abnormally wide gyri (pachygyria). SBH refers to a band of heterotopic gray matter located just beneath the cortex and separated from it by a thin zone of normal white matter. MDS is characterized by lissencephaly, typical facial features, and severe neurologic abnormalities. ILS is characterized by lissencephaly and its direct sequelae: developmental delay, intellectual disability, and seizures.
Joubert syndrome
MedGen UID:
98464
Concept ID:
C0431399
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Wolcott-Rallison dysplasia
MedGen UID:
140926
Concept ID:
C0432217
Disease or Syndrome
Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis, and growth retardation develop at a later age. Other frequent multisystem manifestations include hepatic and renal dysfunction, mental retardation, and cardiovascular abnormalities (summary by Delepine et al., 2000).
Microcephalic osteodysplastic primordial dwarfism type 2
MedGen UID:
96587
Concept ID:
C0432246
Congenital Abnormality
Microcephalic osteodysplastic primordial dwarfism type II is characterized by intrauterine growth retardation, severe proportionate short stature, and microcephaly. It is distinct from Seckel syndrome (see 210600) by more severe growth retardation, radiologic abnormalities, and absent or mild mental retardation (summary by Willems et al., 2010).
Deletion of short arm of chromosome 18
MedGen UID:
96604
Concept ID:
C0432442
Disease or Syndrome
A rare genetic syndrome characterized by the deletion of the short arm of chromosome 18. It is associated with mental and growth retardation, prominent ears and ptosis.
Neurocutaneous melanosis
MedGen UID:
154259
Concept ID:
C0544862
Pathologic Function
Neurocutaneous melanosis, or neuromelanosis, is characterized by the presence of melanin-producing cells within the brain parenchyma or leptomeninges, which may lead to clinically apparent neurologic signs and symptoms, such as seizures. Other neurologic abnormalities, including hydrocephalus, arachnoid cysts, tumors, and syringomyelia, may also occur. The disorder is a rare but severe manifestation of congenital melanocytic nevus syndrome (CMNS; 137550). Some patients with neurocutaneous melanosis or CMNS may develop malignant melanoma. The incidence of neurologic involvement, development of malignant melanoma, and death is significantly associated with the projected adult size of the largest congenital melanocytic nevus, particularly those greater than 40 cm (summary by Kinsler et al., 2008; Kinsler et al., 2013).
Deficiency of guanidinoacetate methyltransferase
MedGen UID:
154356
Concept ID:
C0574080
Disease or Syndrome
The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CRTR) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; about 40% have movement disorder. Onset is between ages three months and three years. Only 14 individuals with AGAT deficiency have been reported. The phenotype of CRTR deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical phenotype of females heterozygous for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype.
Costello syndrome
MedGen UID:
108454
Concept ID:
C0587248
Disease or Syndrome
While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.
UDPglucose-4-epimerase deficiency
MedGen UID:
199598
Concept ID:
C0751161
Disease or Syndrome
Epimerase deficiency galactosemia (GALE deficiency galactosemia) is a continuum comprising three forms: Generalized. Enzyme activity is profoundly decreased in all tissues tested. Peripheral. Enzyme activity is deficient in red blood cells (RBC) and circulating white blood cells, but normal or near normal in all other tissues. Intermediate. Enzyme activity is deficient in red blood cells and circulating white blood cells and less than 50% of normal levels in other cells tested. Infants with generalized epimerase deficiency galactosemia develop clinical findings on a regular milk diet (which contains lactose, a disaccharide of galactose and glucose); manifestations include hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose/lactose from their diet resolves or prevents these acute symptoms. In contrast, neonates with the peripheral or intermediate form generally remain clinically well even on a regular milk diet and are usually only identified by biochemical testing, often in newborn screening programs.
Homocystinuria due to CBS deficiency
MedGen UID:
199606
Concept ID:
C0751202
Disease or Syndrome
Homocystinuria caused by cystathionine ß-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). All four ? or only one ? of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant. Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6-non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.
Spinocerebellar ataxia 5
MedGen UID:
155705
Concept ID:
C0752123
Disease or Syndrome
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosome locus) in which pathogenic variants occur.
Bardet-Biedl syndrome
MedGen UID:
156019
Concept ID:
C0752166
Disease or Syndrome
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Recombinant chromosome 8 syndrome
MedGen UID:
167070
Concept ID:
C0795822
Disease or Syndrome
Recombinant 8 syndrome is a condition that involves heart and urinary tract abnormalities, moderate to severe intellectual disability, and a distinctive facial appearance. The characteristic facial features include a wide, square face; a thin upper lip; a downturned mouth; a small chin (micrognathia); wide-set eyes (hypertelorism); and low-set or unusually shaped ears. People with recombinant 8 syndrome may have overgrowth of the gums (gingival hyperplasia) and abnormal tooth development. Males with this condition frequently have undescended testes (cryptorchidism). Some affected individuals have recurrent ear infections (otitis media) or hearing loss. Many children with recombinant 8 syndrome do not survive past early childhood, usually due to complications related to their heart abnormalities.
Chromosome 9, monosomy 9p
MedGen UID:
167073
Concept ID:
C0795830
Disease or Syndrome
A rare chromosomal anomaly with characteristics of psychomotor developmental delay, facial dysmorphism (trigonocephaly, midface hypoplasia, upslanting palpebral fissures, dysplastic small ears, flat nasal bridge with anteverted nostrils and long philtrum, micrognathia, choanal atresia, short neck), single umbilical artery, omphalocele, inguinal or umbilical hernia, genital abnormalities (hypospadia, cryptorchidism), muscular hypotonia and scoliosis.
Smith-Magenis syndrome
MedGen UID:
162881
Concept ID:
C0795864
Disease or Syndrome
Smith-Magenis syndrome (SMS) is characterized by distinctive physical features (particularly facial features that progress with age), developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbance, and childhood-onset abdominal obesity. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. The majority of individuals function in the mild-to-moderate range of intellectual disability. The behavioral phenotype, including significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change until adulthood. Sensory issues are frequently noted; these may include avoidant behavior, as well as repetitive seeking of textures, sounds, and experiences. Toileting difficulties are common. Significant anxiety is common as are problems with executive functioning, including inattention, distractibility, hyperactivity, and impulsivity. Maladaptive behaviors include frequent outbursts / temper tantrums, attention-seeking behaviors, opposition, aggression, and self-injurious behaviors including self-hitting, self-biting, skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and/or toenails (onychotillomania). Among the stereotypic behaviors described, the spasmodic upper-body squeeze or "self-hug" seems to be highly associated with SMS. An underlying developmental asynchrony, specifically emotional maturity delayed beyond intellectual functioning, may also contribute to maladaptive behaviors in people with SMS.
Craniofacial malformations, asymmetric, with polysyndactyly and abnormal skin and gut development
MedGen UID:
167083
Concept ID:
C0795915
Disease or Syndrome
Curry-Jones syndrome is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas (summary by Twigg et al., 2016).
Pseudoaminopterin syndrome
MedGen UID:
163196
Concept ID:
C0795939
Disease or Syndrome
The pseudoaminopterin syndrome (aminopterin syndrome sine aminopterin; ASSA) is a multiple congenital anomaly disorder characterized by ossification defects of the skull, dysmorphic facial features, delayed development, and variable limb defects. The clinical features resemble the embryopathy caused by maternal treatment with the folic acid antagonist aminopterin, which has been recognized since 1952 (Thiersch, 1952) when aminopterin was used as an abortifacient. The characteristic phenotype of the children who survived infancy after having been exposed to aminopterin or its methyl derivative, methotrexate, in early pregnancy included a very unusual facies, skull anomalies, and skeletal defects (summary by Fraser et al., 1987).
Fine-Lubinsky syndrome
MedGen UID:
163198
Concept ID:
C0795941
Disease or Syndrome
Syndrome with characteristics of psychomotor delay, brachycephaly with flat face, small nose, microstomia, cleft palate, cataract, hearing loss, hypoplastic scrotum and digital anomalies. Less than 10 patients have been described in the literature so far. Although the majority of reported cases were sporadic, the syndrome has been reported in one pair of siblings (a brother and sister) with an apparently autosomal recessive inheritance pattern.
Andermann syndrome
MedGen UID:
162893
Concept ID:
C0795950
Disease or Syndrome
Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy and variable degrees of dysgenesis of the corpus callosum. Mild-to-severe intellectual disability and "psychotic episodes" during adolescence are observed. Sensory modalities are moderately to severely affected beginning in infancy. The average age of onset of walking is 3.8 years; the average age of loss of walking is 13.8 years; the average age of death is 33 years.
Kabuki syndrome
MedGen UID:
162897
Concept ID:
C0796004
Congenital Abnormality
Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects; genitourinary anomalies; cleft lip and/or palate; gastrointestinal anomalies including anal atresia, ptosis, and strabismus; and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.
Peters plus syndrome
MedGen UID:
163204
Concept ID:
C0796012
Disease or Syndrome
Peters plus syndrome is characterized by anterior chamber eye anomalies, short limbs with broad distal extremities, characteristic facial features, cleft lip/palate, and variable developmental delay/intellectual disability. The most common anterior chamber defect is Peters' anomaly, consisting of central corneal clouding, thinning of the posterior cornea, and iridocorneal adhesions. Cataracts and glaucoma are common. Developmental delay is observed in about 80% of children; intellectual disability can range from mild to severe.
Lowry Maclean syndrome
MedGen UID:
167095
Concept ID:
C0796020
Disease or Syndrome
A very rare syndrome with characteristics of microcephaly, craniosynostosis, glaucoma, growth failure and visceral malformations. Only three cases have been reported in the literature in three unrelated families. Dysmorphic features include trigonocephaly, exotropia, cleft palate, beaked nose and low-set ears. All the affected patients have associated congenital visceral malformations including congenital heart defects, diaphragmatic hernia, genital or cerebral abnormalities. The demonstration of congenital glaucoma, hallmark of the syndrome, in the father of an affected patient, supports autosomal dominant inheritance. Prognosis is poor.
Mac Dermot Winter syndrome
MedGen UID:
162900
Concept ID:
C0796024
Disease or Syndrome
A very rare syndrome described in two siblings with manifestation of prenatal onset of growth deficiency, microcephaly, hypoplastic genitalia, and birth onset of convulsions.
Arts syndrome
MedGen UID:
163205
Concept ID:
C0796028
Disease or Syndrome
Arts syndrome, which is part of the spectrum of PRPS1-related disorders, is characterized by profound congenital sensorineural hearing impairment, early-onset hypotonia, delayed motor development, mild to moderate intellectual disability, ataxia, and increased risk of infection, all of which – with the exception of optic atrophy – present before age two years. Signs of peripheral neuropathy develop during early childhood. Twelve of 15 boys from the two Dutch families reported with Arts syndrome died before age six years of complications of infection. Carrier females can show late-onset (age >20 years) hearing impairment and other findings.
Microcephaly with mental retardation and digital anomalies
MedGen UID:
810673
Concept ID:
C0796063
Disease or Syndrome
A rare genetic multiple congenital anomalies/dysmorphic syndrome with characteristics of congenital microcephaly with facial dysmorphism (sloping forehead, prominent nose, mild retrognathia), moderate to severe, non-progressive intellectual disability and symmetrical digital malformations of variable degree, including brachydactyly of the fifth fingers with single flexion crease, clinodactyly, syndactyly, polydactyly and hallux valgus. Congenital anonychia and white cafe au lait-like spots on the skin of hands and feet are also associated. There is evidence this disease is caused by homozygous mutation in the RBBP8 gene on chromosome 18q11.2.
Lissencephaly 2
MedGen UID:
163213
Concept ID:
C0796089
Disease or Syndrome
Lissencephaly with cerebellar hypoplasia (LCH) affects brain development, resulting in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. In addition, the part of the brain that coordinates movement is unusually small and underdeveloped (cerebellar hypoplasia). Other parts of the brain are also often underdeveloped in LCH, including the hippocampus, which plays a role in learning and memory, and the part of the brain that is connected to the spinal cord (the brainstem).Individuals with LCH have moderate to severe intellectual disability and delayed development. They have few or no communication skills, extremely poor muscle tone (hypotonia), problems with coordination and balance (ataxia), and difficulty sitting or standing without support. Most affected children experience recurrent seizures (epilepsy) that begin within the first months of life. Some affected individuals have nearsightedness (myopia), involuntary eye movements (nystagmus), or puffiness or swelling caused by a buildup of fluids in the body's tissues (lymphedema).
C syndrome
MedGen UID:
167105
Concept ID:
C0796095
Disease or Syndrome
The C syndrome, also known as Opitz trigonocephaly syndrome, is a malformation syndrome characterized by trigonocephaly, severe mental retardation, hypotonia, variable cardiac defects, redundant skin, and dysmorphic facial features, including upslanted palpebral fissures, epicanthal folds, depressed nasal bridge, and low-set, posteriorly rotated ears (summary by Kaname et al., 2007). C syndrome shows phenotypic overlap with Bohring-Opitz syndrome, or C-like syndrome (605039), a disorder with more severe features than C syndrome, caused by heterozygous mutation in the ASXL1 gene (612990) on chromosome 20q11.
Orofaciodigital syndrome 8
MedGen UID:
208667
Concept ID:
C0796101
Disease or Syndrome
Oral-facial-digital syndrome is actually a group of related conditions that affect the development of the oral cavity (the mouth and teeth), facial features, and digits (fingers and toes).Researchers have identified at least 13 potential forms of oral-facial-digital syndrome. The different types are classified by their patterns of signs and symptoms. However, the features of the various types overlap significantly, and some types are not well defined. The classification system for oral-facial-digital syndrome continues to evolve as researchers find more affected individuals and learn more about this disorder.The signs and symptoms of oral-facial-digital syndrome vary widely. However, most forms of this disorder involve problems with development of the oral cavity, facial features, and digits. Most forms are also associated with brain abnormalities and some degree of intellectual disability.Abnormalities of the oral cavity that occur in many types of oral-facial-digital syndrome include a split (cleft) in the tongue, a tongue with an unusual lobed shape, and the growth of noncancerous tumors or nodules on the tongue. Affected individuals may also have extra, missing, or defective teeth. Another common feature is an opening in the roof of the mouth (a cleft palate). Some people with oral-facial-digital syndrome have bands of extra tissue (called hyperplastic frenula) that abnormally attach the lip to the gums.Distinctive facial features often associated with oral-facial-digital syndrome include a split in the lip (a cleft lip); a wide nose with a broad, flat nasal bridge; and widely spaced eyes (hypertelorism).Abnormalities of the digits can affect both the fingers and the toes in people with oral-facial-digital syndrome. These abnormalities include fusion of certain fingers or toes (syndactyly), digits that are shorter than usual (brachydactyly), or digits that are unusually curved (clinodactyly). The presence of extra digits (polydactyly) is also seen in most forms of oral-facial-digital syndrome.Other features occur in only one or a few types of oral-facial digital syndrome. These features help distinguish the different forms of the disorder. For example, the most common form of oral-facial-digital syndrome, type I, is associated with polycystic kidney disease. This kidney disease is characterized by the growth of fluid-filled sacs (cysts) that interfere with the kidneys' ability to filter waste products from the blood. Other forms of oral-facial-digital syndrome are characterized by neurological problems, particular changes in the structure of the brain, bone abnormalities, vision loss, and heart defects.
Orofaciodigital syndrome 9
MedGen UID:
162908
Concept ID:
C0796102
Disease or Syndrome
Oral-facial-digital syndrome is actually a group of related conditions that affect the development of the oral cavity (the mouth and teeth), facial features, and digits (fingers and toes).Researchers have identified at least 13 potential forms of oral-facial-digital syndrome. The different types are classified by their patterns of signs and symptoms. However, the features of the various types overlap significantly, and some types are not well defined. The classification system for oral-facial-digital syndrome continues to evolve as researchers find more affected individuals and learn more about this disorder.The signs and symptoms of oral-facial-digital syndrome vary widely. However, most forms of this disorder involve problems with development of the oral cavity, facial features, and digits. Most forms are also associated with brain abnormalities and some degree of intellectual disability.Abnormalities of the oral cavity that occur in many types of oral-facial-digital syndrome include a split (cleft) in the tongue, a tongue with an unusual lobed shape, and the growth of noncancerous tumors or nodules on the tongue. Affected individuals may also have extra, missing, or defective teeth. Another common feature is an opening in the roof of the mouth (a cleft palate). Some people with oral-facial-digital syndrome have bands of extra tissue (called hyperplastic frenula) that abnormally attach the lip to the gums.Distinctive facial features often associated with oral-facial-digital syndrome include a split in the lip (a cleft lip); a wide nose with a broad, flat nasal bridge; and widely spaced eyes (hypertelorism).Abnormalities of the digits can affect both the fingers and the toes in people with oral-facial-digital syndrome. These abnormalities include fusion of certain fingers or toes (syndactyly), digits that are shorter than usual (brachydactyly), or digits that are unusually curved (clinodactyly). The presence of extra digits (polydactyly) is also seen in most forms of oral-facial-digital syndrome.Other features occur in only one or a few types of oral-facial digital syndrome. These features help distinguish the different forms of the disorder. For example, the most common form of oral-facial-digital syndrome, type I, is associated with polycystic kidney disease. This kidney disease is characterized by the growth of fluid-filled sacs (cysts) that interfere with the kidneys' ability to filter waste products from the blood. Other forms of oral-facial-digital syndrome are characterized by neurological problems, particular changes in the structure of the brain, bone abnormalities, vision loss, and heart defects.
Renal hamartomas nephroblastomatosis and fetal gigantism
MedGen UID:
162909
Concept ID:
C0796113
Disease or Syndrome
Perlman syndrome is an autosomal recessive congenital overgrowth syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650). Affected children are large at birth, are hypotonic, and show organomegaly, characteristic facial dysmorphisms (inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad and flat nasal bridge, and low-set ears), renal anomalies (nephromegaly and hydronephrosis), frequent neurodevelopmental delay, and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumor, with a 64% incidence in infants surviving beyond the neonatal period. The tumor is diagnosed at an earlier age in these individuals compared with sporadic cases (less than 2 years and 3-4 years of age, respectively), and there is a high frequency of bilateral tumors (55%). Histologic examination of the kidneys in children with Perlman syndrome shows frequent nephroblastomatosis, which is a precursor lesion for Wilms tumor (summary by Astuti et al., 2012).
Proud Levine Carpenter syndrome
MedGen UID:
163217
Concept ID:
C0796124
Disease or Syndrome
Proud syndrome is an X-linked developmental disorder characterized by agenesis of the corpus callosum, severe mental retardation, seizures, and spasticity. Males are severely affected, whereas females may be unaffected or have a milder phenotype (Proud et al., 1992). Proud syndrome is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome to infantile spasms without brain malformations (EIEE1; 308350) to syndromic (309510) and nonsyndromic (300419) mental retardation (Kato et al., 2004; Wallerstein et al., 2008).
Aicardi Goutieres syndrome 1
MedGen UID:
162912
Concept ID:
C0796126
Disease or Syndrome
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Rosselli-gulienetti syndrome
MedGen UID:
163221
Concept ID:
C0796139
Disease or Syndrome
A syndrome of anhidrosis-hypotrichosis, pili torti, microdontia, nail dysplasia, cleft lip/palate, urogenital abnormalities, and mental retardation.
Parkinsonism, early onset with mental retardation
MedGen UID:
208674
Concept ID:
C0796195
Disease or Syndrome
Waisman syndrome is an X-linked neurologic disorder characterized by delayed psychomotor development, intellectual disability, and early-onset Parkinson disease (summary by Wilson et al., 2014).
Wieacker Wolff syndrome
MedGen UID:
163227
Concept ID:
C0796200
Disease or Syndrome
Wieacker-Wolff syndrome is a severe X-linked recessive neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero (fetal akinesia). Affected boys are born with severe contractures, known as arthrogryposis, and have delayed motor development, facial and bulbar weakness, characteristic dysmorphic facial features, and skeletal abnormalities, such as hip dislocation, scoliosis, and pes equinovarus. Those that survive infancy show mental retardation. Carrier females may have mild features of the disorder (summary by Hirata et al., 2013).
Mental retardation 9, X-linked
MedGen UID:
167112
Concept ID:
C0796215
Disease or Syndrome
Nonsyndromic mental retardation.
Mental retardation 49, X-linked
MedGen UID:
923000
Concept ID:
C0796221
Disease or Syndrome
Raynaud-Claes syndrome is an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development. Additional features include behavioral problems, psychiatric disorders, seizures (variable forms), progressive ataxia, brain abnormalities, and facial dysmorphisms. Some heterozygous females are unaffected, whereas others are affected with a severity spectrum similar to that seen in males (summary by Palmer et al. (2018)).
C-like syndrome
MedGen UID:
208678
Concept ID:
C0796232
Disease or Syndrome
Bohring-Opitz syndrome (BOS) is characterized by distinctive facial features and posture, growth failure, variable but usually severe intellectual disability, and variable anomalies. The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia. The BOS posture, which is most striking in early childhood and often becomes less apparent with age, is characterized by flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints. Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age. Seizures are common and typically responsive to standard epileptic medications. Minor cardiac anomalies and transient bradycardia and apnea may be present. Affected individuals may experience recurrent infections, which also tend to improve with age. Isolated case reports suggest that individuals with BOS are at greater risk for Wilms tumor than the general population, but large-scale epidemiologic studies have not been conducted.
Pettigrew syndrome
MedGen UID:
162924
Concept ID:
C0796254
Disease or Syndrome
Pettigrew syndrome is characterized by mental retardation and highly variable additional features, including choreoathetosis, hydrocephalus, Dandy-Walker malformation, seizures, and iron or calcium deposition in the brain, both between and within families (summary by Cacciagli et al., 2014). See 311510 for another X-linked mental retardation syndrome associated with basal ganglia disease (Waisman syndrome). See 220219 for another mental retardation syndrome with Dandy-Walker malformation.
Carnevale syndrome
MedGen UID:
167115
Concept ID:
C0796279
Disease or Syndrome
The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (summary by Rooryck et al., 2011). For a discussion of genetic heterogeneity of 3MC syndrome, see 3MC1 (257920).
Brachioskeletogenital syndrome
MedGen UID:
923028
Concept ID:
C0809936
Disease or Syndrome
The core phenotype of Elsahy-Waters syndrome consists of brachycephaly, facial asymmetry, marked hypertelorism, proptosis, blepharochalasis, midface hypoplasia, broad nose with concave nasal ridge, and prognathism; radicular dentin dysplasia with consequent obliterated pulp chambers, apical translucent cysts, recurrent infections, and early loss of teeth; vertebral fusions, particularly at C2-C3; and moderate mental retardation. Skin wrinkling over the glabellar region seems common, and in males, hypospadias has always been present. Inter- and intrafamilial variability has been reported regarding the presence of vertebral fusions, hearing loss,and dentigerous cysts. Midface hypoplasia, facial asymmetry, progressive dental anomalies, and impaired cognitive development become more evident in adulthood (Castori et al., 2010).
6-pyruvoyl-tetrahydropterin synthase deficiency
MedGen UID:
209234
Concept ID:
C0878676
Disease or Syndrome
Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; 612349), tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001). HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (233910), caused by mutation in the GCH1 gene (600225), HPABH4C (261630), caused by mutation in the QDPR gene (612676), and HPABH4D (264070), caused by mutation in the PCBD1 gene (126090). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; 261600), caused by mutation in the PAH gene. Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (612716), caused by mutation in the SPR gene (182125), and autosomal dominant dopa-responsive dystonia (DYT5; 128230), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed.
Danon disease
MedGen UID:
209235
Concept ID:
C0878677
Disease or Syndrome
Danon disease is an X-linked dominant disorder predominantly affecting cardiac muscle. Skeletal muscle involvement and mental retardation are variable features. The accumulation of glycogen in muscle and lysosomes originally led to the classification of Danon disease as a variant of glycogen storage disease II (Pompe disease; 232300) with 'normal acid maltase' or alpha-glucosidase (GAA; 606800) (Danon et al., 1981). However, Nishino et al. (2000) stated that Danon disease is not a glycogen storage disease because glycogen is not always increased. Sugie et al. (2005) classified Danon disease as a form of autophagic vacuolar myopathy, characterized by intracytoplasmic autophagic vacuoles with sarcolemmal features. The characteristic vacuole is believed to be an autolysosome surrounded by secondarily-generated membranes containing sarcolemmal proteins, basal lamina, and acetylcholinesterase activity. X-linked myopathy with excessive autophagy (XMEA; 310440) is a distinct disorder with similar pathologic features.
Sialic acid storage disease, severe infantile type
MedGen UID:
203367
Concept ID:
C1096902
Disease or Syndrome
The allelic disorders of free sialic acid metabolism – Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) ? are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. The mildest phenotype is Salla disease, which is characterized by normal appearance and neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild to moderate psychomotor retardation, spasticity, athetosis, and epileptic seizures. The most severe phenotype is ISSD, characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.
Salla disease
MedGen UID:
203368
Concept ID:
C1096903
Disease or Syndrome
The allelic disorders of free sialic acid metabolism – Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD) ? are neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. The mildest phenotype is Salla disease, which is characterized by normal appearance and neurologic findings at birth followed by slowly progressive neurologic deterioration resulting in mild to moderate psychomotor retardation, spasticity, athetosis, and epileptic seizures. The most severe phenotype is ISSD, characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.
Dyskeratosis congenita X-linked
MedGen UID:
216941
Concept ID:
C1148551
Disease or Syndrome
Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. The classic triad may not be present in all individuals. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include: abnormal pigmentation changes not restricted to the upper chest and neck, eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), and dental abnormalities (caries, periodontal disease, taurodauntism). Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome). Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
Deficiency of glycerate kinase
MedGen UID:
226941
Concept ID:
C1291386
Disease or Syndrome
D-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (summary by Sass et al., 2010).
Deficiency of phosphoserine phosphatase
MedGen UID:
452940
Concept ID:
C1291463
Disease or Syndrome
Deficiency of beta-ureidopropionase
MedGen UID:
226944
Concept ID:
C1291512
Disease or Syndrome
Beta-ureidopropionase deficiency is a rare autosomal recessive inborn error of metabolism due to a defect in pyrimidine degradation. Less than 10 patients have been reported, and the phenotype can range from severe neurologic involvement with mental retardation and seizures to normal neurologic development (Yaplito-Lee et al., 2008).
Deficiency of aromatic-L-amino-acid decarboxylase
MedGen UID:
220945
Concept ID:
C1291564
Disease or Syndrome
AADC deficiency is an autosomal recessive inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency (Abeling et al., 2000). The disorder is clinically characterized by vegetative symptoms, oculogyric crises, dystonia, and severe neurologic dysfunction, usually beginning in infancy or childhood (summary by Brun et al., 2010).
Deficiency of ribose-5-phosphate isomerase
MedGen UID:
220946
Concept ID:
C1291609
Disease or Syndrome
SAUL-WILSON SYNDROME
MedGen UID:
722057
Concept ID:
C1300285
Disease or Syndrome
Saul-Wilson syndrome is a rare skeletal dysplasia with characteristic dysmorphic and radiographic findings, as well as early developmental delay, primarily involving speech, with eventual normal cognition. Clinical findings include marked short stature, prominent forehead with an enlarged anterior fontanel, prominent eyes with cataracts, narrow nasal bridge with a convex nasal ridge, micrognathia, clubfoot, brachydactyly, and short distal phalanges of fingers. Radiographic changes include platyspondyly, irregular end plates of vertebral bodies, and hypoplasia of the odontoid process with cervical instability in the spine, coxa valga, overtubulation, metaphyseal flaring and megaepiphyses in the long bones, while the hands and feet exhibit short phalanges, metacarpals and metatarsals, cone-shaped epiphyses of phalanges, and accessory ossification centers of metacarpals and metatarsals (summary by Ferreira et al., 2018).
Shprintzen-Goldberg syndrome
MedGen UID:
231160
Concept ID:
C1321551
Disease or Syndrome
Shprintzen-Goldberg syndrome (SGS) is characterized by: craniosynostosis of the coronal, sagittal, or lambdoid sutures; dolichocephaly; distinctive craniofacial features; skeletal changes (dolichostenomelia, arachnodactyly, camptodactyly, pes planus, pectus excavatum or carinatum, scoliosis, joint hypermobility or contractures and C1/C2 spine malformation); neurologic abnormalities; intellectual disability; and brain anomalies (hydrocephalus, dilatation of the lateral ventricles, and Chiari 1 malformation). Cardiovascular anomalies may include mitral valve prolapse, mitral regurgitation/incompetence, aortic regurgitation, and aortic root dilatation. Minimal subcutaneous fat, abdominal wall defects, myopia, and cryptorchidism in males are also characteristic findings.
Revesz syndrome
MedGen UID:
231230
Concept ID:
C1327916
Disease or Syndrome
A rare severe phenotypic variant of dyskeratosis congenita with onset in early childhood. The syndrome has features of dyskeratosis congenita (for example skin hyper/hypopigmentation, nail dystrophy, high risk of bone marrow failure and cancer, developmental delay sparse and fine hair) in conjunction with bilateral exudative retinopathy and intracranial calcifications.
Neuropathy ataxia retinitis pigmentosa syndrome
MedGen UID:
231285
Concept ID:
C1328349
Disease or Syndrome
Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized.
Currarino triad
MedGen UID:
323460
Concept ID:
C1531773
Disease or Syndrome
Opitz G/BBB syndrome
MedGen UID:
321463
Concept ID:
C1801950
Disease or Syndrome
Individuals with 22q11.2 deletion syndrome (22q11.2DS) have a range of findings including the following: Congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus). Palatal abnormalities (69%), particularly velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate. Characteristic facial features (present in the majority of individuals of northern European heritage). Learning difficulties (70%-90%). An immune deficiency (regardless of the clinical presentation) (77%). Additional findings include the following: Hypocalcemia (50%). Significant feeding and swallowing problems; constipation with or without structural gastrointestinal anomalies (intestinal malrotation, imperforate anus, and Hirschsprung disease). Renal anomalies (31%). Hearing loss (both conductive and sensorineural). Laryngotracheoesophageal anomalies. Growth hormone deficiency. Autoimmune disorders. Seizures (idiopathic or associated with hypocalcemia). CNS anomalies including tethered cord. Skeletal abnormalities (scoliosis with or without vertebral anomalies, clubbed feet, polydactyly, and craniosynostosis). Ophthalmologic abnormalities (strabismus, posterior embryotoxon, tortuous retinal vessels, scleracornea, and anophthalmia). Enamel hypoplasia. Malignancies (rare). Developmental delay (in particular delays in emergence of language), intellectual disability, and learning differences (non-verbal learning disability where the verbal IQ is significantly greater than the performance IQ) are common. Autism or autistic spectrum disorder is found in approximately 20% of children and psychiatric illness (specifically schizophrenia) is present in 25% of adults; however, attention deficit disorder, anxiety, perseveration, and difficulty with social interactions are also common.
Congenital muscular hypertrophy-cerebral syndrome
MedGen UID:
315658
Concept ID:
C1802395
Disease or Syndrome
Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; <5th centile throughout life), hirsutism, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched eyebrows, long eyelashes, short nose with anteverted nares, small widely spaced teeth, and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS.
Peroxisome biogenesis disorders, Zellweger syndrome spectrum
MedGen UID:
330407
Concept ID:
C1832200
Disease or Syndrome
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a PEX gene defect regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
Microcephaly, corpus callosum dysgenesis and cleft lip-palate
MedGen UID:
330448
Concept ID:
C1832369
Disease or Syndrome
Myelodysplasia, immunodeficiency, facial dysmorphism, short stature, and psychomotor delay
MedGen UID:
318627
Concept ID:
C1832442
Disease or Syndrome
Cerebellar ataxia, Cayman type
MedGen UID:
331319
Concept ID:
C1832585
Disease or Syndrome
Cerebellar ataxia Cayman type has characteristics of psychomotor retardation, hypotonia and cerebellar dysfunction (nystagmus, ataxic gait, truncal ataxia, dysarthric speech and intention tremor), associated with cerebellar hypoplasia. The prevalence is unknown, but the disorder is very rare in the general population. However, a founder mutation has led to a high incidence in the Cayman island population. The disorder is transmitted as an autosomal recessive trait and is caused by mutations in the ATCAY gene (19p13.3), encoding Caytaxin.
Congenital disorder of glycosylation type 1D
MedGen UID:
322026
Concept ID:
C1832736
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006). CDG1D is a type I CDG that generally presents with severe neurologic involvement associated with dysmorphism and visual impairment. Liver involvement is sometimes present (summary by Marques-da-Silva et al., 2017). For a discussion of the classification of CDGs, see CDG1A (212065).
Timothy syndrome
MedGen UID:
331395
Concept ID:
C1832916
Disease or Syndrome
Timothy syndrome is a multisystem disorder characterized by cardiac, hand/foot, facial, and neurodevelopmental features. Typical cardiac findings include a rate-corrected QT interval >480 ms, functional 2:1 AV block with bradycardia, tachyarrhythmias, and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy). The diagnosis of Timothy syndrome is generally made within the first few days of life although it may be suspected prenatally due to 2:1 AV block or bradycardia in the fetus. Hand/foot findings are unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three. Facial findings include depressed nasal bridge, low-set ears, thin vermilion border of the upper lip, and round face. Neuropsychiatric involvement includes global developmental delays and autism spectrum disorders. Ventricular tachyarrhythmia is the leading cause of death, followed by infection and complications of intractable hypoglycemia. Average age of death is 2.5 years.
Cleft palate, cardiac defects, and mental retardation
MedGen UID:
318752
Concept ID:
C1832950
Disease or Syndrome
Permanent neonatal diabetes mellitus
MedGen UID:
371484
Concept ID:
C1833104
Disease or Syndrome
Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life (mean age: 7 weeks; range: birth to 26 weeks). The diabetes mellitus is associated with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include intrauterine growth retardation, hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth. The course of PNDM varies by genotype.
Spinal muscular atrophy, lower extremity predominant 1, autosomal dominant
MedGen UID:
322470
Concept ID:
C1834690
Disease or Syndrome
Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. SMALED shows autosomal dominant inheritance with muscle weakness predominantly affecting the proximal lower extremities (Harms et al., 2010). The most common form of SMA (see, e.g., SMA1, 253300) shows autosomal recessive inheritance and is due to mutation in the SMN1 gene (600354) on chromosome 5q. Genetic Heterogeneity of Lower Extremity-Predominant Spinal Muscular Atrophy See also SMALED2A (615290) and SMALED2B (618291), both of which are caused by mutation in the BICD2 gene (609797) on chromosome 9q22. SMALED2A and SMALED2B differ in age at onset and severity, with SMALED2B being more severe.
Cerebelloparenchymal Disorder VI
MedGen UID:
331813
Concept ID:
C1834711
Disease or Syndrome
Cerebellar Granule Cell Hypertrophy and Megalencephaly
MedGen UID:
371886
Concept ID:
C1834712
Disease or Syndrome
Holoprosencephaly 2
MedGen UID:
322517
Concept ID:
C1834877
Disease or Syndrome
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Holoprosencephaly 9
MedGen UID:
324369
Concept ID:
C1835819
Disease or Syndrome
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Holoprosencephaly 7
MedGen UID:
372134
Concept ID:
C1835820
Disease or Syndrome
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Aminoacylase 1 deficiency
MedGen UID:
324393
Concept ID:
C1835922
Disease or Syndrome
Aminoacylase-1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (summary by Ferri et al., 2014).
Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome
MedGen UID:
332113
Concept ID:
C1836033
Disease or Syndrome
CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome refers to a unique constellation of clinical manifestations including microcephaly, severe neurologic impairment, psychomotor retardation, failure to thrive, and facial dysmorphism, as well as palmoplantar keratoderma and late-onset ichthyosis. Brain magnetic resonance imaging (MRI) shows various degrees of cerebral dysgenesis including absence of corpus callosum and cortical dysplasia. The syndrome has been found to be uniformly fatal between the ages of 5 and 12 years (Fuchs-Telem et al., 2011).
Goldberg-Shprintzen megacolon syndrome
MedGen UID:
332131
Concept ID:
C1836123
Disease or Syndrome
Goldberg-Shprintzen syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by intellectual disability, microcephaly, and dysmorphic facial features. Most patients also have Hirschsprung disease and/or gyral abnormalities of the brain, consistent with defects in migration of neural crest cells and neurons. Other features, such as megalocornea or urogenital anomalies, may also be present. Goldberg-Shprintzen syndrome has some resemblance to Mowat-Wilson syndrome (MOWS; 235730) but is genetically distinct (summary by Drevillon et al., 2013). Yomo et al. (1991) referred to this disorder as Goldberg-Shprintzen syndrome, which should not be confused with Shprintzen-Goldberg craniosynostosis syndrome (182212) or 2 other Shprintzen syndromes (192430, 182210).
Generalized epilepsy and paroxysmal dyskinesia
MedGen UID:
332144
Concept ID:
C1836173
Disease or Syndrome
Mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma
MedGen UID:
322893
Concept ID:
C1836330
Disease or Syndrome
MEDNIK is a severe multisystem disorder characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma. It shows phenotypic similarities to CEDNIK (609528) (summary by Montpetit et al., 2008).
Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3
MedGen UID:
373087
Concept ID:
C1836439
Disease or Syndrome
Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Patients with C10ORF2-linked adPEO may have other clinical features including proximal muscle weakness, ataxia, peripheral neuropathy, cardiomyopathy, cataracts, depression, and endocrine abnormalities (summary by Fratter et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640). PEO caused by mutations in the POLG gene (174763) are associated with more complicated phenotypes than those forms caused by mutations in the SLC25A4 (103220) or C10ORF2 genes (Lamantea et al., 2002).
Schindler disease, type 1
MedGen UID:
373113
Concept ID:
C1836544
Disease or Syndrome
Alpha-N-acetylgalactosaminidase (NAGA) deficiency is a very rare lysosomal storage disorder. It is clinically heterogeneous with 3 main phenotypes: type I is an infantile-onset neuroaxonal dystrophy; type II, also known as Kanzaki disease (609242), is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment; and type III is an intermediate disorder with mild to moderate neurologic manifestations (Desnick and Schindler, 2001).
Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease
MedGen UID:
373160
Concept ID:
C1836727
Disease or Syndrome
PCWH syndrome is a complex neurocristopathy that includes features of 4 distinct syndromes: peripheral demyelinating neuropathy (see 118200), central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (see 142623) (Inoue et al., 2004). Inoue et al. (2004) proposed the acronym PCWH for this disorder.
Salt and pepper developmental regression syndrome
MedGen UID:
323005
Concept ID:
C1836824
Disease or Syndrome
Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterized by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss (summary by Fragaki et al., 2013). Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood (summary by Boccuto et al., 2014). Not all patients have overt seizures (Lee et al., 2016).
Fanconi anemia, complementation group J
MedGen UID:
323015
Concept ID:
C1836860
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Fanconi anemia, complementation group I
MedGen UID:
323016
Concept ID:
C1836861
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Mental retardation with optic atrophy, facial dysmorphism, microcephaly, and short stature
MedGen UID:
324635
Concept ID:
C1836915
Disease or Syndrome
Emanuel syndrome
MedGen UID:
323030
Concept ID:
C1836929
Disease or Syndrome
Emanuel syndrome is characterized by pre- and postnatal growth deficiency, microcephaly, hypotonia, severe developmental delays, ear anomalies, preauricular tags or pits, cleft or high-arched palate, congenital heart defects, kidney abnormalities, and genital abnormalities in males.
Stomatin-deficient cryohydrocytosis with neurologic defects
MedGen UID:
332390
Concept ID:
C1837206
Disease or Syndrome
Stomatin-deficient cryohydrocytosis with neurologic defects is an autosomal dominant disorder characterized by delayed psychomotor development, seizures, cataracts, and pseudohyperkalemia resulting from defects in the red blood cell membrane. The disorder combines the neurologic features of Glut1 deficiency syndrome-1 (GLUT1DS1; 606777), resulting from impaired glucose transport at the blood-brain barrier, and hemolytic anemia/pseudohyperkalemia with stomatocytosis, resulting from a cation leak in erythrocytes (summary by Bawazir et al., 2012). For a discussion of clinical and genetic heterogeneity of red cell stomatocyte disorders, see 194380.
Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B6
MedGen UID:
373284
Concept ID:
C1837229
Disease or Syndrome
MDDGB6 is an autosomal recessive congenital muscular dystrophy with mental retardation and structural brain abnormalities (Longman et al., 2003). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Leukodystrophy, hypomyelinating, 2
MedGen UID:
325157
Concept ID:
C1837355
Disease or Syndrome
Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a slowly progressive leukodystrophy that typically presents during the neonatal or early-infantile period with nystagmus, commonly associated with hypotonia, delayed acquisition of motor milestones, speech delay, and dysarthria. Over time the hypotonia typically evolves into spasticity that affects the ability to walk and communicate. Cerebellar signs (gait ataxia, dysmetria, intention tremor, head titubation, and dysdiadochokinesia) frequently manifest during childhood. Some individuals develop extrapyramidal movement abnormalities (choreoathetosis and dystonia). Hearing loss and optic atrophy are observed in rare cases. Motor impairments can lead to swallowing difficulty and orthopedic complications, including hip dislocation and scoliosis. Most individuals have normal cognitive skills or mild intellectual disability – which, however, can be difficult to evaluate in the context of profound motor impairment.
Pyruvate dehydrogenase phosphatase deficiency
MedGen UID:
332448
Concept ID:
C1837429
Disease or Syndrome
Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.
Midface hypoplasia, obesity, developmental delay, and neonatal hypotonia
MedGen UID:
325238
Concept ID:
C1837730
Disease or Syndrome
Larsen-like syndrome
MedGen UID:
325280
Concept ID:
C1837884
Disease or Syndrome
Mental retardation, autosomal recessive 3
MedGen UID:
373870
Concept ID:
C1838023
Disease or Syndrome
Cleft palate, cardiac defect, genital anomalies, and ectrodactyly
MedGen UID:
324947
Concept ID:
C1838121
Disease or Syndrome
Pectus excavatum, macrocephaly, short stature, and dysplastic nails
MedGen UID:
373902
Concept ID:
C1838160
Disease or Syndrome
CODAS syndrome
MedGen UID:
333031
Concept ID:
C1838180
Disease or Syndrome
CODAS is an acronym for cerebral, ocular, dental, auricular, and skeletal anomalies. CODAS syndrome is a rare disorder characterized by a distinctive constellation of features that includes developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts (summary by Strauss et al., 2015).
Oculoectodermal syndrome
MedGen UID:
333068
Concept ID:
C1838329
Disease or Syndrome
Oculoectodermal syndrome (OES) is characterized by the association of epibulbar dermoids and aplasia cutis congenita. Affected individuals exhibit congenital scalp lesions which are atrophic, nonscarring, hairless regions that are often multiple and asymmetric in distribution, and may have associated hamartomas. Ectodermal changes include linear hyperpigmentation that may follow the lines of Blaschko and, rarely, epidermal nevus-like lesions. Epibulbar dermoids may be uni- or bilateral. Additional ocular anomalies such as skin tags of the upper eyelid and rarely optic nerve or retinal changes or microphthalmia can be present. Phenotypic expression is highly variable, and various other abnormalities have occasionally been reported, including growth failure, lymphedema, and cardiovascular defects, as well as neurodevelopmental symptoms such as developmental delay, epilepsy, learning difficulties, and behavioral abnormalities. Benign tumor-like lesions such as nonossifying fibromas of the long bones and giant cell granulomas of the jaws have repeatedly been observed and appear to be age-dependent, becoming a common manifestation in individuals aged 5 years or older (summary by Boppudi et al., 2016).
Pachygyria with mental retardation and seizures
MedGen UID:
333107
Concept ID:
C1838491
Disease or Syndrome
This autosomal recessive neurodevelopmental disorder is characterized by pachygyria, mental retardation, seizures, and diffuse localization of arachnoid cysts. It most likely represents a neuronal migration disorder within the lissencephaly spectrum (summary by Guzel et al., 2007).
Ceroid lipofuscinosis neuronal 7
MedGen UID:
325457
Concept ID:
C1838571
Disease or Syndrome
The neuronal ceroid lipofuscinoses (NCL, or CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally (summary by Mole et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).
Atrioventricular septal defect with blepharophimosis and anal and radial defects
MedGen UID:
374010
Concept ID:
C1838606
Disease or Syndrome
Spondyloepiphyseal dysplasia tarda with characteristic facies
MedGen UID:
325071
Concept ID:
C1838653
Disease or Syndrome
Striatonigral degeneration, infantile, mitochondrial
MedGen UID:
374113
Concept ID:
C1839022
Disease or Syndrome
X-Linked Mental Retardation 89
MedGen UID:
333247
Concept ID:
C1839082
Mental or Behavioral Dysfunction
Hunter Rudd Hoffmann syndrome
MedGen UID:
374138
Concept ID:
C1839125
Disease or Syndrome
Syndrome with characteristics of short stature, trigonocephaly and developmental delay. It has been described in three males. Moderate intellectual deficit was reported in one of the males and the other two patients displayed psychomotor retardation. X-linked transmission has been suggested but autosomal recessive inheritance cannot be ruled out.
Early infantile epileptic encephalopathy 2
MedGen UID:
326463
Concept ID:
C1839333
Disease or Syndrome
Early infantile epileptic encephalopathy-2 is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in mental retardation and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but EIEE2 is considered to be a distinct entity (summary by Fehr et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Pyruvate dehydrogenase E1-alpha deficiency
MedGen UID:
326486
Concept ID:
C1839413
Disease or Syndrome
Genetic defects in the pyruvate dehydrogenase complex are one of the most common causes of primary lactic acidosis in children. Most cases are caused by mutation in the E1-alpha subunit gene on the X chromosome. X-linked PDH deficiency is one of the few X-linked diseases in which a high proportion of heterozygous females manifest severe symptoms. The clinical spectrum of PDH deficiency is broad, ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis (Robinson et al., 1987; Brown et al., 1994). Genetic Heterogeneity of Pyruvate Dehydrogenase Complex Deficiency PDH deficiency can also be caused by mutation in other subunits of the PDH complex, including a form (PDHXD; 245349) caused by mutation in the component X gene (PDHX; 608769) on chromosome 11p13; a form (PDHBD; 614111) caused by mutation in the PDHB gene (179060) on chromosome 3p14; a form (PDHDD; 245348) caused by mutation in the DLAT gene (608770) on chromosome 11q23; a form (PDHPD; 608782) caused by mutation in the PDP1 gene (605993) on chromosome 8q22; and a form (PDHLD; 614462) caused by mutation in the LIAS gene (607031) on chromosome 4p14.
TARP syndrome
MedGen UID:
333324
Concept ID:
C1839463
Disease or Syndrome
The classic features of TARP syndrome are talipes equinovarus, atrial septal defect, Robin sequence (micrognathia, cleft palate, and glossoptosis), and persistent left superior vena cava. Not all patients have all classic features. Some patients have the additional features of central nervous system dysfunction, renal abnormalities, variable cardiac anomalies including hypertrophic obstructive cardiomyopathy, and variable distal limb defects including syndactyly. Most patients die in late prenatal or early postnatal stages (summary by Kaeppler et al., 2018).
Wilson-Turner X-linked mental retardation syndrome
MedGen UID:
333393
Concept ID:
C1839736
Disease or Syndrome
Wilson-Turner syndrome is an X-linked recessive neurologic disorder characterized by intellectual disability, dysmorphic facial features, hypogonadism, short stature, and truncal obesity. Females are unaffected (Wilson et al., 1991).
IFAP syndrome with or without BRESHECK syndrome
MedGen UID:
327007
Concept ID:
C1839988
Disease or Syndrome
The IFAP/BRESHECK syndrome is an X-linked multiple congenital anomaly disorder with variable severity. The classic triad, which defines IFAP, is ichthyosis follicularis, atrichia, and photophobia. Some patients have additional features, including mental retardation, brain anomalies, Hirschsprung disease, corneal opacifications, kidney dysplasia, cryptorchidism, cleft palate, and skeletal malformations, particularly of the vertebrae, which constitutes BRESHECK syndrome (summary by Naiki et al., 2012).
Craniosynostosis with ocular abnormalities and hallucal defects
MedGen UID:
331266
Concept ID:
C1842316
Disease or Syndrome
Craniofacial abnormalities, cataracts, congenital heart disease, sacral neural tube defects, and growth and developmental retardation
MedGen UID:
330832
Concept ID:
C1842363
Disease or Syndrome
Nablus mask-like facial syndrome
MedGen UID:
334165
Concept ID:
C1842464
Disease or Syndrome
Nablus mask-like facial syndrome (NMLFS) is a rare entity defined by distinctive facial features, including blepharophimosis, tight-appearing glistening facial skin, an abnormal hair pattern with an upswept frontal hairline, sparse arched eyebrows, flat and broad nose, long philtrum, distinctive ears, and a happy demeanor (summary by Jain et al., 2010).
Uniparental disomy, paternal, chromosome 14
MedGen UID:
330856
Concept ID:
C1842466
Disease or Syndrome
A rare genetic disease with characteristics of polyhydramnios (mostly due to placentomegaly), fetal macrosomia, abdominal wall defects, skeletal abnormalities (including bell-shaped thorax, coat-hanger appearance of the ribs and decreased mid to wide thorax diameter ratio in infancy), feeding difficulties and impaired swallowing, dysmorphic features (hairy forehead, full cheeks, protruding philtrum, micrognathia), developmental delay and intellectual disability. Additional features may include kyphoscoliosis, joint contractures, diastasis recti, and muscular hypotonia. There is increased risk of hepatoblastoma. The syndrome is an imprinting disorder involving genes within the imprinted region of chromosome 14q32.
GLUT1 deficiency syndrome 2
MedGen UID:
330866
Concept ID:
C1842534
Disease or Syndrome
The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9]), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures in classic early-onset Glut1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. In some infants, apneic episodes and abnormal episodic eye-head movements similar to opsoclonus may precede the onset of seizures. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress. Symptoms often improve substantially when a ketogenic diet is started.
Heterotopia, periventricular, autosomal recessive
MedGen UID:
334110
Concept ID:
C1842563
Disease or Syndrome
Periventricular heterotopia is a condition in which nerve cells (neurons) do not migrate properly during the early development of the fetal brain, from about the 6th week to the 24th week of pregnancy. Heterotopia means "out of place." In normal brain development, neurons form in the periventricular region, located around fluid-filled cavities (ventricles) near the center of the brain. The neurons then migrate outward to form the exterior of the brain (cerebral cortex) in six onion-like layers. In periventricular heterotopia, some neurons fail to migrate to their proper position and form clumps around the ventricles.Periventricular heterotopia usually becomes evident when seizures first appear, often during the teenage years. The nodules around the ventricles are then typically discovered when magnetic resonance imaging (MRI) studies are done. Affected individuals usually have normal intelligence, although some have mild intellectual disability. Difficulty with reading and spelling (dyslexia) and movement problems have been reported in some people with periventricular heterotopia.Less commonly, individuals with periventricular heterotopia may have other features including more severe brain malformations, small head size (microcephaly), developmental delays, recurrent infections, blood vessel abnormalities, stomach problems, or lung disease. Periventricular heterotopia may also occur in association with other conditions such as Ehlers-Danlos syndrome, which results in extremely flexible joints, skin that stretches easily, and fragile blood vessels.
Joubert syndrome 2
MedGen UID:
334114
Concept ID:
C1842577
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Pontocerebellar hypoplasia type 3
MedGen UID:
334225
Concept ID:
C1842687
Congenital Abnormality
Pontocerebellar hypoplasia (PCH) refers to a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem. Clinical features vary, but usually include severe developmental delay, dysmorphic features, seizures, and early death (summary by Durmaz et al., 2009). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Diaphanospondylodysostosis
MedGen UID:
374993
Concept ID:
C1842691
Disease or Syndrome
Diaphanospondylodysostosis is a rare, recessively inherited, perinatal lethal skeletal disorder. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases (summary by Funari et al., 2010).
Chromosome 1p36 deletion syndrome
MedGen UID:
334629
Concept ID:
C1842870
Disease or Syndrome
The constitutional deletion of chromosome 1p36 results in a syndrome with multiple congenital anomalies and mental retardation (Shapira et al., 1997). Monosomy 1p36 is the most common terminal deletion syndrome in humans, occurring in 1 in 5,000 births (Shaffer and Lupski, 2000; Heilstedt et al., 2003). See also neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH; 616975), which shows overlapping features and is caused by heterozygous mutation in the RERE gene (605226) on proximal chromosome 1p36.
Niemann-Pick disease type C2
MedGen UID:
335942
Concept ID:
C1843366
Disease or Syndrome
Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.
Microphthalmia with cyst, bilateral facial clefts, and limb anomalies
MedGen UID:
375210
Concept ID:
C1843492
Disease or Syndrome
Pontocerebellar hypoplasia type 1
MedGen UID:
335969
Concept ID:
C1843504
Congenital Abnormality
Pontocerebellar hypoplasia is a group of related conditions that affect the development of the brain. The term "pontocerebellar" refers to the pons and the cerebellum, which are the brain structures that are most severely affected in many forms of this disorder. The pons is located at the base of the brain in an area called the brainstem, where it transmits signals between the cerebellum and the rest of the brain. The cerebellum, which is located at the back of the brain, normally coordinates movement. The term "hypoplasia" refers to the underdevelopment of these brain regions.Pontocerebellar hypoplasia also causes impaired growth of other parts of the brain, leading to an unusually small head size (microcephaly). This microcephaly is usually not apparent at birth but becomes noticeable as brain growth continues to be slow in infancy and early childhood.Researchers have described at least ten types of pontocerebellar hypoplasia. All forms of this condition are characterized by impaired brain development, delayed development overall, problems with movement, and intellectual disability. The brain abnormalities are usually present at birth, and in some cases they can be detected before birth. Many children with pontocerebellar hypoplasia live only into infancy or childhood, although some affected individuals have lived into adulthood.The two major forms of pontocerebellar hypoplasia are designated as type 1 (PCH1) and type 2 (PCH2). In addition to the brain abnormalities described above, PCH1 causes problems with muscle movement resulting from a loss of specialized nerve cells called motor neurons in the spinal cord, similar to another genetic disorder known as spinal muscular atrophy. Individuals with PCH1 also have very weak muscle tone (hypotonia), joint deformities called contractures, vision impairment, and breathing and feeding problems that are evident from early infancy.Common features of PCH2 include a lack of voluntary motor skills (such as grasping objects, sitting, or walking), problems with swallowing (dysphagia), and an absence of communication, including speech. Affected children typically develop temporary jitteriness (generalized clonus) in early infancy, abnormal patterns of movement described as chorea or dystonia, and stiffness (spasticity). Many also have impaired vision and seizures.The other forms of pontocerebellar hypoplasia, designated as type 3 (PCH3) through type 10 (PCH10), appear to be rare and have each been reported in only a small number of individuals. Because the different types have overlapping features, and some are caused by mutations in the same genes, researchers have proposed that the types be considered as a spectrum instead of distinct conditions.
Biotin-thiamine-responsive basal ganglia disease
MedGen UID:
375289
Concept ID:
C1843807
Disease or Syndrome
Biotin-thiamine-responsive basal ganglia disease (BTBGD) is characterized by recurrent subacute encephalopathy manifest as confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia which, if left untreated, can eventually lead to coma and even death. Dystonia and cogwheel rigidity are nearly always present; hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Episodes are often triggered by febrile illness or mild trauma or surgery. Less frequently, BTBGD presents as chronic or slowly progressive dystonia, seizures, and/or psychomotor delay. Although onset is usually in childhood (ages three to ten 10 years), it is extremely variable, ranging from the newborn period to adulthood. Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days.
Spinocerebellar ataxia 21
MedGen UID:
375311
Concept ID:
C1843891
Disease or Syndrome
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosome locus) in which pathogenic variants occur.
Mental retardation, autosomal recessive 2
MedGen UID:
334541
Concept ID:
C1843942
Disease or Syndrome
Chondrodysplasia punctata 1, X-linked recessive
MedGen UID:
337102
Concept ID:
C1844853
Disease or Syndrome
X-linked chondrodysplasia punctata 1 (CDPX1), a congenital disorder of bone and cartilage development, is caused by a deficiency of the Golgi enzyme arylsulfatase E (ARSE). It is characterized by chondrodysplasia punctata (stippled epiphyses), brachytelephalangy (shortening of the distal phalanges), and nasomaxillary hypoplasia. Although most affected males have minimal morbidity and skeletal findings that improve by adulthood, some have significant medical problems including respiratory compromise, cervical spine stenosis and instability, mixed conductive and sensorineural hearing loss, and intellectual disability.
Catel Manzke syndrome
MedGen UID:
375536
Concept ID:
C1844887
Disease or Syndrome
Catel-Manzke syndrome is characterized by the Pierre Robin anomaly, which comprises cleft palate, glossoptosis, and micrognathia, and a unique form of bilateral hyperphalangy in which there is an accessory bone inserted between the second metacarpal and its corresponding proximal phalanx, resulting in radial deviation of the index finger (summary by Manzke et al., 2008).
Contractures ectodermal dysplasia cleft lip palate
MedGen UID:
375546
Concept ID:
C1844935
Disease or Syndrome
Spinocerebellar ataxia X-linked type 3
MedGen UID:
337124
Concept ID:
C1844936
Disease or Syndrome
This syndrome is a form of spinocerebellar degeneration with onset in infancy of hypotonia, ataxia, sensorineural deafness, developmental delay, esotropia and optic atrophy and by a progressive course leading to death in childhood. It has been described one family with at least six affected males from five different sibships (connected through carrier females). It is transmitted as an X-linked recessive trait.
Pigmentary disorder, reticulate, with systemic manifestations, X-linked
MedGen UID:
336844
Concept ID:
C1845050
Disease or Syndrome
X-linked reticulate pigmentary disorder shows more severe manifestations in hemizygous males compared to heterozygous females. Affected males have early onset of recurrent respiratory infections and failure to thrive resulting from inflammatory gastroenteritis or colitis. Patients also show reticular pigmentation abnormalities of the skin and may develop corneal scarring. Carrier females may be unaffected or have only pigmentary abnormalities along the lines of Blaschko (summary by Starokadomskyy et al., 2016).
ATR-X syndrome
MedGen UID:
337145
Concept ID:
C1845055
Disease or Syndrome
Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is characterized by distinctive craniofacial features, genital anomalies, severe developmental delays, hypotonia, intellectual disability, and mild-to-moderate anemia secondary to alpha-thalassemia. Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short nose, tented vermilion of the upper lip, and thick or everted vermilion of the lower lip with coarsening of the facial features over time. Although all affected individuals have a normal 46,XY karyotype, genital anomalies range from hypospadias and undescended testicles to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Global developmental delays are evident in infancy and some affected individuals never walk independently or develop significant speech.
Mental retardation 91, X-linked
MedGen UID:
375592
Concept ID:
C1845142
Disease or Syndrome
Dent disease 2
MedGen UID:
336867
Concept ID:
C1845167
Disease or Syndrome
Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular-weight (LMW) proteinuria, hypercalciuria, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance. Males younger than age ten years may manifest only LMW proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. Males with Dent disease 2 (caused by pathogenic variants in OCRL) may also have mild intellectual disability, cataracts, and/or elevated muscle enzymes. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely develop CKD.
Mental retardation X-linked with cerebellar hypoplasia and distinctive facial appearance
MedGen UID:
336920
Concept ID:
C1845366
Disease or Syndrome
Stocco dos Santos syndrome
MedGen UID:
335202
Concept ID:
C1845530
Disease or Syndrome
Mental retardation, bilateral congenital hip luxation, and short stature associated the presence of a variant of glucose-6-phosphate dehydrogenase.
FG syndrome 4
MedGen UID:
336965
Concept ID:
C1845546
Disease or Syndrome
CASK-related disorders include a spectrum of phenotypes in both females and males. The two main types of clinical presentation are: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK; and X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate to severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. To date a total of 53 females with MICPCH have been reported, the eldest of whom is 21 years old. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures. Behaviors may include sleep disturbances, hand stereotypies, and self-biting. To date, only seven males have been reported with the severe phenotype. The under-representation in this cohort is likely to be a consequence of early male lethality. These males typically present with intellectual disability and MICPCH, or early-infantile epileptic encephalopathy (Ohtahara syndrome, West syndrome, or early myoclonic epilepsy). In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of X-linked intellectual disability (XLID) with or without nystagmus and additional clinical features. More than 24 males and nine females have been reported. The males have mild to severe intellectual disability, with or without nystagmus and other ocular features. Females are typically normal, with some displaying mild intellectual disability with or without ocular features.
Creatine deficiency, X-linked
MedGen UID:
337451
Concept ID:
C1845862
Disease or Syndrome
The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CRTR) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; about 40% have movement disorder. Onset is between ages three months and three years. Only 14 individuals with AGAT deficiency have been reported. The phenotype of CRTR deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical phenotype of females heterozygous for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype.
Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies
MedGen UID:
337364
Concept ID:
C1846009
Disease or Syndrome
IMAGe syndrome is an acronym for the major findings of intrauterine growth restriction (IUGR), metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary abnormalities (in males). Findings reported in individuals with a clinical and/or molecular diagnosis include: IUGR; Some type of skeletal abnormality (most commonly delayed bone age and short stature and, occasionally, metaphyseal and epiphyseal dysplasia of varying severity); Adrenal insufficiency often presenting in the first month of life as an adrenal crisis or rarely later in childhood with failure to thrive and recurrent vomiting; Genital abnormalities in males (cryptorchidism, micropenis, and hypospadias) but not in females. Hypotonia and developmental delay are reported in some; cognitive outcome appears to be normal in the majority.
Mental retardation, X-linked 72
MedGen UID:
375793
Concept ID:
C1846038
Disease or Syndrome
Adrenomyodystrophy
MedGen UID:
337494
Concept ID:
C1846044
Disease or Syndrome
An extremely rare genetic endocrine disease with characteristics of primary adrenal insufficiency, dystrophic myopathy, hepatic steatosis, severe psychomotor delay, megalocornea, failure to thrive, chronic constipation, and terminal bladder ectasia which can lead to death. There have been no further descriptions in the literature since 1982.
Roifman syndrome
MedGen UID:
375801
Concept ID:
C1846059
Disease or Syndrome
Roifman syndrome is a multisystem disorder characterized by growth retardation, spondyloepiphyseal dysplasia, retinal dystrophy, distinctive facial dysmorphism, and immunodeficiency (summary by de Vries et al., 2006).
MEHMO syndrome
MedGen UID:
375855
Concept ID:
C1846278
Disease or Syndrome
MEHMO syndrome has characteristics of severe intellectual deficit, epilepsy, microcephaly, hypogenitalism and obesity. Growth delay and diabetes are also present. To date, it has been described in seven boys, all of who died within the first two years of life. The causative gene has been located to the 21.1-22.13p region of the X chromosome and the syndrome appears to result from mitochondrial dysfunction.
Polymicrogyria, bilateral frontoparietal
MedGen UID:
376107
Concept ID:
C1847352
Disease or Syndrome
Polymicrogyria is a condition characterized by abnormal development of the brain before birth. The surface of the brain normally has many ridges or folds, called gyri. In people with polymicrogyria, the brain develops too many folds, and the folds are unusually small. The name of this condition literally means too many (poly-) small (micro-) folds (-gyria) in the surface of the brain.Polymicrogyria can affect part of the brain or the whole brain. When the condition affects one side of the brain, researchers describe it as unilateral. When it affects both sides of the brain, it is described as bilateral. The signs and symptoms associated with polymicrogyria depend on how much of the brain, and which particular brain regions, are affected.Researchers have identified multiple forms of polymicrogyria. The mildest form is known as unilateral focal polymicrogyria. This form of the condition affects a relatively small area on one side of the brain. It may cause minor neurological problems, such as mild seizures that can be easily controlled with medication. Some people with unilateral focal polymicrogyria do not have any problems associated with the condition.Bilateral forms of polymicrogyria tend to cause more severe neurological problems. Signs and symptoms of these conditions can include recurrent seizures (epilepsy), delayed development, crossed eyes, problems with speech and swallowing, and muscle weakness or paralysis. The most severe form of the disorder, bilateral generalized polymicrogyria, affects the entire brain. This condition causes severe intellectual disability, problems with movement, and seizures that are difficult or impossible to control with medication.Polymicrogyria most often occurs as an isolated feature, although it can occur with other brain abnormalities. It is also a feature of several genetic syndromes characterized by intellectual disability and multiple birth defects. These include 22q11.2 deletion syndrome, Adams-Oliver syndrome, Aicardi syndrome, Galloway-Mowat syndrome, Joubert syndrome, and Zellweger spectrum disorder.
Cree mental retardation syndrome
MedGen UID:
335673
Concept ID:
C1847361
Disease or Syndrome
Lig4 syndrome
MedGen UID:
339855
Concept ID:
C1847827
Disease or Syndrome
A hereditary disorder associated with impaired DNA double-strand break repair mechanisms with characteristics of microcephaly, unusual facial features, growth and developmental delay, skin anomalies, and pancytopenia, which is associated with combined immunodeficiency. Caused by mutations in the LIG4 gene (13q22-q34). The resulting defect of DNA ligase IV, a component of the classical non-homologous end-joining (NHEJ) pathway, affects the major mechanism of DNA double-strand break repair. Transmission is autosomal recessive.
PHACE syndrome
MedGen UID:
376231
Concept ID:
C1847874
Disease or Syndrome
PHACE is an acronym for a neurocutaneous syndrome encompassing the following features: posterior fossa brain malformations, hemangiomas of the face (large or complex), arterial anomalies, cardiac anomalies, and eye abnormalities. The association is referred to as PHACES when ventral developmental defects, such as sternal clefting or supraumbilical raphe, are present (summary by Bracken et al., 2011).
Hypotonia-cystinuria syndrome
MedGen UID:
341133
Concept ID:
C1848030
Disease or Syndrome
Early infantile epileptic encephalopathy 9
MedGen UID:
338393
Concept ID:
C1848137
Disease or Syndrome
Epileptic encephalopathy-9 is an X-linked disorder characterized by seizure onset in infancy and mild to severe intellectual impairment. Autistic and psychiatric features have been reported in some individuals. The disorder affects heterozygous females only; transmitting males are unaffected (summary by Jamal et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Waardenburg syndrome type 4A
MedGen UID:
341244
Concept ID:
C1848519
Disease or Syndrome
Waardenburg syndrome type 4 (WS4), also known as Waardenburg-Shah syndrome, is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes, congenital sensorineural hearing loss, and Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). WS type 4A is caused by mutation in the EDNRB gene (131244). Clinical Variability of Waardenburg Syndrome Types 1-4 Waardenburg syndrome has been classified into 4 main phenotypes. Type I Waardenburg syndrome (WS1; 193500) is characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia iridis and brilliant blue eyes; congenital sensorineural hearing loss; and 'dystopia canthorum.' WS type II (WS2) is distinguished from type I by the absence of dystopia canthorum. WS type III (WS3; 148820) has dystopia canthorum and is distinguished by the presence of upper limb abnormalities. WS type 4 has the additional feature of Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010). Genetic Heterogeneity of Waardenburg Syndrome Type 4 Waardenburg syndrome type 4 is genetically heterogeneous. WS4B (613265) is caused by mutation in the EDN3 gene (131242) on chromosome 20q13, and WS4C (613266) is caused by mutation in the SOX10 gene (602229) on chromosome 22q13.
Vitiligo, progressive, with mental retardation and urethral duplication
MedGen UID:
336363
Concept ID:
C1848532
Disease or Syndrome
Methylmalonic acidemia with homocystinuria cblD
MedGen UID:
341253
Concept ID:
C1848552
Disease or Syndrome
Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic compications, and/or subacute combined degeneration of the spinal cord.
Methylmalonic acidemia with homocystinuria
MedGen UID:
341256
Concept ID:
C1848561
Disease or Syndrome
Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic compications, and/or subacute combined degeneration of the spinal cord.
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblF TYPE
MedGen UID:
336373
Concept ID:
C1848578
Disease or Syndrome
Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic compications, and/or subacute combined degeneration of the spinal cord.
Teebi syndrome
MedGen UID:
341296
Concept ID:
C1848743
Disease or Syndrome
Thumb, hypoplastic, with choroid coloboma, poorly developed antihelix, and deafness
MedGen UID:
376448
Concept ID:
C1848816
Disease or Syndrome
Thoracic dysplasia-hydrocephalus syndrome
MedGen UID:
338562
Concept ID:
C1848864
Disease or Syndrome
Spondylometaepiphyseal dysplasia short limb-hand type
MedGen UID:
338595
Concept ID:
C1849011
Disease or Syndrome
Spinocerebellar ataxia with dysmorphism
MedGen UID:
336495
Concept ID:
C1849088
Disease or Syndrome
Insulin-like growth factor 1 resistance to
MedGen UID:
338622
Concept ID:
C1849157
Disease or Syndrome
Patients with mutations in the receptor for insulin-like growth factor I show intrauterine growth retardation and postnatal growth failure, resulting in short stature and microcephaly. Other features may include delayed bone age, developmental delay, and dysmorphic features.
Robinow syndrome, autosomal recessive
MedGen UID:
341431
Concept ID:
C1849334
Disease or Syndrome
ROR2-related Robinow syndrome is characterized by distinctive craniofacial features, skeletal abnormalities, and other anomalies. Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism, prominent eyes, midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth with exposed incisors and upper gums, gum hypertrophy, misaligned teeth, ankyloglossia, and micrognathia. Skeletal abnormalities include short stature, mesomelic or acromesomelic limb shortening, hemivertebrae with fusion of thoracic vertebrae, and brachydactyly. Other common features include micropenis with or without cryptorchidism in males and reduced clitoral size and hypoplasia of the labia majora in females, renal tract abnormalities, and nail hypoplasia or dystrophy. The disorder is recognizable at birth or in early childhood.
Richieri Costa Pereira syndrome
MedGen UID:
336581
Concept ID:
C1849348
Disease or Syndrome
Patients with Richieri-Costa-Pereira syndrome display a pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of the mandible, cleft palate/Robin sequence, absence of lower central incisors, minor ear anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability is also a common finding (summary by Favaro et al., 2011).
Radioulnar synostosis, unilateral, with developmental retardation and hypotonia
MedGen UID:
341460
Concept ID:
C1849470
Disease or Syndrome
Pyridoxine-dependent epilepsy
MedGen UID:
340341
Concept ID:
C1849508
Disease or Syndrome
Pyridoxine-dependent epilepsy is characterized by intractable seizures within the first weeks to months of life that are not controlled with antiepileptic drugs but respond both clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). Multiple types of clinical seizures have been reported in individuals with pyridoxine-dependent epilepsy. Dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical; recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates. Infants with the classic neonatal presentation begin to experience seizures soon after birth. Atypical features include: late-onset seizures (seizures that begin from late infancy up until age 3 years); seizures that initially respond to antiepileptic drugs and then become intractable; seizures during early life that do not respond to pyridoxine but are then controlled with pyridoxine several months later; and prolonged seizure-free intervals (=5.5 months) that occur after discontinuation of pyridoxine. Intellectual disability is common. Elevated concentration of a-aminoadipic semialdehyde (a-AASA) in urine and plasma is a strong biomarker of the disorder; pipecolic acid may also be elevated in plasma and cerebrospinal fluid.
Pili torti developmental delay neurological abnormalities
MedGen UID:
342358
Concept ID:
C1849811
Disease or Syndrome
Abnormal hair, joint laxity, and developmental delay (HJDD) is characterized by normal hair at birth that gradually becomes sparse, twisted, brittle, and easily broken, with pili torti and trichorrhexis nodosa observed on light microscopy. Other features include increased joint mobility and cognitive delay (Sharma et al., 2019).
Pellagra like syndrome
MedGen UID:
337955
Concept ID:
C1850052
Disease or Syndrome
PEHO syndrome
MedGen UID:
342404
Concept ID:
C1850055
Disease or Syndrome
PEHO is a severe autosomal recessive neurodevelopmental disorder characterized by extreme cerebellar atrophy due to almost total loss of granule neurons. Affected individuals present in early infancy with hypotonia, profoundly delayed psychomotor development, optic atrophy, progressive atrophy of the cerebellum and brainstem, and dysmyelination. Most patients also develop infantile seizures that are often associated with hypsarrhythmia on EEG, and many have peripheral edema (summary by Anttonen et al., 2017).
PEHO-like syndrome
MedGen UID:
337956
Concept ID:
C1850056
Disease or Syndrome
A rare genetic neurological disease characterised by progressive encephalopathy, early-onset seizures with a hypsarrhythmic pattern, facial and limb oedema, severe hypotonia, early arrest of psychomotor development and craniofacial dysmorphism (evolving microcephaly, narrow forehead, short nose, prominent auricles, open mouth, micrognathia), in the absence of neuro-ophthalmic or neuroradiologic findings. Poor visual responsiveness, growth failure and tapering fingers are also associated. There is evidence the disease is caused by homozygous mutation in the CCDC88A gene on chromosome 2p16.
Raine syndrome
MedGen UID:
342416
Concept ID:
C1850106
Disease or Syndrome
Raine syndrome is a neonatal osteosclerotic bone dysplasia of early and aggressive onset that usually results in death within the first few weeks of life, although there have been some reports of survival into childhood. Radiographic studies show a generalized increase in the density of all bones and a marked increase in the ossification of the skull. The increased ossification of the basal structures of the skull and facial bones underlies the characteristic facial features, which include narrow prominent forehead, proptosis, depressed nasal bridge, and midface hypoplasia. Periosteal bone formation is also characteristic of this disorder and differentiates it from osteopetrosis and other known lethal and nonlethal osteosclerotic bone dysplasias. The periosteal bone formation typically extends along the diaphysis of long bones adjacent to areas of cellular soft tissue (summary by Simpson et al., 2009).
Navajo neurohepatopathy
MedGen UID:
338045
Concept ID:
C1850406
Disease or Syndrome
MPV17-related mitochondrial DNA (mtDNA) maintenance defect presents in the vast majority of affected individuals as an early-onset encephalohepatopathic (hepatocerebral) disease that is typically associated with mtDNA depletion, particularly in the liver. A later-onset neuromyopathic disease characterized by myopathy and neuropathy, and associated with multiple mtDNA deletions in muscle, has also rarely been described. MPV17-related mtDNA maintenance defect, encephalohepatopathic form is characterized by: Hepatic manifestations (liver dysfunction that typically progresses to liver failure, cholestasis, hepatomegaly, and steatosis); Neurologic involvement (developmental delay, hypotonia, microcephaly, and motor and sensory peripheral neuropathy); Gastrointestinal manifestations (gastrointestinal dysmotility, feeding difficulties, and failure to thrive); and Metabolic derangements (lactic acidosis and hypoglycemia). Less frequent manifestations include renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Progressive liver disease often leads to death in infancy or early childhood. Hepatocellular carcinoma has been reported.
Ceroid lipofuscinosis neuronal 1
MedGen UID:
340540
Concept ID:
C1850451
Disease or Syndrome
The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment pattern seen most often in CLN1 is referred to as granular osmiophilic deposits (GROD). The patterns most often observed in CLN2 and CLN3 are 'curvilinear' and 'fingerprint' profiles, respectively. CLN4, CLN5, CLN6, CLN7, and CLN8 show mixed combinations of granular, curvilinear, fingerprint, and rectilinear profiles. The clinical course includes progressive dementia, seizures, and progressive visual failure (Mole et al., 2005). Zeman and Dyken (1969) referred to these conditions as the 'neuronal ceroid lipofuscinoses.' Goebel (1995) provided a comprehensive review of the NCLs and noted that they are possibly the most common group of neurodegenerative diseases in children. Mole et al. (2005) provided a detailed clinical and genetic review of the neuronal ceroid lipofuscinoses. Genetic Heterogeneity of Neuronal Ceroid Lipofuscinosis See also CLN2 (204500), caused by mutation in the TPP1 gene (607998) on chromosome 11p15; CLN3 (204200), caused by mutation in the CLN3 gene (607042) on 16p12; CLN4A (204300), caused by mutation in the CLN6 gene (606725) on 15q21; CLN4B (162350), caused by mutation in the DNAJC5 gene (611203) on 20q13; CLN5 (256731), caused by mutation in the CLN5 gene (608102) on 13q; CLN6 (601780), caused by mutation in the CLN6 gene (602780) on 15q21; CLN7 (610951), caused by mutation in the MFSD8 gene (611124) on 4q28; CLN8 (600143) and the Northern epilepsy variant of CLN8 (610003), caused by mutation in the CLN8 gene (607837) on 8pter; CLN10 (610127), caused by mutation in the CTSD gene (116840) on 11p15; CLN11 (614706), caused by mutation in the GRN gene (138945) on 17q; CLN13 (615362), caused by mutation in the CTSF gene (603539) on 11q13; and CLN14 (611726), caused by mutation in the KCTD7 gene (611725) on 7q11. CLN9 (609055) has not been molecularly characterized. A disorder that was formerly designated neuronal ceroid lipofuscinosis-12 (CLN12) is now considered to be a variable form of Kufor-Rakeb syndrome (KRS; 606693).
Congenital nonprogressive myopathy with Moebius and Robin sequences
MedGen UID:
338115
Concept ID:
C1850746
Disease or Syndrome
Carey-Fineman-Ziter syndrome (CFZS) is a multisystem congenital disorder characterized by hypotonia, Moebius sequence (bilateral congenital facial palsy with impairment of ocular abduction), Pierre Robin complex (micrognathia, glossoptosis, and high-arched or cleft palate), delayed motor milestones, and failure to thrive. More variable features include dysmorphic facial features, brain abnormalities, and intellectual disability. It has been postulated that many clinical features in CFZS may be secondary effects of muscle weakness during development or brainstem anomalies (summary by Pasetti et al., 2016). Di Gioia et al. (2017) determined that CFZS represents a slowly progressive congenital myopathy resulting from a defect in myoblast fusion.
Cerebrooculofacioskeletal syndrome 3
MedGen UID:
342008
Concept ID:
C1851443
Disease or Syndrome
Cerebrooculofacioskeletal syndrome is a severe, progressive neurologic disorder characterized by prenatal onset of arthrogryposis, microcephaly, and growth failure. Postnatal features include severe developmental delay, congenital cataracts (in some), and marked UV sensitivity of the skin. Survival beyond 6 years of age is rare. COFS represents the severe end of the spectrum of disorders caused by mutations in nucleotide excision repair (NER) genes, with Cockayne syndrome and xeroderma pigmentosum being milder NER-related phenotypes (summary by Drury et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of cerebrooculofacioskeletal syndrome, see COFS1 (214150).
Cutis Gyrata syndrome of Beare and Stevenson
MedGen UID:
377668
Concept ID:
C1852406
Disease or Syndrome
The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome (isolated coronal synostosis caused by the p.Pro250Arg pathogenic variant in FGFR3). Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.
Cornelia de Lange syndrome 3
MedGen UID:
339902
Concept ID:
C1853099
Disease or Syndrome
Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; <5th centile throughout life), hirsutism, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched eyebrows, long eyelashes, short nose with anteverted nares, small widely spaced teeth, and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS.
Cerebrooculofacioskeletal syndrome 4
MedGen UID:
342798
Concept ID:
C1853100
Disease or Syndrome
Cerebrooculofacioskeletal syndrome-4 is a severe autosomal recessive disorder characterized by growth retardation, dysmorphic facial features, arthrogryposis, and neurologic abnormalities. Cellular studies show a defect in both transcription-coupled and global genome nucleotide excision repair (TC-NER and GG-NER) (summary by Jaspers et al., 2007 and Kashiyama et al., 2013). For a discussion of genetic heterogeneity of cerebrooculofacioskeletal syndrome, see 214150.
Cerebrooculofacioskeletal syndrome 2
MedGen UID:
342799
Concept ID:
C1853102
Disease or Syndrome
Severe congenital neutropenia
MedGen UID:
343974
Concept ID:
C1853118
Disease or Syndrome
Severe congenital neutropenia is a condition that causes affected individuals to be prone to recurrent infections. People with this condition have a shortage (deficiency) of neutrophils, a type of white blood cell that plays a role in inflammation and in fighting infection. The deficiency of neutrophils, called neutropenia, is apparent at birth or soon afterward. It leads to recurrent infections beginning in infancy, including infections of the sinuses, lungs, and liver. Affected individuals can also develop fevers and inflammation of the gums (gingivitis) and skin. Approximately 40 percent of affected people have decreased bone density (osteopenia) and may develop osteoporosis, a condition that makes bones progressively more brittle and prone to fracture. In people with severe congenital neutropenia, these bone disorders can begin at any time from infancy through adulthood.Approximately 20 percent of people with severe congenital neutropenia develop certain cancerous conditions of the blood, particularly myelodysplastic syndrome or leukemia during adolescence.Some people with severe congenital neutropenia have additional health problems such as seizures, developmental delay, or heart and genital abnormalities.
Joubert syndrome 6
MedGen UID:
342805
Concept ID:
C1853153
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
22q13.3 deletion syndrome
MedGen UID:
339994
Concept ID:
C1853490
Disease or Syndrome
Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguishes Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior.
Genitopatellar syndrome
MedGen UID:
381208
Concept ID:
C1853566
Disease or Syndrome
KAT6B-related disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker variant of Ohdo syndrome (Ohdo syndrome, SBBYS variant, or SBBYSS [Say-Barber-Biesecker-Young-Simpson syndrome]). Both phenotypes are characterized by significant global developmental delay / intellectual disability, hypotonia, genital abnormalities in males (cryptorchidism), and patellar hypoplasia/agenesis. Congenital heart defects, dental anomalies, hearing loss, and thyroid anomalies are common to both phenotypes. Also observed in GPS are flexion contractures of the hips and knees, clubfoot, agenesis of the corpus callosum with microcephaly, and hydronephrosis and/or multiple renal cysts. In SBBYS lower-extremity joint stiffness, long thumbs / great toes, immobile mask-like face, blepharophimosis/ptosis, and lacrimal duct anomalies are observed.
Sener syndrome
MedGen UID:
342924
Concept ID:
C1853616
Disease or Syndrome
Fryns-Aftimos syndrome
MedGen UID:
340016
Concept ID:
C1853623
Disease or Syndrome
Iris coloboma, ptosis, hypertelorism, broad nasal bridge, short stature, and mental retardation are the main elements of this syndrome.
Congenital disorder of glycosylation type 2B
MedGen UID:
342954
Concept ID:
C1853736
Disease or Syndrome
A form of congenital disorders of N-linked glycosylation characterised by generalised hypotonia, craniofacial dysmorphism (prominent occiput, short palpebral fissures, long eyelashes, broad nose, high arched palate, retrognathia), hypoplastic genitalia, seizures, feeding difficulties, hypoventilation, severe hypogammaglobulinaemia with generalised oedema and increased resistance to particular viral infections (particularly to enveloped viruses). The disease is caused by loss-of-function mutations in the gene MOGS (2p13.1).
Autism 5
MedGen UID:
340048
Concept ID:
C1853755
Disease or Syndrome
IDDAS is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, autism spectrum disorder, and language deficits (Deriziotis et al., 2014; den Hoed et al., 2018).
Frontoocular syndrome
MedGen UID:
344278
Concept ID:
C1854405
Disease or Syndrome
Macrocephaly/autism syndrome
MedGen UID:
381416
Concept ID:
C1854416
Disease or Syndrome
Macrocephaly/autism syndrome is an autosomal dominant disorder characterized by increased head circumference, abnormal facial features, and delayed psychomotor development resulting in autistic behavior or mental retardation (Herman et al., 2007). Some patients may have a primary immunodeficiency disorder with recurrent infections associated with variably abnormal T- and B-cell function (Tsujita et al., 2016).
Temtamy preaxial brachydactyly syndrome
MedGen UID:
381425
Concept ID:
C1854466
Disease or Syndrome
A rare genetic dysostosis syndrome with characteristics of bilateral symmetrical preaxial brachydactyly associated with hyperphalangy, motor developmental delay and intellectual disability, growth retardation, sensorineural hearing loss, dental abnormalities (including misalignment of teeth, talon cusps, microdontia), and facial dysmorphism that includes plagiocephaly, round face, hypertelorism, malar hypoplasia, malformed ears, microstomia and micro/retrognathia. There is evidence the disease is caused by homozygous mutation in the CHSY1 gene on chromosome 15q26.
Noonan syndrome 2
MedGen UID:
344290
Concept ID:
C1854469
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Mesomelic dysplasia Savarirayan type
MedGen UID:
343129
Concept ID:
C1854470
Disease or Syndrome
Severely hypoplastic and triangular-shaped tibiae and absence of the fibulae.Two sporadic cases have been described. Moderate mesomelia of the upper limbs, proximal widening of the ulnas, pelvic anomalies and marked bilateral glenoid hypoplasia also reported.
Wiedemann-Steiner syndrome
MedGen UID:
340266
Concept ID:
C1854630
Disease or Syndrome
Wiedemann-Steiner syndrome is a congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature; consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, wide nasal bridge, and downslanting and vertically narrow palpebral fissures; mild to moderate intellectual disability; behavioral difficulties; and hypertrichosis on the back (summary by Jones et al., 2012 and Miyake et al., 2016).
Molybdenum cofactor deficiency, complementation group C
MedGen UID:
340761
Concept ID:
C1854990
Disease or Syndrome
Molybdenum cofactor deficiency is a rare condition characterized by brain dysfunction (encephalopathy) that worsens over time. Babies with this condition appear normal at birth, but within a week they have difficulty feeding and develop seizures that do not improve with treatment (intractable seizures). Brain abnormalities, including deterioration (atrophy) of brain tissue, lead to severe developmental delay; affected individuals usually do not learn to sit unassisted or to speak. A small percentage of affected individuals have an exaggerated startle reaction (hyperekplexia) to unexpected stimuli such as loud noises. Other features of molybdenum cofactor deficiency can include a small head size (microcephaly) and facial features that are described as "coarse."Tests reveal that affected individuals have high levels of chemicals called sulfite, S-sulfocysteine, xanthine, and hypoxanthine in the urine and low levels of a chemical called uric acid in the blood.Because of the serious health problems caused by molybdenum cofactor deficiency, affected individuals usually do not survive past early childhood.
Methylmalonic aciduria cblB type
MedGen UID:
344420
Concept ID:
C1855102
Disease or Syndrome
Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.
Methylmalonic aciduria cblA type
MedGen UID:
344422
Concept ID:
C1855109
Disease or Syndrome
Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
MedGen UID:
344424
Concept ID:
C1855114
Disease or Syndrome
Isolated methylmalonic acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated methylmalonic acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult methylmalonic acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of methylmalonic acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy.
3-methylglutaconic aciduria type IV
MedGen UID:
344425
Concept ID:
C1855126
Disease or Syndrome
The category of 3-methylglutaconic aciduria type IV (MGCA4) represents a heterogeneous unclassified group of patients who share mild or intermittent urinary excretion of 3-methylglutaconic acid. MGCA excretion is a nonspecific finding observed in many other disorders caused by defects in mitochondrial energy metabolism (Gunay-Aygun, 2005). For a general phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA1 (250950)
METHYLCOBALAMIN DEFICIENCY, cblG TYPE
MedGen UID:
344426
Concept ID:
C1855128
Disease or Syndrome
Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic compications, and/or subacute combined degeneration of the spinal cord.
Retinitis pigmentosa with or without skeletal anomalies
MedGen UID:
381579
Concept ID:
C1855188
Disease or Syndrome
Marfanoid mental retardation syndrome, autosomal
MedGen UID:
343326
Concept ID:
C1855347
Disease or Syndrome
Pyruvate dehydrogenase E3-binding protein deficiency
MedGen UID:
343383
Concept ID:
C1855553
Disease or Syndrome
Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.
Pyruvate dehydrogenase E2 deficiency
MedGen UID:
343386
Concept ID:
C1855565
Disease or Syndrome
Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.
Ketoadipicaciduria
MedGen UID:
340920
Concept ID:
C1855626
Disease or Syndrome
Keratoconus posticus circumscriptus
MedGen UID:
340922
Concept ID:
C1855645
Disease or Syndrome
Arima syndrome
MedGen UID:
340930
Concept ID:
C1855675
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Baraitser-Winter syndrome
MedGen UID:
340943
Concept ID:
C1855722
Disease or Syndrome
Baraitser-Winter syndrome is a condition that affects the development of many parts of the body, particularly the face and the brain.An unusual facial appearance is the most common characteristic of Baraitser-Winter syndrome. Distinctive facial features can include widely spaced eyes (hypertelorism), large eyelid openings, droopy eyelids (ptosis), high-arched eyebrows, a broad nasal bridge and tip of the nose, a long space between the nose and upper lip (philtrum), full cheeks, and a pointed chin.Structural brain abnormalities are also present in most people with Baraitser-Winter syndrome. These abnormalities are related to impaired neuronal migration, a process by which nerve cells (neurons) move to their proper positions in the developing brain. The most frequent brain abnormality associated with Baraitser-Winter syndrome is pachygyria, which is an area of the brain that has an abnormally smooth surface with fewer folds and grooves. Less commonly, affected individuals have lissencephaly, which is similar to pachygyria but involves the entire brain surface. These structural changes can cause mild to severe intellectual disability, developmental delay, and seizures.Other features of Baraitser-Winter syndrome can include short stature, ear abnormalities and hearing loss, heart defects, presence of an extra (duplicated) thumb, and abnormalities of the kidneys and urinary system. Some affected individuals have limited movement of large joints, such as the elbows and knees, which may be present at birth or develop over time. Rarely, people with Baraitser-Winter syndrome have involuntary muscle tensing (dystonia).
Vici syndrome
MedGen UID:
340962
Concept ID:
C1855772
Disease or Syndrome
Vici syndrome is a rare congenital multisystem disorder characterized by agenesis of the corpus callosum (ACC), cataracts, pigmentary defects, progressive cardiomyopathy, and variable immunodeficiency. Affected individuals also have profound psychomotor retardation and hypotonia due to a myopathy (summary by Finocchi et al., 2012).
Bartter syndrome, type 2, antenatal
MedGen UID:
343428
Concept ID:
C1855849
Disease or Syndrome
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
Homocystinuria-Megaloblastic anemia due to defect in cobalamin metabolism, cblE complementation type
MedGen UID:
344640
Concept ID:
C1856057
Disease or Syndrome
Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic compications, and/or subacute combined degeneration of the spinal cord.
Homocysteinemia due to MTHFR deficiency
MedGen UID:
383829
Concept ID:
C1856058
Disease or Syndrome
Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. In the classic form, both thermostable and thermolabile enzyme variants have been identified (Rosenblatt et al., 1992).
Growth retardation, small and puffy hands and feet, and eczema
MedGen UID:
343510
Concept ID:
C1856242
Disease or Syndrome
Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome
MedGen UID:
384026
Concept ID:
C1856972
Disease or Syndrome
The proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome is a rare, autosomal recessive, usually prenatally lethal disorder characterized by hydranencephaly, a distinctive glomerular vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications. It is usually diagnosed by ultrasound between 26 and 33 weeks' gestation (summary by Meyer et al., 2010). Rarely, affected individuals may survive, but are severely impaired with almost no neurologic development (Kvarnung et al., 2016).
Donnai Barrow syndrome
MedGen UID:
347406
Concept ID:
C1857277
Disease or Syndrome
Donnai-Barrow syndrome (DBS) is characterized by typical craniofacial features (large anterior fontanelle, wide metopic suture, widow's peak, markedly widely spaced eyes, enlarged globes, downslanted palpebral fissures, posteriorly rotated ears, depressed nasal bridge, and short nose. Ocular complications include high myopia, retinal detachment, retinal dystrophy, and progressive vision loss. Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed.
Leigh syndrome, French Canadian type
MedGen UID:
387801
Concept ID:
C1857355
Disease or Syndrome
The French Canadian type of Leigh syndrome is an autosomal recessive severe neurologic disorder with onset in infancy. Features include delayed psychomotor development, mental retardation, mild dysmorphic facial features, hypotonia, ataxia, and the development of lesions in the brainstem and basal ganglia. Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of Leigh syndrome, see 256000.
Craniotelencephalic dysplasia
MedGen UID:
347462
Concept ID:
C1857471
Disease or Syndrome
Characterised by frontal encephalocoele, craniosynostosis, and developmental delay.
Temtamy syndrome
MedGen UID:
347474
Concept ID:
C1857512
Disease or Syndrome
Temtamy syndrome is a mental retardation/multiple congenital anomaly syndrome characterized by variable craniofacial dysmorphism, ocular coloboma, seizures, and brain abnormalities, including abnormalities of the corpus callosum and thalamus (summary by Akizu et al., 2013).
Cortical blindness, retardation, and postaxial polydactyly
MedGen UID:
347487
Concept ID:
C1857568
Disease or Syndrome
COACH syndrome
MedGen UID:
387879
Concept ID:
C1857662
Disease or Syndrome
COACH syndrome is an autosomal recessive disorder characterized by mental retardation, ataxia due to cerebellar hypoplasia, and hepatic fibrosis. Other features, such as coloboma and renal cysts, may be variable. COACH syndrome is considered by some to be a subtype of Joubert syndrome (JBTS; see 213300) with congenital hepatic fibrosis. Identification of liver disease in these patients is critical because some may develop complications such as portal hypertension with fatal variceal bleeding (Brancati et al., 2009; Doherty et al., 2010).
Diabetes mellitus, neonatal, with congenital hypothyroidism
MedGen UID:
347541
Concept ID:
C1857775
Disease or Syndrome
Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome is characterized by intrauterine growth retardation and onset of nonimmune diabetes mellitus within the first few weeks of life. Other features include renal parenchymal disease, primarily renal cystic dysplasia, and hepatic disease, with hepatitis in some patients and hepatic fibrosis and cirrhosis in others. Facial dysmorphism, when present, consistently involves low-set ears, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. Most patients exhibit developmental delay (Dimitri et al., 2015).
Williams-Beuren region duplication syndrome
MedGen UID:
347562
Concept ID:
C1857844
Disease or Syndrome
7q11.23 duplication syndrome is characterized by distinctive facial features; cardiovascular disease (dilation of the ascending aorta in 46%); neurologic abnormalities (hypotonia, adventitious movements, and abnormal gait and station); speech sound disorders including motor speech disorders (childhood apraxia of speech and/or dysarthria) and phonologic disorders; behavior problems including anxiety disorders (especially social anxiety disorder [social phobia]), selective mutism, attention deficit hyperactivity disorder (ADHD), oppositional disorders, physical aggression, and autism spectrum disorders (ASD); delayed motor, speech, and social skills in early childhood; and intellectual ability ranging from intellectual disability (~18%) to borderline intellectual ability (~20%) to low average to high average (the remainder). Approximately 30% of individuals with the 7q11.23 duplication have one or more congenital anomalies.
Primary autosomal recessive microcephaly 3
MedGen UID:
347619
Concept ID:
C1858108
Disease or Syndrome
Autosomal recessive primary microcephaly (often shortened to MCPH, which stands for "microcephaly primary hereditary") is a condition in which infants are born with a very small head and a small brain. The term "microcephaly" comes from the Greek words for "small head."Infants with MCPH have an unusually small head circumference compared to other infants of the same sex and age. Head circumference is the distance around the widest part of the head, measured by placing a measuring tape above the eyebrows and ears and around the back of the head. Affected infants' brain volume is also smaller than usual, although they usually do not have any major abnormalities in the structure of the brain. The head and brain grow throughout childhood and adolescence, but they continue to be much smaller than normal.MCPH causes intellectual disability, which is typically mild to moderate and does not become more severe with age. Most affected individuals have delayed speech and language skills. Motor skills, such as sitting, standing, and walking, may also be mildly delayed.People with MCPH usually have few or no other features associated with the condition. Some have a narrow, sloping forehead; mild seizures; problems with attention or behavior; or short stature compared to others in their family. The condition typically does not affect any other major organ systems or cause other health problems.
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency
MedGen UID:
346817
Concept ID:
C1858424
Disease or Syndrome
Cardioencephalomyopathy due to cytochrome c oxidase deficiency is an autosomal recessive mitochondrial disorder characterized by onset of cardiomyopathy either in utero or in the first days of life. Most patients also show neurologic abnormalities, such as abnormal breathing pattern, nystagmus, and gyral abnormalities, consistent with encephalopathy. The disorder is usually fatal in early infancy (summary by Papadopoulou et al., 1999). Genetic Heterogeneity of Fatal Infantile Cardioencephalomyopathy Due to Cytochrome c Oxidase Deficiency See also CEMCOX2 (615119), caused by mutation in the COX15 gene (603646) on chromosome 10q24; CEMCOX3 (616500), caused by mutation in the COA5 gene (613920) on chromosome 2q11; and CEMCOX4 (616501), caused by mutation in the COA6 gene (614772) on chromosome 1q42. For a phenotypic description and a discussion of genetic heterogeneity of cytochrome c oxidase deficiency, see 220110.
Primary autosomal recessive microcephaly 2
MedGen UID:
346929
Concept ID:
C1858535
Disease or Syndrome
Microcephaly-2 with or without cortical malformations is an autosomal recessive neurodevelopmental disorder showing phenotypic variability. Classically, primary microcephaly is a clinical diagnosis made when an individual has a head circumference more than 3 standard deviations (SD) below the age- and sex-matched population mean, and mental retardation with no other associated malformations and with no apparent etiology (Hofman, 1984). Patients with WDR62 mutations have head circumferences ranging from low-normal to severe (-9.8 SD), and most patients with brain scans have shown various types of cortical malformations. All have delayed psychomotor development; seizures are variable (summary by Yu et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Congenital Cataracts, Facial Dysmorphism, and Neuropathy
MedGen UID:
346973
Concept ID:
C1858726
Congenital Abnormality
Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils); mildly dysmorphic facial features apparent in late childhood; and a hypo/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade. Secondary scoliosis and foot deformities are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild non-progressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Roma/Gypsy population.
Chromosomal instability with tissue-specific radiosensitivity
MedGen UID:
347797
Concept ID:
C1859091
Cell or Molecular Dysfunction
Griscelli syndrome type 1
MedGen UID:
347092
Concept ID:
C1859194
Disease or Syndrome
Griscelli syndrome type 1 (GS1) represents hypomelanosis with a primary neurologic deficit and without immunologic impairment or manifestations of hemophagocytic syndrome (Menasche et al., 2002). Griscelli syndrome with immune impairment, or Griscelli syndrome type 2 (607624), is caused by mutation in the RAB27A gene (603868). Griscelli syndrome type 3 (609227), characterized by hypomelanosis with no immunologic or neurologic manifestations, can be caused by mutation in the melanophilin (MLPH; 606526) or MYO5A genes. Griscelli syndrome is a rare autosomal recessive disorder that results in pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. While most patients also develop hemophagocytic syndrome, leading to death in the absence of bone marrow transplantation (Menasche et al., 2000), some show severe neurologic impairment early in life without apparent immune abnormalities. Bahadoran et al. (2003) characterized GS1 as comprising hypomelanosis and severe central nervous system dysfunction, corresponding to the 'dilute' phenotype in the mouse, and GS2 as comprising hypomelanosis and lymphohistiocytotic hemophagocytosis, corresponding to the 'ashen' phenotype in mouse. Anikster et al. (2002), Menasche et al. (2002), Huizing et al. (2002), and Bahadoran et al. (2003, 2003) suggested that Elejalde syndrome (256710) in some patients and GS1 represent the same entity.
Spinocerebellar ataxia, autosomal recessive 2
MedGen UID:
349134
Concept ID:
C1859298
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-2 is an neurologic disorder characterized by onset of impaired motor development and ataxic gait in early childhood. Additional features often include loss of fine motor skills, dysarthria, nystagmus, cerebellar signs, and delayed cognitive development with intellectual disability. Brain imaging shows cerebellar atrophy. Overall, the disorder is non- or slowly progressive, with survival into adulthood (summary by Jobling et al., 2015).
Cerebellar hypoplasia with endosteal sclerosis
MedGen UID:
347849
Concept ID:
C1859301
Disease or Syndrome
3-methylcrotonyl CoA carboxylase 2 deficiency
MedGen UID:
347898
Concept ID:
C1859499
Disease or Syndrome
3-methylcrotonyl-CoA carboxylase deficiency (also known as 3-MCC deficiency) is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have a shortage of an enzyme that helps break down proteins containing a particular building block (amino acid) called leucine.Infants with 3-MCC deficiency appear normal at birth but usually develop signs and symptoms in infancy or early childhood. The characteristic features of this condition, which can range from mild to life-threatening, include feeding difficulties, recurrent episodes of vomiting and diarrhea, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, this disorder can lead to delayed development, seizures, and coma. Many of these complications can be prevented with early detection and lifelong management with a low-protein diet and appropriate supplements. Some people with gene mutations that cause 3-MCC deficiency never experience any signs or symptoms of the condition.The characteristic features of 3-MCC deficiency are similar to those of Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.
Berry aneurysm, cirrhosis, pulmonary emphysema, and cerebral calcification
MedGen UID:
347170
Concept ID:
C1859519
Disease or Syndrome
Bardet-Biedl syndrome 3
MedGen UID:
347179
Concept ID:
C1859564
Disease or Syndrome
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Bardet-Biedl syndrome 8
MedGen UID:
347181
Concept ID:
C1859566
Disease or Syndrome
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Arthrogryposis renal dysfunction cholestasis syndrome
MedGen UID:
347219
Concept ID:
C1859722
Disease or Syndrome
Microphthalmia syndromic 3
MedGen UID:
347232
Concept ID:
C1859773
Disease or Syndrome
SOX2-related eye disorders are characterized by anophthalmia and/or microphthalmia that is usually bilateral, severe, and apparent at birth or by prenatal ultrasound examination. Other common findings include brain malformations, esophageal atresia, cryptorchidism and/or micropenis in males, and hypogonadotropic hypogonadism and/or pituitary hypoplasia. Postnatal growth failure, delayed motor development, and learning disability are common.
2-aminoadipic 2-oxoadipic aciduria
MedGen UID:
395350
Concept ID:
C1859817
Finding
Triosephosphate isomerase deficiency
MedGen UID:
349893
Concept ID:
C1860808
Disease or Syndrome
Triosephosphate isomerase deficiency is an autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. Many patients die from respiratory failure in childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Some patients may show additional signs such as dystonic posturing and/or spasticity. Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells (summary by Fermo et al., 2010).
Noonan syndrome 3
MedGen UID:
349931
Concept ID:
C1860991
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Thumb stiff brachydactyly mental retardation
MedGen UID:
396073
Concept ID:
C1861166
Disease or Syndrome
Forebrain defects
MedGen UID:
348301
Concept ID:
C1861235
Disease or Syndrome
Idiopathic basal ganglia calcification childhood-onset
MedGen UID:
396262
Concept ID:
C1861967
Disease or Syndrome
Bilateral striopallidodentate calcinosis, also known as idiopathic basal ganglia calcification (IBGC), is characterized by the accumulation of calcium deposits in different brain regions and is associated with a neurodegenerative clinical phenotype. The changes seen in IBGC occur in the absence of calcium or parathyroid hormone (PTH; 168450) metabolic disorders, such as hypoparathyroidism (see 146200) or pseudohypoparathyroidism (PHP; see 103580). See also the adult-onset form (213600), which is sometimes erroneously referred to as 'Fahr disease.'
Brachmann-de Lange-like facial changes with microcephaly, metatarsus adductus, and developmental delay
MedGen UID:
396307
Concept ID:
C1862171
Disease or Syndrome
Hemophagocytic lymphohistiocytosis, familial, 2
MedGen UID:
400366
Concept ID:
C1863727
Disease or Syndrome
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.
Hemophagocytic lymphohistiocytosis, familial, 4
MedGen UID:
350245
Concept ID:
C1863728
Disease or Syndrome
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.
Craniosynostosis, anal anomalies, and porokeratosis
MedGen UID:
351066
Concept ID:
C1864186
Disease or Syndrome
A very rare condition with characteristics of craniosynostosis and clavicular hypoplasia, delayed closure of the fontanelle, anal anomalies, genitourinary malformations and skin eruptions. It has been described in seven patients from four unrelated families. Cranial abnormalities include a coronal synostosis with wide-open anterior and posterior fontanelles and large parietal foramina. In some patients the skin eruption has been classified as porokeratosis. Sensorineural hearing loss and mild to severe developmental delay are common. The condition is transmitted as an autosomal recessive trait.
Muenke syndrome
MedGen UID:
355217
Concept ID:
C1864436
Disease or Syndrome
Muenke syndrome is defined by the presence of the specific FGFR3 pathogenic variant – c.749C>G – that results in the protein change p.Pro250Arg. Muenke syndrome is characterized by considerable phenotypic variability: features may include coronal synostosis (more often bilateral than unilateral); synostosis of other sutures, all sutures (pan synostosis), or no sutures; or macrocephaly. Bilateral coronal synostosis typically results in brachycephaly (reduced anteroposterior dimension of the skull), although turribrachycephaly (a "tower-shaped" skull) or a cloverleaf skull can be observed. Unilateral coronal synostosis results in anterior plagiocephaly (asymmetry of the skull and face). Other craniofacial findings typically include: temporal bossing; widely spaced eyes, ptosis or proptosis (usually mild); midface retrusion (usually mild); and highly arched palate or cleft lip and palate. Strabismus is common. Other findings can include: hearing loss (in 33%-100% of affected individuals); developmental delay (~33%); epilepsy; intracranial anomalies; intellectual disability; carpal bone and/or tarsal bone fusions; brachydactyly, broad toes, broad thumbs, and/or clinodactyly; and radiographic findings of thimble-like (short and broad) middle phalanges and/or cone-shaped epiphyses. Phenotypic variability is considerable even within the same family. Of note, some individuals who have the p.Pro250Arg pathogenic variant may have no signs of Muenke syndrome on physical or radiographic examination.
Chromosome 16p13.3 deletion syndrome, proximal
MedGen UID:
350477
Concept ID:
C1864648
Disease or Syndrome
Growth and mental retardation, mandibulofacial dysostosis, microcephaly, and cleft palate
MedGen UID:
355264
Concept ID:
C1864652
Disease or Syndrome
Mandibulofacial dysostosis with microcephaly (MFDM) is characterized by malar and mandibular hypoplasia; microcephaly (congenital or postnatal onset); malformations of the pinna, auditory canal, and/or middle ear (ossicles and semi-circular canals) with associated conductive hearing loss; and distinctive facial features (metopic ridge, up- or downslanting palpebral fissures, prominent glabella, broad nasal bridge, bulbous nasal tip, and everted lower lip). Associated craniofacial malformations may include cleft palate, choanal atresia, and facial asymmetry. Intellectual disability is a prominent feature. Major extracranial malformations include: esophageal atresia (~40%), congenital heart disease (~40%), and thumb abnormalities (~25%). Short stature is present in approximately one third of individuals.
Hypomyelination and Congenital Cataract
MedGen UID:
501134
Concept ID:
C1864663
Congenital Abnormality
Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor development in the first year of life, followed by slowly progressive neurologic impairment manifest as ataxia, spasticity (brisk tendon reflexes and bilateral extensor plantar responses), and mild to moderate cognitive impairment. Dysarthria and truncal hypotonia are observed. Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur. In a few cases cataracts may be absent.
Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 4
MedGen UID:
350480
Concept ID:
C1864668
Disease or Syndrome
Progressive external ophthalmoplegia-4 is an autosomal dominant form of mitochondrial disease that variably affects skeletal muscle, the nervous system, the liver, and the gastrointestinal tract. Age at onset ranges from infancy to adulthood. The phenotype ranges from relatively mild, with adult-onset skeletal muscle weakness and weakness of the external eye muscles, to severe, with a multisystem disorder characterized by delayed psychomotor development, lactic acidosis, constipation, and liver involvement (summary by Young et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640).
Microphthalmia syndromic 6
MedGen UID:
355268
Concept ID:
C1864689
Disease or Syndrome
Microphthalmia, anophthalmia, and coloboma comprise the MAC spectrum of ocular malformations. Microphthalmia refers to a globe with a total axial length that is at least two standard deviations below the mean for age. Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Coloboma refers to the ocular malformations that result from failure of closure of the optic fissure. Chorioretinal coloboma refers to coloboma of the retina and choroid. Iris coloboma causes the iris to appear keyhole-shaped. Microphthalmia, anophthalmia, and coloboma may be unilateral or bilateral; when bilateral they may occur in any combination.
Microphthalmia syndromic 5
MedGen UID:
350491
Concept ID:
C1864690
Disease or Syndrome
Microphthalmia, anophthalmia, and coloboma comprise the MAC spectrum of ocular malformations. Microphthalmia refers to a globe with a total axial length that is at least two standard deviations below the mean for age. Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Coloboma refers to the ocular malformations that result from failure of closure of the optic fissure. Chorioretinal coloboma refers to coloboma of the retina and choroid. Iris coloboma causes the iris to appear keyhole-shaped. Microphthalmia, anophthalmia, and coloboma may be unilateral or bilateral; when bilateral they may occur in any combination.
Pyridoxal 5'-phosphate-dependent epilepsy
MedGen UID:
350498
Concept ID:
C1864723
Disease or Syndrome
PNPOD is an autosomal recessive inborn error of metabolism resulting in vitamin B6 deficiency that manifests as neonatal-onset severe seizures and subsequent encephalopathy. Patients with PNPO mutations tend to respond better to treatment with pyridoxal 5-prime phosphate (PLP) than with pyridoxine (summary by Plecko et al., 2014).
Frias syndrome
MedGen UID:
400621
Concept ID:
C1864825
Disease or Syndrome
Frias syndrome is characterized by mild exophthalmia, palpebral ptosis, hypertelorism, short square hands with minimal proximal syndactyly between the second and third fingers, small broad great toes, and short stature. Some patients may exhibit bilateral pedunculated postminimi (summary by Martinez-Fernandez et al., 2014).
Holoprosencephaly 5
MedGen UID:
355304
Concept ID:
C1864827
Disease or Syndrome
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having "microform" HPE.
Combined oxidative phosphorylation deficiency 3
MedGen UID:
355842
Concept ID:
C1864840
Disease or Syndrome
Camptodactyly, tall stature, and hearing loss syndrome
MedGen UID:
355844
Concept ID:
C1864852
Disease or Syndrome
Koolen-de Vries syndrome
MedGen UID:
355853
Concept ID:
C1864871
Disease or Syndrome
Koolen-de Vries syndrome (KdVS) is characterized by developmental delay / intellectual disability, neonatal/childhood hypotonia, dysmorphisms, congenital malformations, and behavioral features. Psychomotor developmental delay is noted in all individuals from an early age. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability. Other findings include speech and language delay (100%), epilepsy (~33%), congenital heart defects (25%-50%), renal and urologic anomalies (25%-50%), and cryptorchidism (71% of males). Behavior in most is described as friendly, amiable, and cooperative.
Deficiency of 2-methylbutyryl-CoA dehydrogenase
MedGen UID:
355324
Concept ID:
C1864912
Disease or Syndrome
2-Methylbutyryl-CoA dehydrogenase (MBD) deficiency is an autosomal recessive metabolic disorder of impaired isoleucine degradation. It is most often ascertained via newborn screening and is usually clinically asymptomatic, although some patients have been reported to have delayed development and neurologic signs. Therefore, the clinical relevance of the deficiency is unclear (Sass et al.., 2008).
Natural killer cell and glucocorticoid deficiency with DNA repair defect
MedGen UID:
351256
Concept ID:
C1864947
Disease or Syndrome
Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by Gineau et al., 2012).
Brachyphalangy, polydactyly, and tibial aplasia/hypoplasia
MedGen UID:
355340
Concept ID:
C1864965
Disease or Syndrome
Megalencephaly cutis marmorata telangiectatica congenita
MedGen UID:
355421
Concept ID:
C1865285
Disease or Syndrome
PIK3CA-associated segmental overgrowth includes disorders of brain (e.g., MCAP [megalencephaly-capillary malformation] syndrome, hemimegalencephaly); and segmental body overgrowth (e.g., CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome, fibroadipose hyperplasia [FH]). Heterozygous (usually somatic mosaic) pathogenic variants of PIK3CA are causative. MCAP syndrome is characterized by the major findings of (1) megalencephaly (MEG) or hemimegalencephaly (HMEG) associated with neurologic findings of hypotonia, seizures, and mild to severe intellectual disability; and (2) cutaneous capillary malformations with focal or generalized somatic overgrowth. Additional findings can include digital anomalies (syndactyly, polydactyly), cortical malformations – most distinctively polymicrogyria (PMG); and variable connective tissue dysplasia. CLOVES (or CLOVE) syndrome and fibroadipose hyperplasia (FH) may be associated with (1) MEG or HMEG; and (2) patchy segmental overgrowth associated with skeletal anomalies, lipomatosis, vascular malformations, and epidermal nevi.
Ethylmalonic encephalopathy
MedGen UID:
355966
Concept ID:
C1865349
Disease or Syndrome
Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder characterized by developmental delay / mild-to-severe intellectual disability; generalized infantile hypotonia that evolves into hypertonia, spasticity, and (in some instances) dystonia; generalized tonic-clonic seizures; and generalized microvascular damage (diffuse and spontaneous relapsing petechial purpura, hemorrhagic suffusions of mucosal surfaces, and chronic hemorrhagic diarrhea). Infants sometimes have frequent vomiting and loss of social interaction. Speech is delayed and in some instances absent. Swallowing difficulties and failure to thrive are common. Children may be unable to walk without support and may be wheelchair bound. Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of children die in the first decade.
Desmosterolosis
MedGen UID:
400801
Concept ID:
C1865596
Disease or Syndrome
Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (summary by Waterham et al., 2001).
Gracile bone dysplasia
MedGen UID:
356331
Concept ID:
C1865639
Disease or Syndrome
Gracile bone dysplasia is a perinatally lethal condition characterized by gracile bones with thin diaphyses, premature closure of basal cranial sutures, and microphthalmia (summary by Unger et al., 2013).
Pierpont syndrome
MedGen UID:
356049
Concept ID:
C1865644
Disease or Syndrome
Pierpont syndrome is a multiple congenital anomaly syndrome associated with learning disability. Key features include distinctive facial characteristics, especially when smiling, plantar fat pads, and other limb anomalies (summary by Burkitt Wright et al., 2011).
Ehlers-Danlos syndrome, musculocontractural type
MedGen UID:
356497
Concept ID:
C1866294
Disease or Syndrome
The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility (Beighton et al., 1998). The major characteristics of the musculocontractural form of EDS include distinctive craniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, muscular hypotonia, hyperextensible thin skin with easy bruisability and atrophic scarring, wrinkled palms, joint hypermobility, and ocular involvement (summary by Malfait et al., 2010). Janecke et al. (2015) reviewed the clinical findings in 34 reported EDSMC patients, 31 with CHST14 mutations and 3 with DSE (605942) mutations (see 615539), and stated that the disorder can be recognized based on the presence of distal arthrogryposis, including adducted thumbs or clenched fists and talipes equinovarus, as well as hands with atypically shallow palmar creases and tapering fingers, and neonatal muscular hypotonia. Characteristic craniofacial features include brachycephaly, large fontanel, hypertelorism, downslanting palpebral fissures, microcorneae, strabismus, prominent nasolabial folds, short philtrum, thin upper lip, small mouth, high palate, microretrognathia, and prominent and often low-set and posteriorly rotated ears. In addition, EDSMC patients show muscular hypoplasia and weakness, which has been confirmed by ultrasound and electromyography, and intellectual development appears to be normal. Genetic Heterogeneity of Musculocontractural Ehlers-Danlos Syndrome Ehlers-Danlos syndrome musculocontractural type 2 (EDSMC2; 615539) is caused by mutation in the DSE gene (605942) on chromosome 6q22.
PTEN hamartoma tumor syndrome with granular cell tumor
MedGen UID:
400984
Concept ID:
C1866376
Neoplastic Process
Proteus-like syndrome
MedGen UID:
356222
Concept ID:
C1866398
Disease or Syndrome
Proteus like syndrome describes patients who do not meet the diagnostic criteria for Proteus syndrome but who share a multitude of characteristic clinical features of the disease. The prevalence is unknown. The main clinical features include skeletal overgrowth, hamartomous overgrowth of multiple tissues, cerebriform connective tissue nevi, vascular malformations and linear epidermal nevi. Mutations in the PTEN gene are found in 50% of Proteus-like syndrome cases, making them a part of the PTEN harmatoma syndrome group.
Bartter syndrome, type 1, antenatal
MedGen UID:
355727
Concept ID:
C1866495
Disease or Syndrome
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
Char syndrome
MedGen UID:
358356
Concept ID:
C1868570
Disease or Syndrome
Char syndrome is characterized by the triad of typical facial features, patent ductus arteriosus (PDA), and aplasia or hypoplasia of the middle phalanges of the fifth fingers. Typical facial features are flat midface, flat nasal bridge and broad flat nasal tip, wide-set eyes, downslanting palpebral fissures, mild ptosis, short philtrum resulting in a triangular mouth, and thickened (patulous) everted lips.
Thanatophoric dysplasia type 1
MedGen UID:
358383
Concept ID:
C1868678
Disease or Syndrome
Thanatophoric dysplasia (TD) is a short-limb dwarfism syndrome that is usually lethal in the perinatal period. TD is divided into type I, characterized by micromelia with bowed femurs and, uncommonly, the presence of cloverleaf skull deformity (Kleeblattschädel) of varying severity; and type II, characterized by micromelia with straight femurs and uniform presence of moderate-to-severe cloverleaf skull deformity. Other features common to type I and type II include: short ribs, narrow thorax, macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most affected infants die of respiratory insufficiency shortly after birth. Rare long-term survivors have been reported.
4p partial monosomy syndrome
MedGen UID:
408255
Concept ID:
C1956097
Disease or Syndrome
Wolf-Hirschhorn syndrome is a congenital malformation syndrome characterized by pre- and postnatal growth deficiency, developmental disability of variable degree, characteristic craniofacial features ('Greek warrior helmet' appearance of the nose, high forehead, prominent glabella, hypertelorism, high-arched eyebrows, protruding eyes, epicanthal folds, short philtrum, distinct mouth with downturned corners, and micrognathia), and a seizure disorder (Battaglia et al., 2008).
PTEN hamartoma tumor syndrome
MedGen UID:
368366
Concept ID:
C1959582
Neoplastic Process
The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome. CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is approximately 35%. The risk for endometrial cancer may approach 28%. BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis. PS is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.
Mevalonic aciduria
MedGen UID:
368373
Concept ID:
C1959626
Disease or Syndrome
Mevalonic aciduria, the first recognized defect in the biosynthesis of cholesterol and isoprenoids, is a consequence of a deficiency of mevalonate kinase (ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36). Mevalonic acid accumulates because of failure of conversion to 5-phosphomevalonic acid, which is catalyzed by mevalonate kinase. Mevalonic acid is synthesized from 3-hydroxy-3-methylglutaryl-CoA, a reaction catalyzed by HMG-CoA reductase (142910). Mevalonic aciduria is characterized by dysmorphology, psychomotor retardation, progressive cerebellar ataxia, and recurrent febrile crises, usually manifesting in early infancy, accompanied by hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rash. The febrile crises are similar to those observed in hyperimmunoglobulinemia D and to periodic fever syndrome (HIDS; 260920), which is also caused by mutation in the MVK gene (summary by Prietsch et al., 2003).
Mental retardation, X-linked, syndromic 13
MedGen UID:
368466
Concept ID:
C1968550
Disease or Syndrome
The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.
Severe neonatal-onset encephalopathy with microcephaly
MedGen UID:
409616
Concept ID:
C1968556
Disease or Syndrome
The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.
Joubert syndrome 7
MedGen UID:
369401
Concept ID:
C1969053
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Noonan syndrome 5
MedGen UID:
370589
Concept ID:
C1969057
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Pontocerebellar hypoplasia type 6
MedGen UID:
370596
Concept ID:
C1969084
Congenital Abnormality
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Mitochondrial trifunctional protein deficiency
MedGen UID:
370665
Concept ID:
C1969443
Disease or Syndrome
Mitochondrial trifunctional protein deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting).Signs and symptoms of mitochondrial trifunctional protein deficiency may begin during infancy or later in life. Features that occur during infancy include feeding difficulties, lack of energy (lethargy), low blood sugar (hypoglycemia), weak muscle tone (hypotonia), and liver problems. Infants with this disorder are also at high risk for serious heart problems, breathing difficulties, coma, and sudden death. Signs and symptoms of mitochondrial trifunctional protein deficiency that may begin after infancy include hypotonia, muscle pain, a breakdown of muscle tissue, and a loss of sensation in the extremities (peripheral neuropathy).Problems related to mitochondrial trifunctional protein deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.
Mental retardation, autosomal recessive 4
MedGen UID:
370844
Concept ID:
C1970179
Disease or Syndrome
Mental retardation, autosomal recessive 6
MedGen UID:
370848
Concept ID:
C1970198
Disease or Syndrome
Mental retardation, autosomal recessive 5
MedGen UID:
370849
Concept ID:
C1970199
Disease or Syndrome
Polyhydramnios, megalencephaly, and symptomatic epilepsy
MedGen UID:
370203
Concept ID:
C1970203
Disease or Syndrome
Phosphoserine aminotransferase deficiency
MedGen UID:
410026
Concept ID:
C1970253
Disease or Syndrome
Deficiency of phosphoserine aminotransferase (PSAT) is characterized biochemically by low plasma and cerebrospinal fluid (CSF) concentrations of serine and glycine and clinically by intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation. Outcome is poor once the individual becomes symptomatic, but treatment with serine and glycine supplementation from birth can lead to a normal outcome (Hart et al., 2007).
Choreoathetosis, hypothyroidism, and neonatal respiratory distress
MedGen UID:
369694
Concept ID:
C1970269
Disease or Syndrome
NKX2-1-related disorders range from benign hereditary chorea (BHC) to choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress (also known as brain-lung-thyroid syndrome). Childhood-onset chorea, the hallmark of NKX2-1-related disorders, may or may not be associated with respiratory distress syndrome or congenital hypothyroidism. Chorea generally begins in early infancy or about age one year (most commonly) or in late childhood or adolescence, and progresses into the second decade after which it remains static or (rarely) remits. Pulmonary disease, the second most common manifestation, can include respiratory distress syndrome in neonates, interstitial lung disease in young children, and pulmonary fibrosis in older persons. The risk for pulmonary carcinoma is increased in young adults with an NKX2-1-related disorder. Thyroid dysfunction, the result of dysembryogenesis, can present as congenital hypothyroidism or compensated hypothyroidism. The risk for thyroid cancer is unknown and may not be increased. In one review, 50% of affected individuals had the full brain-lung-thyroid syndrome, 30% had involvement of brain and thyroid only, and 13% had isolated chorea only.
Congenital disorder of glycosylation type 2F
MedGen UID:
370234
Concept ID:
C1970344
Disease or Syndrome
An extremely rare form of carbohydrate deficient glycoprotein syndrome characterised clinically in the single reported case by repeated haemorrhagic incidents, including severe pulmonary haemorrhage.
Osteogenesis imperfecta type 8
MedGen UID:
410075
Concept ID:
C1970458
Disease or Syndrome
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses.
Phosphoglycerate kinase 1 deficiency
MedGen UID:
410166
Concept ID:
C1970848
Disease or Syndrome
Phosphoglycerate kinase-1 deficiency is an X-linked recessive condition with a highly variable clinical phenotype that includes hemolytic anemia, myopathy, and neurologic involvement. Patients can express 1, 2, or all 3 of these manifestations (Shirakawa et al., 2006).
Macrocephalus
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
I cell disease
MedGen UID:
435914
Concept ID:
C2673377
Disease or Syndrome
GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.
Hypomagnesemia 4, renal
MedGen UID:
388692
Concept ID:
C2673648
Disease or Syndrome
Bardet-Biedl syndrome 13
MedGen UID:
393032
Concept ID:
C2673873
Disease or Syndrome
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Bardet-Biedl syndrome 14
MedGen UID:
393033
Concept ID:
C2673874
Disease or Syndrome
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Severe achondroplasia with developmental delay and acanthosis nigricans
MedGen UID:
393098
Concept ID:
C2674173
Congenital Abnormality
SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) is a rare disorder of bone growth characterized by skeletal, brain, and skin abnormalities.All people with this condition have extremely short stature with particularly short arms and legs. Other features include unusual bowing of the leg bones; a small chest with short ribs and curved collar bones; short, broad fingers; and folds of extra skin on the arms and legs. Structural abnormalities of the brain cause seizures, profound developmental delay, and intellectual disability. Several affected individuals also have had episodes in which their breathing slows or stops for short periods (apnea). Acanthosis nigricans, a progressive skin disorder characterized by thick, dark, velvety skin, is another characteristic feature of SADDAN that develops in infancy or early childhood.
Loeys-Dietz syndrome 2
MedGen UID:
382398
Concept ID:
C2674574
Disease or Syndrome
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Chromosome 10q26 deletion syndrome
MedGen UID:
436306
Concept ID:
C2674937
Disease or Syndrome
10q26 deletion syndrome is a condition that results from the loss (deletion) of a small piece of chromosome 10 in each cell. The deletion occurs on the long (q) arm of the chromosome at a position designated 10q26.The signs and symptoms of 10q26 deletion syndrome vary widely, even among affected members of the same family. Among the more common features associated with this chromosomal change are distinctive facial features, mild to moderate intellectual disability, growth problems, and developmental delay. People with 10q26 deletion syndrome often have delayed development of speech and of motor skills such as sitting, crawling, and walking. Some have limited speech throughout life. Affected individuals may experience seizures, attention-deficit/hyperactivity disorder (ADHD), poor impulse control (impulsivity), or exhibit autistic behaviors that affect communication and social interaction.A range of facial features is seen in people with 10q26 deletion syndrome, but not all affected individuals have these features. Facial features of people with 10q26 deletion syndrome may include a prominent or beaked nose, a broad nasal bridge, a small jaw (micrognathia), malformed ears that are low set, a thin upper lip, and an unusually small head size (microcephaly). Many affected individuals have widely spaced eyes (hypertelorism) that do not look in the same direction (strabismus). Some people with this condition have a short neck with extra folds of skin (webbed neck).Less common signs and symptoms can occur in 10q26 deletion syndrome. Skeletal problems include a spine that curves to the side (scoliosis), limited movement in the elbows or other joints, or curved fifth fingers and toes (clinodactyly). Slow growth before and after birth can also occur in affected individuals. Males with this condition may have genital abnormalities, such as a small penis (micropenis), undescended testes (cryptorchidism), or the urethra opening on the underside of the penis (hypospadias). Some people with 10q26 deletion syndrome have kidney abnormalities, heart defects, breathing problems, recurrent infections, or hearing or vision problems.
3q29 microdeletion syndrome
MedGen UID:
393265
Concept ID:
C2674949
Disease or Syndrome
3q29 recurrent deletion is characterized by global developmental delay and/or intellectual disability, and commonly, speech delay, and increased risk for neuropsychiatric disorders (including autism spectrum disorder, anxiety disorder, psychosis, and/or schizophrenia). Other common findings are failure to thrive and feeding problems in infancy that persist into childhood, heart defects (especially patent ductus arteriosus), gastrointestinal disorders (including gastroesophageal reflux disease), and dental abnormalities. To date findings in fewer than 50 affected individuals have been reported.
Arginine:glycine amidinotransferase deficiency
MedGen UID:
436367
Concept ID:
C2675179
Disease or Syndrome
The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CRTR) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; about 40% have movement disorder. Onset is between ages three months and three years. Only 14 individuals with AGAT deficiency have been reported. The phenotype of CRTR deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical phenotype of females heterozygous for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype.
Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis
MedGen UID:
436369
Concept ID:
C2675184
Disease or Syndrome
22q11.2 duplication syndrome
MedGen UID:
436417
Concept ID:
C2675369
Disease or Syndrome
22q11.2 duplication is defined for this GeneReview as the presence of a common 3-Mb or 1.5-Mb proximal tandem duplication. The 22q11.2 duplication phenotype appears to be generally mild and highly variable; findings range from apparently normal to intellectual disability / learning disability, delayed psychomotor development, growth retardation, and/or hypotonia. The high frequency with which the 22q11.2 duplication is found in an apparently normal parent of a proband suggests that many individuals can harbor a duplication of 22q11.2 with no discernible phenotypic effect.
Chromosome 15q26-qter deletion syndrome
MedGen UID:
390804
Concept ID:
C2675463
Disease or Syndrome
Mental retardation, autosomal dominant 5
MedGen UID:
382611
Concept ID:
C2675473
Disease or Syndrome
SYNGAP1-related intellectual disability (SYNGAP1-ID) is characterized by developmental delay (DD) or intellectual disability (ID) (100% of affected individuals), generalized epilepsy (~84%), and autism spectrum disorder (ASD) and other behavioral abnormalities (=50%). To date more than 50 individuals with SYNGAP1-ID have been reported. In the majority DD/ID was moderate to severe; in some it was mild. The epilepsy is generalized; a subset of individuals with epilepsy have myoclonic astatic epilepsy (Doose syndrome) or epilepsy with myoclonic absences. Behavioral abnormalities can include stereotypic behaviors (e.g., hand flapping, obsessions with certain objects) as well as poor social development. Feeding difficulties can be significant in some.
Chromosome 6pter-p24 deletion syndrome
MedGen UID:
393396
Concept ID:
C2675486
Disease or Syndrome
Severe congenital neutropenia 4, autosomal recessive
MedGen UID:
436454
Concept ID:
C2675526
Disease or Syndrome
G6PC3 deficiency is characterized by severe congenital neutropenia which occurs in a phenotypic continuum that includes the following: Isolated severe congenital neutropenia (nonsyndromic). Classic G6PC3 deficiency (severe congenital neutropenia plus cardiovascular and/or urogenital abnormalities). Severe G6PC3 deficiency (classic G6PC3 deficiency plus involvement of non-myeloid hematopoietic cell lines, additional extra-hematologic features, and pulmonary hypertension; known as Dursun syndrome). Neutropenia usually presents with recurrent bacterial infections in the first few months of life. Intrauterine growth restriction (IUGR), failure to thrive (FTT), and poor postnatal growth are common. Other findings in classic and severe G6PC3 deficiency can include inflammatory bowel disease (IBD) resembling Crohn's disease, and endocrine disorders (growth hormone deficiency, hypogonadotropic hypogonadism, and delayed puberty).
Chromosome 1q41-q42 deletion syndrome
MedGen UID:
382704
Concept ID:
C2675857
Disease or Syndrome
Nonsyndromic holoprosencephaly is an abnormality of brain development that also affects the head and face. Normally, the brain divides into two halves (hemispheres) during early development. Holoprosencephaly occurs when the brain fails to divide properly into the right and left hemispheres. This condition is called nonsyndromic to distinguish it from other types of holoprosencephaly caused by genetic syndromes, chromosome abnormalities, or substances that cause birth defects (teratogens). The severity of nonsyndromic holoprosencephaly varies widely among affected individuals, even within the same family.Nonsyndromic holoprosencephaly can be grouped into four types according to the degree of brain division. From most to least severe, the types are known as alobar, semi-lobar, lobar, and middle interhemispheric variant (MIHV). In the most severe forms of nonsyndromic holoprosencephaly, the brain does not divide at all. These affected individuals have one central eye (cyclopia) and a tubular nasal structure (proboscis) located above the eye. Most babies with severe nonsyndromic holoprosencephaly die before birth or soon after. In the less severe forms, the brain is partially divided and the eyes are usually set close together (hypotelorism). The life expectancy of these affected individuals varies depending on the severity of symptoms.People with nonsyndromic holoprosencephaly often have a small head (microcephaly), although they can develop a buildup of fluid in the brain (hydrocephalus) that causes increased head size (macrocephaly). Other features may include an opening in the roof of the mouth (cleft palate) with or without a split in the upper lip (cleft lip), one central front tooth instead of two (a single maxillary central incisor), and a flat nasal bridge. The eyeballs may be abnormally small (microphthalmia) or absent (anophthalmia).Some individuals with nonsyndromic holoprosencephaly have a distinctive pattern of facial features, including a narrowing of the head at the temples, outside corners of the eyes that point upward (upslanting palpebral fissures), large ears, a short nose with upturned nostrils, and a broad and deep space between the nose and mouth (philtrum). In general, the severity of facial features is directly related to the severity of the brain abnormalities. However, individuals with mildly affected facial features can have severe brain abnormalities. Some people do not have apparent structural brain abnormalities but have some of the facial features associated with this condition. These individuals are considered to have a form of the disorder known as microform holoprosencephaly and are typically identified after the birth of a severely affected family member.Most people with nonsyndromic holoprosencephaly have developmental delay and intellectual disability. Affected individuals also frequently have a malfunctioning pituitary gland, which is a gland located at the base of the brain that produces several hormones. Because pituitary dysfunction leads to the partial or complete absence of these hormones, it can cause a variety of disorders. Most commonly, people with nonsyndromic holoprosencephaly and pituitary dysfunction develop diabetes insipidus, a condition that disrupts the balance between fluid intake and urine excretion. Dysfunction in other parts of the brain can cause seizures, feeding difficulties, and problems regulating body temperature, heart rate, and breathing. The sense of smell may be diminished (hyposmia) or completely absent (anosmia) if the part of the brain that processes smells is underdeveloped or missing.
Diamond-Blackfan anemia 5
MedGen UID:
382705
Concept ID:
C2675859
Disease or Syndrome
Diamond-Blackfan anemia (DBA) in its classic form is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50% of affected individuals, and growth retardation in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia, no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.
2p15-16.1 microdeletion syndrome
MedGen UID:
390902
Concept ID:
C2675875
Disease or Syndrome
Chromosome 2p16.1-p15 deletion syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and variable but distinctive dysmorphic features, including microcephaly, bitemporal narrowing, smooth and long philtrum, hypertelorism, downslanting palpebral fissures, broad nasal root, thin upper lip, and high palate. Many patients have behavioral disorders, including autistic features, as well as structural brain abnormalities, such as pachygyria or hypoplastic corpus callosum. Those with deletions including the BCL11A gene (606557) also have persistence of fetal hemoglobin (HbF), which is asymptomatic and does not affected hematologic parameters or susceptibility to infection (summary by Funnell et al., 2015). Point mutation in the BCL11A gene causes intellectual developmental disorder with persistence of fetal hemoglobin (617101), which shows overlapping features. See also fetal hemoglobin quantitative trait locus-5 (HBFQTL5; 142335).
Hypomyelinating leukodystrophy 7
MedGen UID:
390993
Concept ID:
C2676243
Disease or Syndrome
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.
Bone fragility with contractures, arterial rupture, and deafness
MedGen UID:
382811
Concept ID:
C2676285
Disease or Syndrome
Chromosome 2q32-q33 deletion syndrome
MedGen UID:
436765
Concept ID:
C2676739
Disease or Syndrome
SATB2-associated syndrome (SAS) is a multisystem disorder characterized by significant neurodevelopmental compromise with limited to absent speech, behavioral issues, and craniofacial anomalies. All individuals described to date have manifest developmental delay / intellectual disability, with severe speech delay. Affected individuals often have hypotonia and feeding difficulties in infancy. Behavioral issues may include autistic features, hyperactivity, and aggressiveness. Craniofacial anomalies may include palatal abnormalities (cleft palate, high-arched palate, and bifid uvula), micrognathia, and abnormal shape or size of the upper central incisors. Less common features include skeletal anomalies (osteopenia, pectus deformities, kyphosis/lordosis, and scoliosis), growth restriction, strabismus/refractive errors, congenital heart defects, genitourinary anomalies, and epilepsy. While dysmorphic features have been described in individuals with this condition, these features are not typically distinctive enough to allow for a clinical diagnosis of SAS.
Thrombophilia, hereditary, due to protein C deficiency, autosomal recessive
MedGen UID:
394120
Concept ID:
C2676759
Disease or Syndrome
Autosomal recessive protein C deficiency resulting from homozygous or compound heterozygous PROC mutations is a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia (Millar et al., 2000).
Osteopetrosis autosomal recessive 7
MedGen UID:
436770
Concept ID:
C2676766
Disease or Syndrome
Osteopetrosis is a bone disease that makes bones abnormally dense and prone to breakage (fracture). Researchers have described several major types of osteopetrosis, which are usually distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked. The different types of the disorder can also be distinguished by the severity of their signs and symptoms.Autosomal dominant osteopetrosis (ADO), which is also called Albers-Schönberg disease, is typically the mildest type of the disorder. Some affected individuals have no symptoms. In these people, the unusually dense bones may be discovered by accident when an x-ray is done for another reason. In affected individuals who develop signs and symptoms, the major features of the condition include multiple bone fractures, abnormal side-to-side curvature of the spine (scoliosis) or other spinal abnormalities, arthritis in the hips, and a bone infection called osteomyelitis. These problems usually become apparent in late childhood or adolescence.Autosomal recessive osteopetrosis (ARO) is a more severe form of the disorder that becomes apparent in early infancy. Affected individuals have a high risk of bone fracture resulting from seemingly minor bumps and falls. Their abnormally dense skull bones pinch nerves in the head and face (cranial nerves), often resulting in vision loss, hearing loss, and paralysis of facial muscles. Dense bones can also impair the function of bone marrow, preventing it from producing new blood cells and immune system cells. As a result, people with severe osteopetrosis are at risk of abnormal bleeding, a shortage of red blood cells (anemia), and recurrent infections. In the most severe cases, these bone marrow abnormalities can be life-threatening in infancy or early childhood.Other features of autosomal recessive osteopetrosis can include slow growth and short stature, dental abnormalities, and an enlarged liver and spleen (hepatosplenomegaly). Depending on the genetic changes involved, people with severe osteopetrosis can also have brain abnormalities, intellectual disability, or recurrent seizures (epilepsy).A few individuals have been diagnosed with intermediate autosomal osteopetrosis (IAO), a form of the disorder that can have either an autosomal dominant or an autosomal recessive pattern of inheritance. The signs and symptoms of this condition become noticeable in childhood and include an increased risk of bone fracture and anemia. People with this form of the disorder typically do not have life-threatening bone marrow abnormalities. However, some affected individuals have had abnormal calcium deposits (calcifications) in the brain, intellectual disability, and a form of kidney disease called renal tubular acidosis.Rarely, osteopetrosis can have an X-linked pattern of inheritance. In addition to abnormally dense bones, the X-linked form of the disorder is characterized by abnormal swelling caused by a buildup of fluid (lymphedema) and a condition called anhydrotic ectodermal dysplasia that affects the skin, hair, teeth, and sweat glands. Affected individuals also have a malfunctioning immune system (immunodeficiency), which allows severe, recurrent infections to develop. Researchers often refer to this condition as OL-EDA-ID, an acronym derived from each of the major features of the disorder.
Joubert syndrome 8
MedGen UID:
436772
Concept ID:
C2676771
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Leukodystrophy, hypomyelinating, 4
MedGen UID:
383026
Concept ID:
C2677109
Disease or Syndrome
Coenzyme Q10 deficiency, primary, 4
MedGen UID:
436985
Concept ID:
C2677589
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Congenital disorder of glycosylation type 1N
MedGen UID:
383145
Concept ID:
C2677590
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006). For a discussion of the classification of CDGs, see CDG1A (212065).
Stevenson-Carey syndrome
MedGen UID:
383183
Concept ID:
C2677763
Disease or Syndrome
Camptodactyly syndrome Guadalajara type 3
MedGen UID:
394371
Concept ID:
C2677809
Disease or Syndrome
Mental retardation and microcephaly with pontine and cerebellar hypoplasia
MedGen UID:
437070
Concept ID:
C2677903
Disease or Syndrome
CASK-related disorders include a spectrum of phenotypes in both females and males. The two main types of clinical presentation are: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK; and X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate to severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. To date a total of 53 females with MICPCH have been reported, the eldest of whom is 21 years old. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures. Behaviors may include sleep disturbances, hand stereotypies, and self-biting. To date, only seven males have been reported with the severe phenotype. The under-representation in this cohort is likely to be a consequence of early male lethality. These males typically present with intellectual disability and MICPCH, or early-infantile epileptic encephalopathy (Ohtahara syndrome, West syndrome, or early myoclonic epilepsy). In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of X-linked intellectual disability (XLID) with or without nystagmus and additional clinical features. More than 24 males and nine females have been reported. The males have mild to severe intellectual disability, with or without nystagmus and other ocular features. Females are typically normal, with some displaying mild intellectual disability with or without ocular features.
Craniofacioskeletal syndrome
MedGen UID:
394716
Concept ID:
C2678036
Disease or Syndrome
Christianson syndrome
MedGen UID:
394455
Concept ID:
C2678194
Disease or Syndrome
Christianson syndrome (referred to as CS in this GeneReview), an X-linked disorder, is characterized in males by cognitive dysfunction, behavioral disorder, and neurologic findings (e.g., seizures, ataxia, postnatal microcephaly, and eye movement abnormalities). Males with CS typically present with developmental delay, later meeting criteria for severe intellectual disability (ID). Behaviorally, autism spectrum disorder and hyperactivity are common, and may resemble the behaviors observed in Angelman syndrome. Hypotonia and oropharyngeal dysphagia in infancy may result in failure to thrive. Seizures, typically beginning before age three years, can include infantile spasms and tonic, tonic-clonic, myoclonic, and atonic seizures. Subsequently, regression (e.g., loss of ambulation and ability to feed independently) may occur. Manifestations in heterozygous females range from asymptomatic to mild ID and/or behavioral issues.
Mental retardation with panhypopituitarism, X-linked
MedGen UID:
394771
Concept ID:
C2678223
Disease or Syndrome
Chromosome 22q11.2 deletion syndrome, distal
MedGen UID:
395634
Concept ID:
C2678480
Disease or Syndrome
Temple-Baraitser syndrome
MedGen UID:
395636
Concept ID:
C2678486
Disease or Syndrome
Temple-Baraitser syndrome is a rare developmental disorder characterized by severe mental retardation and anomalies of the first ray of the upper and lower limbs with absence/hypoplasia of the nails. Most patients also have seizures; various dysmorphic facial features have been reported (summary by Jacquinet et al., 2010).
Waardenburg syndrome type 2E
MedGen UID:
398476
Concept ID:
C2700405
Disease or Syndrome
Waardenburg syndrome type 2 is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and the absence of 'dystopia canthorum,' the lateral displacement of the inner canthus of each eye, which is seen in some other forms of WS (review by Read and Newton, 1997). Individuals with WS type 2E, which is caused by mutation in the SOX10 gene (602229), may have neurologic abnormalities, including mental impairment, myelination defects, and ataxia. Waardenburg syndrome type 2 is genetically heterogeneous (see WS2A; 193510). For a description of other clinical variants of Waardenburg syndrome, see WS1 (193500), WS3 (148820), and WS4 (277580).
Orofaciodigital syndrome 6
MedGen UID:
411200
Concept ID:
C2745997
Disease or Syndrome
Orofaciodigital syndrome type VI (OFD6), or Varadi syndrome, is a rare autosomal recessive disorder distinguished from other orofaciodigital syndromes by metacarpal abnormalities with central polydactyly and by cerebellar abnormalities, including the molar tooth sign (summary by Doss et al., 1998 and Lopez et al., 2014).
Combined d-2- and l-2-hydroxyglutaric aciduria
MedGen UID:
412535
Concept ID:
C2746066
Disease or Syndrome
Combined D-2- and L-2-hydroxyglutaric aciduria (D-2-HG and L-2-HG) is an autosomal recessive neurometabolic disorder characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death. Brain imaging shows abnormalities including enlarged ventricles, delayed myelination, and germinal layer cysts (summary by Muntau et al., 2000). See also isolated L-2-hydroxyglutaric aciduria (236792) and isolated D-2-hydroxyglutaric aciduria (see 600721).
SeSAME syndrome
MedGen UID:
411243
Concept ID:
C2748572
Disease or Syndrome
Syndrome with characteristics of seizures, sensorineural deafness, ataxia, intellectual deficit, and electrolyte imbalance. It has been described in five patients from four families. The disease is caused by homozygous or compound heterozygous mutations in the KCNJ10 gene, encoding a potassium channel expressed in the brain, spinal cord, inner ear and kidneys. Transmission is autosomal recessive.
Fibrosis of extraocular muscles, congenital, 3a, with or without extraocular involvement
MedGen UID:
412638
Concept ID:
C2748801
Disease or Syndrome
Congenital fibrosis of the extraocular muscles (CFEOM) refers to at least eight genetically defined strabismus syndromes (CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, Tukel syndrome, and CFEOM3 with polymicrogyria) characterized by congenital non-progressive ophthalmoplegia (inability to move the eyes) with or without ptosis (droopy eyelids) affecting part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique). In general, affected individuals have severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze. Individuals with CFEOM frequently compensate for the ophthalmoplegia by maintaining abnormal head positions at rest and by moving their heads rather than their eyes to track objects. Individuals with CFEOM3A may also have intellectual disability, social disability, Kallmann syndrome, facial weakness, and vocal cord paralysis; and/or may develop a progressive sensorimotor axonal polyneuropathy. Individuals with Tukel syndrome also have postaxial oligodactyly or oligosyndactyly of the hands. Those with CFEOM3 with polymicrogyria also have microcephaly and intellectual disability.
Joubert syndrome 10
MedGen UID:
440688
Concept ID:
C2749019
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Aicardi Goutieres syndrome 5
MedGen UID:
413116
Concept ID:
C2749659
Disease or Syndrome
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Chromosome 3q29 microduplication syndrome
MedGen UID:
440897
Concept ID:
C2749873
Disease or Syndrome
3q29 microduplication syndrome (also known as 3q29 duplication syndrome) is a condition that results from the copying (duplication) of a small piece of chromosome 3 in each cell. The duplication occurs on the long (q) arm of the chromosome at a position designated q29.The features associated with 3q29 microduplication syndrome vary widely. Some individuals with this chromosomal change have very mild or no related signs and symptoms, and the duplication is discovered because they undergo genetic testing only after a family member is diagnosed. Other people with a 3q29 microduplication have delayed development (particularly speech delay) and intellectual disability or learning difficulties. Although most affected individuals have no major birth defects, eye abnormalities, heart defects, and an unusually small head (microcephaly) can occur. 3q29 microduplication syndrome may increase the likelihood of being overweight or obese, although it is hard to determine whether these weight issues are caused by the duplication.
Roifman-Chitayat syndrome
MedGen UID:
442377
Concept ID:
C2750068
Disease or Syndrome
An extremely rare combined immunodeficiency disorder characterised by primary immunodeficiency manifesting with repeated bacterial, viral and fungal infections, in association with neurological manifestations (hypotonia, cerebellar ataxia, myoclonic seizures), developmental delay, optic atrophy, facial dysmorphism (high forehead, hypoplastic supraorbital ridges, palpebral oedema, hypertelorism, flat nasal bridge, broad nasal root and tip, anteverted nares, thin lower lip overlapped by upper lip, square chin) and skeletal anomalies (short metacarpals/metatarsals with cone-shaped epiphyses, osteopenia).
Spondylometaphyseal dysplasia, megarbane-dagher-melki type
MedGen UID:
413221
Concept ID:
C2750075
Disease or Syndrome
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 2
MedGen UID:
412914
Concept ID:
C2750234
Disease or Syndrome
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ) is a genetically heterogeneous disorder characterized by congenital cerebellar ataxia and mental retardation (summary by Gulsuner et al., 2011). For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).
Pitt-Hopkins-like syndrome 1
MedGen UID:
413258
Concept ID:
C2750246
Disease or Syndrome
PTHSL1 is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioral abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging (summary by Smogavec et al., 2016).
Noonan syndrome 6
MedGen UID:
413028
Concept ID:
C2750732
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Polymicrogyria with optic nerve hypoplasia
MedGen UID:
442565
Concept ID:
C2750798
Disease or Syndrome
The tubulinopathies are a wide and overlapping range of brain malformations caused by mutation of one of seven genes encoding different isotypes of tubulin. Brain malformations include: A range of lissencephalies (classic lissencephaly, lissencephaly with cerebellar hypoplasia, lissencephaly with agenesis of the corpus callosum, and centrally predominant pachygyria), Polymicrogyria-like cortical dysplasia, Simplified gyral pattern, and Microlissencephaly often in combination with dysplastic basal ganglia, corpus callosum abnormalities, and hypoplasia or dysplasia of the brain stem and cerebellum. Clinical features include motor and intellectual disabilities, epilepsy, and ocular findings of varying severity.
Chromosome 5p13 duplication syndrome
MedGen UID:
416385
Concept ID:
C2750805
Disease or Syndrome
Myopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delay
MedGen UID:
416525
Concept ID:
C2751320
Disease or Syndrome
Hypomyelination, global cerebral
MedGen UID:
414492
Concept ID:
C2751855
Disease or Syndrome
Stargardt macular degeneration absent or hypoplastic corpus callosum mental retardation and dysmorphic features
MedGen UID:
414494
Concept ID:
C2751864
Disease or Syndrome
Microcephaly, growth retardation, cataract, hearing loss, and unusual appearance
MedGen UID:
416652
Concept ID:
C2751870
Disease or Syndrome
Hadziselimovic syndrome
MedGen UID:
414129
Concept ID:
C2751878
Disease or Syndrome
A rare syndrome with characteristics of onset growth retardation (low birth weight and short stature), hypotonia, developmental delay and intellectual disability associated with microcephaly and craniofacial (low anterior hairline, hypotelorism, thick lips with carp-shaped mouth, high-arched palate, low-set ears), cardiac (conotruncal heart malformations such as tetralogy of Fallot and skeletal (hypoplastic thumbs and first metacarpals) abnormalities.
Cerebral palsy, spastic quadriplegic, 1
MedGen UID:
442852
Concept ID:
C2751938
Disease or Syndrome
Cerebral palsy (CP) is defined as a nonprogressive but not unchanging disorder of posture or movement, caused by an abnormality of the brain and first evident at the stage of rapid brain development (Hughes and Newton, 1992). The most common forms result from factors surrounding difficulties before or at birth, such as severe perinatal asphyxia, congenital infection, prematurity, and multiple pregnancy (Blair and Stanley, 1988; Stanley, 1994). More rarely, familial clustering or absence of pre- or postpartum events indicate that there are genetic forms of the disorder (Lynex et al., 2004). Cerebral palsy can be classified according to the type of movement disorder: spastic cerebral palsy accounts for approximately 60% of cases and can be subdivided into hemiplegic, diplegic, quadriplegic, and monoplegic types, whereas other forms include athetoid/dyskinetic, ataxic (605388), and mixed (Gustavson et al., 1969). Genetic Heterogeneity of Spastic Quadriplegic Cerebral Palsy See also CPSQ2 (612900), caused by deletion of the ANKRD15 gene (KANK1; 607704) inherited on the paternal allele, and CPSQ3 (617008), caused by mutation in the ADD3 gene (601568) on 10q24. Related phenotypes that were formerly classified in the CPSQ series include spastic paraplegia-47 (SPG47; 614066), spastic paraplegia-50 (SPG50; 612936), spastic paraplegia-51 (SPG51; 613744), and spastic paraplegia-52 (614067).
Autosomal recessive cutis laxa type 2B
MedGen UID:
414526
Concept ID:
C2751987
Disease or Syndrome
The phenotype of autosomal recessive cutis laxa type II (ARCL2) includes cutis laxa of variable severity, abnormal growth, developmental delay, and associated skeletal abnormalities (summary by Morava et al., 2009). No specific clinical features distinguish ARCL2A (219200), which includes a glycosylation defect, and ARCL2B, in which abnormal glycosylation has not been reported (Morava et al., 2009; Guernsey et al., 2009). For a phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).
Growth retardation, developmental delay, coarse facies, and early death
MedGen UID:
414158
Concept ID:
C2752001
Congenital Abnormality
Growth retardation, developmental delay, and facial dysmorphism (GDFD) is an autosomal recessive multiple congenital anomaly syndrome characterized by severe psychomotor retardation, poor overall growth, and dysmorphic facial features. Additional features may include cardiac malformations and deafness (summary by Daoud et al., 2016).
Spastic paraplegia 50, autosomal recessive
MedGen UID:
442869
Concept ID:
C2752008
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become non-ambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Ring chromosome 14
MedGen UID:
419284
Concept ID:
C2930916
Cell or Molecular Dysfunction
Ring chromosome 14 syndrome is a condition characterized by seizures and intellectual disability. Recurrent seizures (epilepsy) develop in infancy or early childhood. In many cases, the seizures are resistant to treatment with anti-epileptic drugs. Most people with ring chromosome 14 syndrome also have some degree of intellectual disability or learning problems. Development may be delayed, particularly the development of speech and of motor skills such as sitting, standing, and walking.Additional features of ring chromosome 14 syndrome can include slow growth and short stature, a small head (microcephaly), puffy hands and/or feet caused by a buildup of fluid (lymphedema), and subtle differences in facial features. Some affected individuals have problems with their immune system that lead to recurrent infections, especially involving the respiratory system. Abnormalities of the retina, the specialized tissue at the back of the eye that detects light and color, have also been reported in some people with this condition. These changes typically do not affect vision. Major birth defects are rarely seen with ring chromosome 14 syndrome.
Congenital disorder of glycosylation type 1C
MedGen UID:
443952
Concept ID:
C2930997
Disease or Syndrome
Congenital disorders of glycosylation, previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are caused by defects in mannose addition during N-linked oligosaccharide assembly. CDGs can be divided into 2 types, depending on whether they impair lipid-linked oligosaccharide (LLO) assembly and transfer (CDG I), or affect trimming of the protein-bound oligosaccharide or the addition of sugars to it (CDG II) (Orlean, 2000). CDG Ic is characterized by psychomotor retardation with delayed walking and speech, hypotonia, seizures, and sometimes protein-losing enteropathy. It is the second largest subtype of CDG (summary by Sun et al., 2005). For a discussion of the classification of CDGs, see CDG1A (212065). Freeze and Aebi (1999) reviewed CDG Ib (602579) and CDG Ic.
ALG12-congenital disorder of glycosylation
MedGen UID:
443954
Concept ID:
C2931001
Disease or Syndrome
Congenital disorders of glycosylation (CDG), previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are a group of hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans. For a general discussion of CDGs, see CDG1A (212065) and CDG1B (602579).
Congenital disorder of glycosylation type 1J
MedGen UID:
419694
Concept ID:
C2931004
Disease or Syndrome
Like all CDGs, which are caused by a shortage of precursor monosaccharide phosphate or deficiencies in the glycosyltransferases required for lipid-linked oligosaccharide precursor (LLO) synthesis, CDG Ij is caused by a defect in the formation of DPAGT1, the first dolichyl-linked intermediate of the protein N-glycosylation pathway. For a general discussion of CDGs, see CDG1A (212065).
Congenital disorder of glycosylation type 1K
MedGen UID:
419308
Concept ID:
C2931005
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) comprise a group of multisystem diseases with mostly severe psychomotor and mental retardation. Type I CDG comprises those disorders in which there are defects that affect biosynthesis of dolichol-linked oligosaccharides in the cytosol or the endoplasmic reticulum (ER), as well as defects involving the transfer of oligosaccharides onto nascent glycoproteins. Type II CDG comprises all defects of further trimming and elongation of N-linked oligosaccharides in the ER and Golgi (Schwarz et al., 2004). CDG1K is a type I CDG characterized by predominant neurologic involvement. Survival ranges from the second day of life to adulthood. The liver is affected in a minority of patients and shows hepatomegaly, edema, ascites, cholestatic jaundice, portal hypertension, and Budd-Chiari syndrome (summary by Marques-da-Silva et al., 2017). For a general discussion of CDGs, see CDG1A (212065).
ALG9 congenital disorder of glycosylation
MedGen UID:
443955
Concept ID:
C2931006
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) that represent defects of dolichol-linked oligosaccharide assembly are classified as CDG type I. For a general description and a discussion of the classification of CDGs, see CDG1A (212065).
Congenital disorder of glycosylation type 2D
MedGen UID:
419310
Concept ID:
C2931009
Disease or Syndrome
Congenital disorders of glycosylation (CDG) are a group of hereditary multisystem disorders that are commonly associated with severe psychomotor and mental retardation. The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type I CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type II CDG comprises defects of trimming, elongation, and processing of protein-bound glycans (summary by Hansske et al., 2002). For a general discussion of CDGs, see CDG1A (212065).
Puerto rican infant hypotonia syndrome
MedGen UID:
443987
Concept ID:
C2931142
Disease or Syndrome
This syndrome is characterised principally by non-progressive central hypotonia, chronic constipation, severe psychomotor retardation, abnormal dermatoglyphics, dysharmonic skeletal maturation and disproportionate muscle fibres. Seizures or an abnormal electroencephalograph were also reported. To date, the syndrome has been reported in three unrelated Puerto Rican boys.
Myopathy, autophagic vacuolar, infantile-onset
MedGen UID:
419364
Concept ID:
C2931230
Disease or Syndrome
Infantile-onset autophagic vacuolar myopathy is characterized by increased cardiac and skeletal muscle glycogen with normal acid maltase (GAA; 606800). Skeletal muscle biopsy shows characteristic intracytoplasmic vacuoles that stain for sarcolemmal proteins and complement proteins. Similar pathologic findings are seen in Danon disease (300257), caused by mutation in the LAMP2 gene (309060) on chromosome Xq24, and X-linked myopathy with excessive autophagy (XMEA; 310440), which has been mapped to Xq28.
Chromosome 17, trisomy 17p11 2
MedGen UID:
444010
Concept ID:
C2931246
Disease or Syndrome
Potocki-Lupski syndrome (PTLS) is characterized by cognitive, behavioral, and medical manifestations. Cognitively, most individuals present with developmental delay, later meeting criteria for moderate intellectual disability. Behaviorally, issues with attention, hyperactivity, withdrawal, and anxiety may be seen. Some individuals meet criteria for autism spectrum disorder. Medically, hypotonia, oropharyngeal dysphagia leading to failure to thrive, congenital heart disease, hypoglycemia associated with growth hormone deficiency, and mildly dysmorphic facial features are observed. Medical manifestations typically lead to identification of PTLS in infancy; however, those with only behavioral and cognitive manifestations may be identified in later childhood.
Intrauterine growth retardation with increased mitomycin C sensitivity
MedGen UID:
419040
Concept ID:
C2931307
Disease or Syndrome
Chromosome 3pter-p25 deletion syndrome
MedGen UID:
419050
Concept ID:
C2931337
Cell or Molecular Dysfunction
Characteristic features of the distal 3p- syndrome include low birth weight, microcephaly, trigonocephaly, hypotonia, psychomotor and growth retardation, ptosis, telecanthus, downslanting palpebral fissures, and micrognathia. Postaxial polydactyly, renal anomalies, cleft palate, congenital heart defects (especially atrioventricular septal defects), preauricular pits, sacral dimple, and gastrointestinal anomalies are variable features. Although intellectual deficits are almost invariably associated with cytogenetically visible 3p deletions, rare patients with a 3p26-p25 deletion and normal intelligence or only mild abnormalities have been described (summary by Shuib et al., 2009).
Oculocerebral hypopigmentation syndrome of preus
MedGen UID:
419131
Concept ID:
C2931646
Disease or Syndrome
A rare congenital syndrome characterised by skin and hair hypopigmentation, growth retardation, and intellectual deficit that are associated with a combination of various additional clinical anomalies such as ocular albinism, cataract, delayed neuropsychomotor development, sensorineural hearing loss, dolicocephaly, high arched palate, widely spaced teeth, anaemia, and/or nystagmus.
Sulfite oxidase deficiency
MedGen UID:
419484
Concept ID:
C2931746
Disease or Syndrome
The spectrum of isolated sulfite oxidase deficiency ranges from classic early-onset (severe) disease to late-onset (mild) disease. Classic ISOD is characterized in the first few hours to days of life by intractable seizures, feeding difficulties, and rapidly progressive encephalopathy manifest as abnormal tone (especially opisthotonus, spastic quadriplegia, and pyramidal signs) followed by progressive microcephaly and profound intellectual disability. Lens subluxation or dislocation, another characteristic finding, may be evident after the newborn period. Children usually die during the first few months of life. Late-onset ISOD manifests between ages six and 18 months and is characterized by ectopia lentis (variably present), developmental delay/regression, movement disorder characterized by dystonia and choreoathetosis, ataxia, and (rarely) acute hemiplegia due to metabolic stroke. The clinical course may be progressive or episodic. In the episodic form encephalopathy, dystonia, choreoathetosis, and/or ataxia are intermittent.
Hypertryptophanemia, familial
MedGen UID:
419177
Concept ID:
C2931837
Disease or Syndrome
Congenital hypertryptophanemia, which is accompanied by hyperserotonemia, does not appear to have significant clinical consequences (Ferreira et al., 2017).
Bardet-Biedl syndrome 1
MedGen UID:
422452
Concept ID:
C2936862
Disease or Syndrome
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Bardet-Biedl syndrome 2
MedGen UID:
422453
Concept ID:
C2936863
Disease or Syndrome
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Opitz-Frias syndrome
MedGen UID:
424842
Concept ID:
C2936904
Disease or Syndrome
X-linked Opitz G/BBB syndrome (X-OS) is a multiple-congenital-anomaly disorder characterized by facial anomalies (hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum), and laryngotracheoesophageal defects. Developmental delay and intellectual disability are observed in about 50% of affected males. Cleft lip and/or palate are present in approximately 50% of affected individuals. Other malformations (present in <50% of individuals) include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female heterozygotes usually manifest hypertelorism only.
Benign familial neonatal seizures 1
MedGen UID:
460425
Concept ID:
C3149074
Disease or Syndrome
KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes caused by a heterozygous pathogenic variant in KCNQ2. The clinical features of KCNQ2-related disorders range from KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) at the mild end to KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) at the severe end. KCNQ2-BFNE is characterized by a wide spectrum of seizure types (tonic or apneic episodes, focal clonic activity, or autonomic changes) that start in otherwise healthy infants between the second and eighth day of life and spontaneously disappear between the first and the sixth to 12th month of life. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are generally brief, lasting one to two minutes. Rarely, KCNQ2-BFNE may evolve into status epilepticus. About 10%-15% of individuals with BFNE develop epileptic seizures later in life. KCNQ2-NEE is characterized by multiple daily seizures beginning in the first week of life that are mostly tonic, with associated focal motor and autonomic features. Seizures generally cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI can show basal ganglia and thalamic hyperintensities that later resolve. Moderate to severe developmental impairment is present.
Chromosome 16p12.1 deletion syndrome, 520-kb
MedGen UID:
460626
Concept ID:
C3149276
Disease or Syndrome
16p12.2 recurrent deletion is characterized by variable clinical findings that do not constitute a recognizable syndrome. Of note, the significant bias in ascertainment of individuals undergoing clinical chromosomal microarray analysis (i.e., children with intellectual disability and developmental delay; individuals with schizophrenia) makes it difficult to accurately associate specific phenotypes with the 16p12.2 recurrent deletion. Findings commonly observed in children (probands) with this deletion include: developmental delay, cognitive impairment (ranging from mild to profound), growth impairment (including short stature), cardiac malformations, epilepsy, and psychiatric and/or behavioral problems. Other findings can include: hearing loss, dental abnormalities, renal and genital anomalies (the latter in males), and cleft palate ± cleft lip.
16p11.2 deletion syndrome
MedGen UID:
461504
Concept ID:
C3150154
Disease or Syndrome
The 16p11.2 recurrent microdeletion phenotype is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder (ASD). Developmental delays are related to diminished language, cognitive function, and motor impairments. While IQ scores range from mild intellectual disability to normal, those with IQ scores in the average range typically have other developmental issues such as language delay or ASD. Expressive language appears to be more affected than receptive language. Seizures are observed in approximately 20% of individuals with the recurrent microdeletion. Macrocephaly is common, usually becoming apparent by age two years. Chiari malformations/cerebellar ectopia are the most frequently observed structural brain abnormalities. In individuals with the 16p11.2 recurrent microdeletion the frequency of birth defects of all types is slightly increased, with vertebral anomalies appearing to be most frequent.
Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B1
MedGen UID:
461765
Concept ID:
C3150415
Disease or Syndrome
Congenital muscular dystrophies resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) are characterized by early onset of muscle weakness, usually before ambulation is achieved; mental retardation and mild brain anomalies are variable (Balci et al., 2005; Godfrey et al., 2007). Congenital muscular dystrophy-dystroglycanopathies with or without mental retardation (type B) represent the intermediate range of the spectrum of dystroglycanopathies. They are less severe than muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A; see MDDGA1, 236670), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), and more severe than limb-girdle muscular dystrophy-dystroglycanopathy (type C; see MDDGC1, 609308). Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with or without Mental Retardation (Type B) Congenital muscular dystrophy with mental retardation due to defective glycosylation of DAG1 is genetically heterogeneous. See also MDDGB2 (613156), caused by mutation in the POMT2 gene (607439); MDDGB3 (613151), caused by mutation in the POMGNT1 gene (606822); MDDGB4 (613152), caused by mutation in the FKTN gene (607440); MDDGB5 (616612), caused by mutation in the FKRP gene (606596); MDDGB6 (608840), caused by mutation in the LARGE gene (603590); and MDDGB14 (615351), caused by mutation in the GMPPB gene (615320).
Chromosome 17q23.1-q23.2 deletion syndrome
MedGen UID:
461957
Concept ID:
C3150607
Disease or Syndrome
Autoimmune disease, syndromic multisystem
MedGen UID:
461999
Concept ID:
C3150649
Disease or Syndrome
Warsaw breakage syndrome
MedGen UID:
462008
Concept ID:
C3150658
Disease or Syndrome
Warsaw syndrome is characterized by the clinical triad of severe congenital microcephaly, growth restriction, and sensorineural hearing loss due to cochlear hypoplasia. Intellectual disability is typically in the mild-to-moderate range. Severe speech delay is common. Gross and fine motor milestones are usually attained at the usual time, although a few individuals have mild delays. Additional common features include skeletal anomalies and cardiovascular anomalies. Abnormal skin pigmentation and genitourinary malformations have also been reported. Some individuals have had increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane and mitomycin C.
Arthrogryposis, renal dysfunction, and cholestasis 2
MedGen UID:
462022
Concept ID:
C3150672
Disease or Syndrome
Chromosome 14q11-q22 deletion syndrome
MedGen UID:
462057
Concept ID:
C3150707
Disease or Syndrome
Chromosome 16p13.3 duplication syndrome
MedGen UID:
462058
Concept ID:
C3150708
Disease or Syndrome
Chromosome 4q21 deletion syndrome
MedGen UID:
462106
Concept ID:
C3150756
Disease or Syndrome
Chromosome 6q11-q14 deletion syndrome
MedGen UID:
462140
Concept ID:
C3150790
Disease or Syndrome
The cardinal features of chromosome 6q11-q14 interstitial deletions include hypotonia, short stature, skeletal/limb anomalies, umbilical hernia, and urinary tract anomalies, as well as characteristic facial features including upslanting palpebral fissures, low-set and/or dysplastic ears, and high-arched palate (summary by Wang et al., 2009).
Nephronophthisis 11
MedGen UID:
462146
Concept ID:
C3150796
Disease or Syndrome
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recognized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype, inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Combined oxidative phosphorylation deficiency 7
MedGen UID:
462151
Concept ID:
C3150801
Disease or Syndrome
Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia
MedGen UID:
462153
Concept ID:
C3150803
Disease or Syndrome
Noonan syndrome-like disorder is a developmental disorder resembling Noonan syndrome (NS1; 163950) and characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. There is extensive phenotypic heterogeneity and variable expressivity (summary by Martinelli et al., 2010). Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; 607785), as also seen in patients with Noonan syndrome (summary by Niemeyer et al., 2010).
Chromosome 4q32.1-q32.2 triplication syndrome
MedGen UID:
462207
Concept ID:
C3150857
Disease or Syndrome
Chromosome 16p12.2-p11.2 deletion syndrome, 7.1- to 8.7-MB
MedGen UID:
462208
Concept ID:
C3150858
Disease or Syndrome
The chromosome 16p12.2-p11.2 deletion syndrome is characterized phenotypically by dysmorphic facial features, feeding difficulties, recurrent ear infections, developmental delay, and cognitive impairment. Additional features, such as heart defects and short stature, are variable (Ballif et al., 2007; Battaglia et al., 2009). The pericentric region of chromosome 16, specifically involving 16p12-p11, is a structurally complex region enriched in repetitive sequence elements, rendering this region susceptible to deletion or rearrangement (Ballif et al., 2007). There are several phenotypes associated with variation in this region: see 611913 for a deletion or duplication at 16p11.2 associated with autism; see 136570 for discussion of a recurrent 520-kb deletion at 16p12.1 associated with developmental delay and craniofacial dysmorphism; and see 613444 for a 220-kb deletion at 16p11.2 associated with isolated severe early-onset obesity and obesity with developmental delay. Battaglia et al. (2009) emphasized that the region at chromosome 16p11.2 that confers susceptibility to autism (AUTS14; see 611913) is located more centromeric to and is distinct from the 16p12.2-p11.2 region involved in the multiple congenital anomalies and intellectual disability phenotype.
Forsythe-wakeling syndrome
MedGen UID:
462209
Concept ID:
C3150859
Disease or Syndrome
Cranioectodermal dysplasia 2
MedGen UID:
462224
Concept ID:
C3150874
Disease or Syndrome
Cranioectodermal dysplasia (CED), a ciliopathy also known as Sensenbrenner syndrome, is a multisystem disorder with skeletal involvement (narrow thorax, shortened proximal limbs, and brachydactyly), ectodermal features (widely-spaced hypoplastic teeth, hypodontia, sparse hair, skin laxity, abnormal nails), joint laxity, growth retardation, and characteristic facial features (frontal bossing, low-set simple ears, high forehead, telecanthus/epicanthus, full cheeks, everted lower lip). Most affected children develop nephronophthisis that often leads to end-stage renal disease (ESRD) in infancy or childhood, a major cause of morbidity and mortality. Hepatic fibrosis and retinal dystrophy, other manifestations of ciliopathies, are also observed. Dolichocephaly, often secondary to sagittal craniosynostosis, is a primary manifestation that distinguishes CED from most other ciliopathies. Brain malformations and developmental delay may also occur.
Agenesis of the corpus callosum and congenital lymphedema
MedGen UID:
462237
Concept ID:
C3150887
Disease or Syndrome
Chromosome 19p13.13 deletion syndrome
MedGen UID:
462244
Concept ID:
C3150894
Disease or Syndrome
19p13.13 deletion syndrome is a condition that results from a chromosomal change in which a small piece of chromosome 19 is deleted in each cell. The deletion occurs on the short (p) arm of the chromosome at a position designated p13.13.Features commonly associated with this chromosomal change include an unusually large head size (macrocephaly), tall stature, and intellectual disability that is usually moderate in severity. Many affected individuals have significantly delayed development, including speech, and children may speak few or no words. Weak muscle tone (hypotonia) and problems with coordinating muscle movement (ataxia) contribute to delays in gross motor skills (such as sitting and walking) and fine motor skills (such as holding a pencil).Other signs and symptoms that can occur with 19p13.13 deletion syndrome include seizures, abnormalities of brain structure, and mild differences in facial features (such as a prominent forehead). Many affected individuals have problems with feeding and digestion, including constipation, diarrhea, vomiting, and abdominal pain. Eye problems that can impair vision are also common. These include eyes that do not point in the same direction (strabismus) and underdevelopment of the optic nerves, which carry visual information from the eyes to the brain.The signs and symptoms of 19p13.13 deletion syndrome vary among affected individuals. In part, this variation occurs because the size of the deletion, and the number of genes it affects, varies from person to person.
Charcot-Marie-Tooth disease, recessive intermediate B
MedGen UID:
462247
Concept ID:
C3150897
Disease or Syndrome
Spastic paraplegia 48, autosomal recessive
MedGen UID:
462251
Concept ID:
C3150901
Disease or Syndrome
Spastic paraplegia-48 is an autosomal recessive neurologic disorder characterized by spasticity of the lower limbs resulting in gait difficulties. Most patients have onset in mid- or late-adulthood, although childhood onset has been reported in 1 patient. Additional features may include parkinsonism, urinary incontinence, neuropathy, and mild cognitive impairment (summary by Hirst et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).
D-2-hydroxyglutaric aciduria 2
MedGen UID:
462259
Concept ID:
C3150909
Disease or Syndrome
2-hydroxyglutaric aciduria is a condition that causes progressive damage to the brain. The major types of this disorder are called D-2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA).The main features of D-2-HGA are delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain (the cerebrum), which controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory. Researchers have described two subtypes of D-2-HGA, type I and type II. The two subtypes are distinguished by their genetic cause and pattern of inheritance, although they also have some differences in signs and symptoms. Type II tends to begin earlier and often causes more severe health problems than type I. Type II may also be associated with a weakened and enlarged heart (cardiomyopathy), a feature that is typically not found with type I.L-2-HGA particularly affects a region of the brain called the cerebellum, which is involved in coordinating movements. As a result, many affected individuals have problems with balance and muscle coordination (ataxia). Additional features of L-2-HGA can include delayed development, seizures, speech difficulties, and an unusually large head (macrocephaly). Typically, signs and symptoms of this disorder begin during infancy or early childhood. The disorder worsens over time, usually leading to severe disability by early adulthood.Combined D,L-2-HGA causes severe brain abnormalities that become apparent in early infancy. Affected infants have severe seizures, weak muscle tone (hypotonia), and breathing and feeding problems. They usually survive only into infancy or early childhood.
Congenital disorder of glycosylation type 1P
MedGen UID:
462263
Concept ID:
C3150913
Disease or Syndrome
A form of congenital disorders of N-linked glycosylation with characteristics of facial dysmorphism (microcephaly, high forehead, low posterior hairline, strabismus), hypotonia, failure to thrive, intractable seizures, developmental delay, persistent vomiting and gastric bleeding. Additional features that may be observed include fat pads anomalies, inverted nipples, and body temperature oscillation. The disease is caused by mutations in the gene ALG11 (13q14.3).
Mitochondrial DNA depletion syndrome 4B, MNGIE type
MedGen UID:
462264
Concept ID:
C3150914
Disease or Syndrome
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
Mental retardation, anterior maxillary protrusion, and strabismus
MedGen UID:
462274
Concept ID:
C3150924
Disease or Syndrome
Chromosome 17q11.2 deletion syndrome, 1.4 MB
MedGen UID:
462278
Concept ID:
C3150928
Disease or Syndrome
Approximately 5 to 20% of all patients with neurofibromatosis type I (162200) carry a heterozygous deletion of approximately 1.4 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al., 2000; Jenne et al., 2001), which is caused by nonallelic homologous recombination of NF1 repeats A and C (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, an excessive number of early-onset neurofibromas (Venturin et al., 2004), and an increased risk for malignant peripheral nerve sheath tumors (De Raedt et al., 2003).
Beaulieu-Boycott-Innes syndrome
MedGen UID:
462289
Concept ID:
C3150939
Disease or Syndrome
Beaulieu-Boycott-Innes syndrome (BBIS) is an autosomal recessive neurodevelopmental disorder characterized by delayed development, moderate to severe intellectual disability, and dysmorphic facial features. Other developmental anomalies, such as cardiac and renal defects, cryptorchidism in males, submucous cleft palate, and corpus callosum dysgenesis, may also be present (summary by Beaulieu et al., 2013 and Amos et al., 2017).
Rubinstein-Taybi syndrome 2
MedGen UID:
462291
Concept ID:
C3150941
Disease or Syndrome
Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic craniofacial features are downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect. Additional features include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryptorchidism, feeding problems, recurrent infections, and severe constipation.
Early infantile epileptic encephalopathy 7
MedGen UID:
462336
Concept ID:
C3150986
Disease or Syndrome
KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes caused by a heterozygous pathogenic variant in KCNQ2. The clinical features of KCNQ2-related disorders range from KCNQ2-related benign familial neonatal epilepsy (KCNQ2-BFNE) at the mild end to KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-NEE) at the severe end. KCNQ2-BFNE is characterized by a wide spectrum of seizure types (tonic or apneic episodes, focal clonic activity, or autonomic changes) that start in otherwise healthy infants between the second and eighth day of life and spontaneously disappear between the first and the sixth to 12th month of life. Motor activity may be confined to one body part, migrate to other body regions, or generalize. Seizures are generally brief, lasting one to two minutes. Rarely, KCNQ2-BFNE may evolve into status epilepticus. About 10%-15% of individuals with BFNE develop epileptic seizures later in life. KCNQ2-NEE is characterized by multiple daily seizures beginning in the first week of life that are mostly tonic, with associated focal motor and autonomic features. Seizures generally cease between ages nine months and four years. At onset, EEG shows a burst-suppression pattern or multifocal epileptiform activity; early brain MRI can show basal ganglia and thalamic hyperintensities that later resolve. Moderate to severe developmental impairment is present.
Early infantile epileptic encephalopathy 11
MedGen UID:
462337
Concept ID:
C3150987
Disease or Syndrome
Early infantile epileptic encephalopathy-11 is an autosomal dominant seizure disorder characterized by infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities (Ogiwara et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Spastic paraplegia 51, autosomal recessive
MedGen UID:
462406
Concept ID:
C3151056
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become non-ambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Hypermethioninemia with s-adenosylhomocysteine hydrolase deficiency
MedGen UID:
462408
Concept ID:
C3151058
Disease or Syndrome
Hypermethioninemia is an excess of a particular protein building block (amino acid), called methionine, in the blood. This condition can occur when methionine is not broken down (metabolized) properly in the body.People with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit intellectual disability and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage.Hypermethioninemia can occur with other metabolic disorders, such as homocystinuria, tyrosinemia and galactosemia, which also involve the faulty breakdown of particular molecules. It can also result from liver disease or excessive dietary intake of methionine from consuming large amounts of protein or a methionine-enriched infant formula.
Chromosome 17p13.1 deletion syndrome
MedGen UID:
462419
Concept ID:
C3151069
Disease or Syndrome
Pontocerebellar hypoplasia type 2D
MedGen UID:
462490
Concept ID:
C3151140
Disease or Syndrome
PCH2D is an autosomal recessive disorder characterized by progressive microcephaly, postnatal onset of progressive atrophy of the cerebrum and cerebellum, profound mental retardation, spasticity, and variable seizures (summary by Ben-Zeev et al., 2003). For a general phenotypic description and a discussion of genetic heterogeneity of pontocerebellar hypoplasia type 2, see PCH2A (277470).
Limb-girdle muscular dystrophy-dystroglycanopathy, type C9
MedGen UID:
462534
Concept ID:
C3151184
Disease or Syndrome
MDDGC9 is an autosomal recessive muscular dystrophy showing onset in early childhood. It is part of a group of similar disorders resulting from defective glycosylation of DAG1, collectively known as 'dystroglycanopathies' (summary by Hara et al., 2011). For a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type C, see MDDGC1 (609308).
Megaloblastic anemia due to dihydrofolate reductase deficiency
MedGen UID:
462555
Concept ID:
C3151205
Disease or Syndrome
Dihydrofolate reductase deficiency is an autosomal recessive metabolic disorder characterized by the hematologic findings of megaloblastic anemia and variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy (Banka et al., 2011) to childhood absence epilepsy with learning difficulties to lack of symptoms (Cario et al., 2011). Treatment with folinic acid can ameliorate some of the symptoms.
Mental retardation, autosomal dominant 6
MedGen UID:
462761
Concept ID:
C3151411
Mental or Behavioral Dysfunction
GRIN2B-related neurodevelopmental disorder is characterized by mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties), as well as epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common. Other infantile- or childhood-onset findings include microcephaly; dystonic, dyskinetic, or choreiform movement disorder; and/or cortical visual impairment. Brain MRI reveals a malformation of cortical development in a minority of affected individuals. To date, fewer than 100 individuals with GRIN2B-related neurodevelopmental disorder have been reported.
Dyskeratosis congenita, autosomal dominant, 2
MedGen UID:
462793
Concept ID:
C3151443
Disease or Syndrome
Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. The classic triad may not be present in all individuals. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include: abnormal pigmentation changes not restricted to the upper chest and neck, eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), and dental abnormalities (caries, periodontal disease, taurodauntism). Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome). Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
Lissencephaly 4
MedGen UID:
462811
Concept ID:
C3151461
Disease or Syndrome
Lissencephaly-4 is an autosomal recessive neurodevelopmental disorder characterized by lissencephaly, severe brain atrophy, extreme microcephaly (head circumference of more than 10 standard deviations (SD) below the mean), and profound mental retardation. It has also been referred to as 'microlissencephaly' (summary by Bakircioglu et al., 2011 and Alkuraya et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).
Spastic ataxia
MedGen UID:
462969
Concept ID:
C3151619
Disease or Syndrome
This progressive neurodegenerative disorder is characterized by early childhood onset of spastic ataxia with mental retardation, cerebellar signs, and variable optic atrophy (Hogan and Bauman, 1977).
Combined oxidative phosphorylation deficiency 6
MedGen UID:
463103
Concept ID:
C3151753
Disease or Syndrome
NSDHL-Related Disorders
MedGen UID:
463131
Concept ID:
C3151781
Disease or Syndrome
The NSDHL-related disorders include: CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked condition that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked disorder that affects males. CHILD syndrome is characterized by unilateral distribution of ichthyosiform (yellow scaly) skin lesions and ipsilateral limb defects that range from shortening of the metacarpals and phalanges to absence of the entire limb. Intellect is usually normal. The ichthyosiform skin lesions are usually present at birth or in the first weeks of life; new lesions can develop in later life. Nail changes are also common. The heart, lung, and kidneys can also be involved. CK syndrome (named for the initials of the original proband) is characterized by mild to severe cognitive impairment and behavior problems (aggression, attention deficit hyperactivity disorder, and irritability). All affected males reported have developed seizures in infancy and have cerebral cortical malformations and microcephaly. All have distinctive facial features, a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. Strabismus is common. Optic atrophy is also reported.
Moyamoya disease 4 with short stature, hypergonadotropic hypogonadism, and facial dysmorphism
MedGen UID:
463207
Concept ID:
C3151857
Disease or Syndrome
This multisystem disorder is characterized by moyamoya disease, short stature, hypergonadotropic hypogonadism, and facial dysmorphism. Other variable features include dilated cardiomyopathy, premature graying of the hair, and early-onset cataracts. Moyamoya disease is a progressive cerebrovascular disorder characterized by stenosis or occlusion of the internal carotid arteries and the main branches, leading to the development of small collateral vessels (moyamoya vessels) at the base of the brain. Affected individuals can develop acute neurologic events due to stroke-like episodes (summary by Miskinyte et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350).
D-2-hydroxyglutaric aciduria 1
MedGen UID:
463405
Concept ID:
C3152055
Disease or Syndrome
D-2-hydroxyglutaric aciduria is a neurometabolic disorder first described by Chalmers et al. (1980). Clinical symptoms include developmental delay, epilepsy, hypotonia, and dysmorphic features. Mild and severe phenotypes were characterized (van der Knaap et al., 1999). The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and, often, cardiomyopathy. The mild phenotype has a more variable clinical presentation. Genetic Heterogeneity of D-2-Hydroxyglutaric Aciduria D-2-hydroxyglutaric aciduria-2 (D2HGA2; 613657) is caused by heterozygous mutation in the mitochondrial isocitrate dehydrogenase-2 gene (IDH2; 147650) on chromosome 15q26.
Fanconi anemia, complementation group E
MedGen UID:
463628
Concept ID:
C3160739
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Niemann-Pick disease type C1
MedGen UID:
465922
Concept ID:
C3179455
Disease or Syndrome
Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.
Chromosome 15q11.2 deletion syndrome
MedGen UID:
467404
Concept ID:
C3180937
Disease or Syndrome
A heterozygous deletion of chromosome 15q11.2 may increase the susceptibility to neuropsychiatric or neurodevelopmental problems, including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, and possibly seizures (summary by Doornbos et al., 2009 and Burnside et al., 2011). See also chromosome 15q11.2 duplication syndrome (608636).
2-methyl-3-hydroxybutyric aciduria
MedGen UID:
781653
Concept ID:
C3266731
Disease or Syndrome
HSD10 mitochondrial disease most commonly presents as an X-linked neurodegenerative disorder with highly variable severity and age at onset ranging from the neonatal period to early childhood. The features are usually multisystemic, consistent with mitochondrial dysfunction. Some affected males have a severe infantile form associated with cardiomyopathy that may result in death in early childhood, whereas other rare patients may have juvenile onset or even atypical presentations with normal neurologic development. More severely affected males show developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation. Heterozygous females may show non-progressive developmental delay and intellectual disability, but may also be clinically normal. Although the diagnosis can be aided by the observation of increased urinary levels of metabolites of isoleucine breakdown (2-methyl-3 hydroxybutyrate and tiglylglycine), there is not a correlation between these laboratory features and the phenotype. In addition, patients do not develop severe metabolic crises in the neonatal period as observed in other organic acidurias, but may show persistent lactic acidosis, most likely reflecting mitochondrial dysfunction (summary by Rauschenberger et al., 2010; review by Zschocke, 2012). In a review of the disorder, Zschocke (2012) noted that although this disorder was originally thought to be an inborn error of branched-chain fatty acid and isoleucine metabolism resulting from decreased HSD17B10 dehydrogenase activity (HSD17B10 'deficiency'), subsequent studies have shown that the HSD17B10 gene product has additional functions and also acts as a component of the mitochondrial RNase P holoenzyme, which is involved in mitochondrial tRNA processing and maturation and ultimately mitochondrial protein synthesis. The multisystemic features of HSD10MD most likely result from the adverse effect of HSD17B10 mutations on mitochondrial function, rather than from the effects on the dehydrogenase activity (see PATHOGENESIS below).
X-Linked mental retardation 90
MedGen UID:
477074
Concept ID:
C3275443
Disease or Syndrome
X-Linked Mental Retardation 88
MedGen UID:
477075
Concept ID:
C3275444
Disease or Syndrome
Mental retardation, X-linked, syndromic 17
MedGen UID:
477091
Concept ID:
C3275460
Disease or Syndrome
Mental retardation, X-linked, syndromic, chudley-schwartz type
MedGen UID:
477102
Concept ID:
C3275471
Disease or Syndrome
Cerebral-cerebellar-coloboma syndrome, X-linked
MedGen UID:
477118
Concept ID:
C3275487
Disease or Syndrome
A rare genetic syndrome with cerebellar malformation as a major feature. Characteristics included cerebellar vermis hypo or aplasia, ventriculomegaly, agenesis of corpus callosum and abnormalities of the brainstem and cerebral cortex in association with ocular coloboma. Clinically, patients show hydrocephalus at birth, neonatal hypotonia with abnormal breathing pattern, and ocular abnormalities with impaired vision, severe psychomotor delay, and seizures.
Kabuki syndrome 2
MedGen UID:
477126
Concept ID:
C3275495
Disease or Syndrome
Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects; genitourinary anomalies; cleft lip and/or palate; gastrointestinal anomalies including anal atresia, ptosis, and strabismus; and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.
Chromosome Xq27.3-q28 duplication syndrome
MedGen UID:
477152
Concept ID:
C3275521
Disease or Syndrome
Chromosome Xq27.3-q28 duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by mild mental retardation, mild facial dysmorphism, short stature, and primary testicular failure manifest as high-pitched voice, sparse body hair, abdominal obesity, and small testes. Female carriers may have short stature and premature ovarian failure (summary by Rio et al., 2010).
Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency 1
MedGen UID:
477906
Concept ID:
C3276276
Disease or Syndrome
A distinct group of inborn defects of complex V (ATP synthase) is represented by the enzyme deficiency due to nuclear genome mutations characterized by a selective inhibition of ATP synthase biogenesis. Biochemically, the patients show a generalized decrease in the content of ATP synthase complex which is less than 30% of normal. Most cases present with neonatal-onset hypotonia, lactic acidosis, hyperammonemia, hypertrophic cardiomyopathy, and 3-methylglutaconic aciduria. Many patients die within a few months or years (summary by Mayr et al., 2010). Genetic Heterogeneity of Mitochondrial Complex V Deficiency Other nuclear types of mitochondrial complex V deficiency include MC5DN2 (614052), caused by mutation in the TMEM70 gene (612418) on chromosome 8q21; MC5DN3 (614053), caused by mutation in the ATP5E gene (ATP5F1E; 606153) on chromosome 20q13; MC5DN4 (615228), caused by mutation in the ATP5A1 gene (ATP5FA1; 164360) on chromosome 18q; and MC5DN5 (618120), caused by mutation in the ATP5D gene (ATP5F1D; 603150) on chromosome 19p13. Mutations in the mitochondrial-encoded MTATP6 (516060) and MTATP8 (516070) genes can also cause mitochondrial complex V deficiency (see, e.g., 500015).
Multiple mitochondrial dysfunctions syndrome 1
MedGen UID:
478062
Concept ID:
C3276432
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome is a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death (summary by Seyda et al., 2001). Genetic Heterogeneity of Multiple Mitochondrial Dysfunctions Syndrome See also MMDS2 (614299), caused by mutation in the BOLA3 gene (613183) on chromosome 2p13; MMDS3 (615330), caused by mutation in the IBA57 gene (615316) on chromosome 1q42; MMDS4 (616370), caused by mutation in the ISCA2 gene (615317) on chromosome 14q24; MMDS5 (617613), caused by mutation in the ISCA1 gene (611006) on chromosome 9q21; and MMDS6 (617954), caused by mutation in the PMPCB gene (603131) on chromosome 7q22.
Geleophysic dysplasia 1
MedGen UID:
479777
Concept ID:
C3278147
Disease or Syndrome
Geleophysic dysplasia, a progressive condition resembling a lysosomal storage disorder, is characterized by short stature, short hands and feet, progressive joint limitation and contractures, distinctive facial features, progressive cardiac valvular disease, and thickened skin. Intellect is normal. Major findings are likely to be present in the first year of life. Cardiac, respiratory, and lung involvement result in death before age five years in approximately 33% of individuals with ADAMTSL2-related geleophysic dysplasia.
Microcephaly with chorioretinopathy, autosomal recessive
MedGen UID:
480111
Concept ID:
C3278481
Disease or Syndrome
Microcephaly and chorioretinopathy is an autosomal recessive developmental disorder characterized by delayed psychomotor development and visual impairment, often accompanied by short stature (summary by Martin et al., 2014). Genetic Heterogeneity of Microcephaly and Chorioretinopathy See also MCCRP2 (616171), caused by mutation in the PLK4 gene (605031) on chromosome 4q27, and MCCRP3 (616335), caused by mutation in the TUBGCP4 gene (609610) on chromosome 15q15. An autosomal dominant form of microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is caused by heterozygous mutation in the KIF11 gene (148760) on chromosome 10q23. See also Mirhosseini-Holmes-Walton syndrome (autosomal recessive pigmentary retinopathy and mental retardation; 268050), which has been mapped to chromosome 8q21.3-q22.1.
Leukotriene c4 synthase deficiency
MedGen UID:
481292
Concept ID:
C3279662
Disease or Syndrome
An extremely rare fatal neurometabolic developmental disorder with clinical characteristics of muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.
Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency 2
MedGen UID:
481329
Concept ID:
C3279699
Disease or Syndrome
Mitochondrial complex V deficiency is a shortage (deficiency) of a protein complex called complex V or a loss of its function. Complex V is found in cell structures called mitochondria, which convert the energy from food into a form that cells can use. Complex V is the last of five mitochondrial complexes that carry out a multistep process called oxidative phosphorylation, through which cells derive much of their energy.Mitochondrial complex V deficiency can cause a wide variety of signs and symptoms affecting many organs and systems of the body, particularly the nervous system and the heart. The disorder can be life-threatening in infancy or early childhood. Affected individuals may have feeding problems, slow growth, low muscle tone (hypotonia), extreme fatigue (lethargy), and developmental delay. They tend to develop elevated levels of lactic acid in the blood (lactic acidosis), which can cause nausea, vomiting, weakness, and rapid breathing. High levels of ammonia in the blood (hyperammonemia) can also occur in affected individuals, and in some cases result in abnormal brain function (encephalopathy) and damage to other organs.Another common feature of mitochondrial complex V deficiency is hypertrophic cardiomyopathy. This condition is characterized by thickening (hypertrophy) of the heart (cardiac) muscle that can lead to heart failure. People with mitochondrial complex V deficiency may also have a characteristic pattern of facial features, including a high forehead, curved eyebrows, outside corners of the eyes that point downward (downslanting palpebral fissures), a prominent bridge of the nose, low-set ears, thin lips, and a small chin (micrognathia).Some people with mitochondrial complex V deficiency have groups of signs and symptoms that are classified as a specific syndrome. For example, mitochondrial complex V deficiency can cause a condition called neuropathy, ataxia, and retinitis pigmentosa (NARP). NARP causes a variety of signs and symptoms chiefly affecting the nervous system. Beginning in childhood or early adulthood, most people with NARP experience numbness, tingling, or pain in the arms and legs (sensory neuropathy); muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have cognitive impairment and an eye disorder called retinitis pigmentosa that causes vision loss.A condition called Leigh syndrome can also be caused by mitochondrial complex V deficiency. Leigh syndrome is characterized by progressive loss of mental and movement abilities (developmental or psychomotor regression) and typically results in death within 2 to 3 years after the onset of symptoms. Both NARP and Leigh syndrome can also have other causes.
N-acetylaspartate deficiency
MedGen UID:
481346
Concept ID:
C3279716
Disease or Syndrome
Spastic paraplegia 47, autosomal recessive
MedGen UID:
481368
Concept ID:
C3279738
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become non-ambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Spastic paraplegia 52, autosomal recessive
MedGen UID:
481373
Concept ID:
C3279743
Disease or Syndrome
AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become non-ambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe.
Multiple congenital anomalies-hypotonia-seizures syndrome 1
MedGen UID:
481405
Concept ID:
C3279775
Disease or Syndrome
Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293). Genetic Heterogeneity of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome MCAHS2 (300868) is caused by mutation in the PIGA gene (311770) on chromosome Xp22, and MCAHS3 (615398) is caused by mutation in the PIGT gene (610272) on chromosome 20q13. Knaus et al. (2018) provided a review of the main clinical features of the different types of MCAHS, noting that patients with mutations in the PIGN, PIGA, and PIGT genes have distinct patterns of facial anomalies that can be detected by computer-assisted comparison. Some individuals with MCAHS may have variable increases in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. Knaus et al. (2018) concluded that a distinction between MCAHS and HPMRS1 (239300), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified together under the more encompassing term of 'GPI biosynthesis defects' (GPIBD).
Methylmalonate semialdehyde dehydrogenase deficiency
MedGen UID:
481470
Concept ID:
C3279840
Disease or Syndrome
Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (summary by Marcadier et al., 2013).
Mental retardation, autosomal dominant 2
MedGen UID:
481472
Concept ID:
C3279842
Disease or Syndrome
Cortical malformations, occipital
MedGen UID:
481505
Concept ID:
C3279875
Disease or Syndrome
Occipital cortical malformations (OCCM) is an autosomal recessive condition in which affected individuals develop seizures, sometimes associated with transient visual changes. Brain MRI shows both pachygyria and polymicrogyria restricted to the lateral occipital lobes (summary by Barak et al., 2011).
Mental retardation, autosomal recessive 15
MedGen UID:
481757
Concept ID:
C3280127
Disease or Syndrome
Hyperphosphatasia with mental retardation syndrome 3
MedGen UID:
481783
Concept ID:
C3280153
Disease or Syndrome
Hyperphosphatasia with mental retardation syndrome-3 is an autosomal recessive disorder usually characterized by severe mental retardation, hypotonia with very poor motor development, poor speech, and increased serum alkaline phosphatase (summary by Hansen et al., 2013). However, the severity of the disorder can also vary to include milder intellectual disability (Krawitz et al., 2013). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of HPMRS, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Hereditary sensory and autonomic neuropathy type IIC
MedGen UID:
481798
Concept ID:
C3280168
Disease or Syndrome
Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.
Adams-Oliver syndrome 2
MedGen UID:
481812
Concept ID:
C3280182
Disease or Syndrome
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Holoprosencephaly 11
MedGen UID:
481845
Concept ID:
C3280215
Disease or Syndrome
Spinocerebellar ataxia, autosomal recessive 11
MedGen UID:
481856
Concept ID:
C3280226
Disease or Syndrome
Microcephaly, epilepsy, and diabetes syndrome
MedGen UID:
481870
Concept ID:
C3280240
Disease or Syndrome
MEDS is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, simplified gyral pattern, severe epilepsy, and infantile diabetes (summary by Poulton et al., 2011).
Mental retardation, autosomal dominant 9
MedGen UID:
481913
Concept ID:
C3280283
Disease or Syndrome
An autosomal dominant condition caused by mutation(s) in the KIF1A gene, encoding kinesin-like protein KIF1A. It is characterized by microcephaly, intellectual disability, and delayed psychomotor development. The condition is progressive, occurs in early infancy, and is of variable severity.
Combined malonic and methylmalonic aciduria
MedGen UID:
481944
Concept ID:
C3280314
Disease or Syndrome
Combined malonic and methylmalonic aciduria (CMAMMA) is a condition characterized by high levels of certain chemicals, known as malonic acid and methylmalonic acid, in the body. A distinguishing feature of this condition is higher levels of methylmalonic acid than malonic acid in the urine, although both are elevated.The signs and symptoms of CMAMMA can begin in childhood. In some children, the buildup of acids causes the blood to become too acidic (ketoacidosis), which can damage the body's tissues and organs. Other signs and symptoms may include involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (failure to thrive), low blood sugar (hypoglycemia), and coma. Some affected children have an unusually small head size (microcephaly).Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases.
Chromosome 15q25 deletion syndrome
MedGen UID:
481985
Concept ID:
C3280355
Disease or Syndrome
Neurodegeneration with brain iron accumulation 4
MedGen UID:
482001
Concept ID:
C3280371
Disease or Syndrome
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (e.g., emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism.
Multiple mitochondrial dysfunctions syndrome 2
MedGen UID:
482008
Concept ID:
C3280378
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).
Hypermethioninemia due to adenosine kinase deficiency
MedGen UID:
482011
Concept ID:
C3280381
Disease or Syndrome
Hypermethioninemia due to adenosine kinase deficiency is an autosomal recessive inborn error of metabolism characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy); homocysteine is typically normal (summary by Bjursell et al., 2011).
Spinocerebellar ataxia, autosomal recessive 12
MedGen UID:
482082
Concept ID:
C3280452
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-12 is a neurologic disorder characterized by onset of generalized seizures in infancy, delayed psychomotor development with mental retardation, and cerebellar ataxia. Some patients may also show spasticity (summary by Mallaret et al., 2014).
Mental retardation, autosomal recessive 27
MedGen UID:
482168
Concept ID:
C3280538
Disease or Syndrome
Encephalopathy due to defective mitochondrial and peroxisomal fission 1
MedGen UID:
482290
Concept ID:
C3280660
Disease or Syndrome
Encephalopathy due to defective mitochondrial and peroxisomal fission-1 is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by Sheffer et al., 2016; Fahrner et al., 2016). Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission See also EMPF2 (617086), caused by mutation in the MFF gene (614785) on chromosome 2q36.
Joubert syndrome 14
MedGen UID:
482396
Concept ID:
C3280766
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Ichthyosis, spastic quadriplegia, and mental retardation
MedGen UID:
482486
Concept ID:
C3280856
Disease or Syndrome
ISQMR is a severe autosomal recessive disorder characterized by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures (summary by Aldahmesh et al., 2011).
Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type)
MedGen UID:
482496
Concept ID:
C3280866
Disease or Syndrome
Episodic encephalopathy due to thiamine pyrophosphokinase deficiency is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (summary by Mayr et al., 2011). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).
Joubert syndrome 15
MedGen UID:
482527
Concept ID:
C3280897
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Congenital cataracts, hearing loss, and neurodegeneration
MedGen UID:
482595
Concept ID:
C3280965
Disease or Syndrome
Huppke-Brendel syndrome (HBS) is characterized by bilateral congenital cataracts, sensorineural hearing loss, and severe developmental delay. To date, six individuals with HBS have been reported in the literature. All presented in infancy with axial hypotonia; motor delay was apparent in the first few months of life with lack of head control and paucity of limb movement. Seizures have been reported infrequently. In all individuals described to date serum copper and ceruloplasmin levels were very low or undetectable. Brain MRI examination showed hypomyelination, cerebellar hypoplasia mainly affecting the vermis, and wide subarachnoid spaces. None of the individuals reported to date were able to sit or walk independently. All affected individuals died between age ten months and six years.
Porencephaly 2
MedGen UID:
482600
Concept ID:
C3280970
Disease or Syndrome
Brain small vessel disease-2 is an autosomal dominant disorder characterized by variable neurologic impairment resulting from disturbed vascular supply that leads to cerebral degeneration. The disorder is often associated with 'porencephaly' on brain imaging. Affected individuals typically have hemiplegia, seizures, and intellectual disability, although the severity is variable (summary by Yoneda et al., 2012). For a discussion of genetic heterogeneity of brain small vessel disease, see BSVD1 (175780).
Rigidity and multifocal seizure syndrome, lethal neonatal
MedGen UID:
482659
Concept ID:
C3281029
Disease or Syndrome
Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (summary by Saitsu et al., 2014).
Psychomotor retardation, epilepsy, and craniofacial dysmorphism
MedGen UID:
482685
Concept ID:
C3281055
Disease or Syndrome
Congenital disorder of glycosylation type Ir
MedGen UID:
482714
Concept ID:
C3281084
Disease or Syndrome
A form of congenital disorders of N-linked glycosylation with characteristics of failure to thrive, developmental delay, hypotonia, strabismus and hepatic dysfunction. The disease is caused by mutations in the gene DDOST (1p36.1).
Encephalomyopathy, mitochondrial, due to voltage-dependent anion channel deficiency
MedGen UID:
482736
Concept ID:
C3281106
Disease or Syndrome
Chromosome 16q22 deletion syndrome
MedGen UID:
482782
Concept ID:
C3281152
Disease or Syndrome
The interstitial 16q22 deletion syndrome is a multiple congenital anomaly disorder associated with failure to thrive in infancy, poor growth, delayed psychomotor development, hypotonia, and dysmorphic features, including large anterior fontanel, high forehead, diastasis of the cranial sutures, broad nasal bridge, hypertelorism, low-set abnormal ears, and short neck. The phenotypic features and deletion sizes are variable, but deletion of 16q22 appears to be critical for manifestations of the syndrome (summary by Fujiwara et al., 1992).
Early infantile epileptic encephalopathy 13
MedGen UID:
482821
Concept ID:
C3281191
Disease or Syndrome
SCN8A-related epilepsy with encephalopathy is characterized by developmental delay, seizure onset in the first 18 months of life (mean 4 months), and intractable epilepsy characterized by multiple seizure types (generalized tonic-clonic seizures, infantile spasms, and absence and focal seizures). Epilepsy syndromes can include Lennox-Gastaut syndrome, West syndrome, and epileptic encephalopathies (e.g., Dravet syndrome). Hypotonia and movement disorders including dystonia, ataxia, and choreoathetosis are common. Psychomotor development varies from normal prior to seizure onset (with subsequent slowing or regression after seizure onset) to abnormal from birth. Intellectual disability, present in all, ranges from mild to severe (in ~50% of affected individuals). Autistic features are noted in some. Sudden unexpected death in epilepsy (SUDEP) of unknown cause has been reported in approximately 10% of published cases. To date SCN8A-related epilepsy with encephalopathy has been reported in the literature in about 50 individuals.
Leukoencephalopathy, brain calcifications, and cysts
MedGen UID:
482830
Concept ID:
C3281200
Disease or Syndrome
Leukoencephalopathy, brain calcifications, and cysts (LCC), also known as Labrune syndrome, is characterized by a constellation of features restricted to the central nervous system, including leukoencephalopathy, brain calcifications, and cysts, resulting in spasticity, dystonia, seizures, and cognitive decline (summary by Labrune et al., 1996). See also cerebroretinal microangiopathy with calcifications and cysts (CRMCC; 612199), an autosomal recessive disorder caused by mutation in the CTC1 gene (613129) that shows phenotypic similarities to Labrune syndrome. CRMCC includes the neurologic findings of intracranial calcifications, leukodystrophy, and brain cysts, but also includes retinal vascular abnormalities and other systemic manifestations, such as osteopenia with poor bone healing, a high risk of gastrointestinal bleeding, hair, skin, and nail changes, and anemia and thrombocytopenia. Although Coats plus syndrome and Labrune syndrome were initially thought to be manifestations of the same disorder, namely CRMCC, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic (Anderson et al., 2012; Polvi et al., 2012).
Coffin-Siris syndrome 1
MedGen UID:
482831
Concept ID:
C3281201
Disease or Syndrome
Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.
Combined oxidative phosphorylation deficiency 9
MedGen UID:
482864
Concept ID:
C3281234
Disease or Syndrome
Fanconi anemia, complementation group L
MedGen UID:
854018
Concept ID:
C3469528
Disease or Syndrome
Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract – are more common in individuals with FA.
Fanconi-Bickel syndrome
MedGen UID:
501176
Concept ID:
C3495427
Disease or Syndrome
Fanconi-Bickel syndrome is a rare but well-defined clinical entity, inherited in an autosomal recessive mode and characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose (Manz et al., 1987). Because no underlying enzymatic defect in carbohydrate metabolism had been identified and because metabolism of both glucose and galactose is impaired, a primary defect of monosaccharide transport across the membranes had been suggested (Berry et al., 1995; Fellers et al., 1967; Manz et al., 1987; Odievre, 1966). Use of the term glycogenosis type XI introduced by Hug (1987) is to be discouraged because glycogen accumulation is not due to the proposed functional defect of phosphoglucomutase, an essential enzyme in the common degradative pathways of both glycogen and galactose, but is secondary to nonfunctional glucose transport.
Spastic paraplegia 53, autosomal recessive
MedGen UID:
761340
Concept ID:
C3539494
Disease or Syndrome
SPG53 is an autosomal recessive neurologic disorder characterized by onset in infancy of delayed motor development progressing to upper and lower limb spasticity with impaired walking. Affected individuals also show mild to moderate cognitive impairment (summary by Zivony-Elboum et al., 2012).
Spastic paraplegia 54, autosomal recessive
MedGen UID:
761341
Concept ID:
C3539495
Disease or Syndrome
Spastic paraplegia-54 is a complicated form of spastic paraplegia, a neurodegenerative disorder affecting fibers of the corticospinal tract. Affected individuals have delayed psychomotor development, intellectual disability, and early-onset spasticity of the lower limbs. Brain MRI shows a thin corpus callosum and periventricular white matter lesions. Brain magnetic resonance spectroscopy shows an abnormal lipid peak (summary by Schuurs-Hoeijmakers et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.
Spastic paraplegia 55, autosomal recessive
MedGen UID:
761342
Concept ID:
C3539506
Disease or Syndrome
Pontine tegmental cap dysplasia
MedGen UID:
762040
Concept ID:
C3541340
Disease or Syndrome
Pontine tegmental cap dysplasia (PTCD) refers to a neurologic condition characterized by a distinct pattern of hindbrain malformations apparent on brain imaging. The abnormalities affect the pons, medulla, and cerebellum. In neuroradiologic studies, the ventral side of the pons is flattened, whereas there is vaulting ('capping') of the dorsal pontine border into the fourth ventricle. Affected individuals show a variety of neurologic deficits, most commonly sensorineural deafness, impaired cranial nerve function, and variable psychomotor retardation (summary by Barth et al., 2007).
Mitochondrial complex III deficiency
MedGen UID:
762097
Concept ID:
C3541471
Disease or Syndrome
Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (de Lonlay et al., 2001; De Meirleir et al., 2003). Genetic Heterogeneity of Mitochondrial Complex III Deficiency Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (615157), caused by mutation in the TTC19 gene (613814) on chromosome 17p12; MC3DN3 (615158), caused by mutation in the UQCRB gene (191330) on chromosome 8q; MC3DN4 (615159), caused by mutation in the UQCRQ gene (612080) on chromosome 5q31; MC3DN5 (615160), caused by mutation in the UQCRC2 gene (191329) on chromosome 16p12; MC3DN6 (615453), caused by mutation in the CYC1 gene (123980) on chromosome 8q24; MC3DN7 (615824), caused by mutation in the UQCC2 gene (614461) on chromosome 6p21; MC3DN8 (615838), caused by mutation in the LYRM7 gene (615831) on chromosome 5q23; and MC3DN9 (616111), caused by mutation in the UQCC3 gene (616097) on chromosome 11q12. See also MTYCB (516020) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene.
Nephronophthisis 15
MedGen UID:
762112
Concept ID:
C3541853
Disease or Syndrome
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recognized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype, inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis
MedGen UID:
762199
Concept ID:
C3542022
Disease or Syndrome
SOFT syndrome is characterized by severely short long bones, peculiar facies associated with paucity of hair, and nail anomalies. Growth retardation is evident on prenatal ultrasound as early as the second trimester of pregnancy, and affected individuals reach a final stature consistent with a height age of 6 years to 8 years. Relative macrocephaly is present during early childhood but head circumference is markedly low by adulthood. Psychomotor development is normal. Facial dysmorphism includes a long, triangular face with prominent nose and small ears, and affected individuals have an unusual high-pitched voice. Clinodactyly, brachydactyly, and hypoplastic distal phalanges and fingernails are present in association with postpubertal sparse and short hair. Typical skeletal findings include short and thick long bones with mild irregular metaphyseal changes, short femoral necks, and hypoplastic pelvis and sacrum. All long bones of the hand are short, with major delay of carpal ossification and cone-shaped epiphyses. Vertebral body ossification is also delayed (summary by Sarig et al., 2012).
Peroxisome biogenesis disorder 5B
MedGen UID:
762202
Concept ID:
C3542026
Disease or Syndrome
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX2 gene have cells of complementation group 5 (CG5, equivalent to CG10 and CGF). For information on the history of PBD complementation groups, see 214100.
Spastic paraplegia 49, autosomal recessive
MedGen UID:
762260
Concept ID:
C3542549
Disease or Syndrome
SPG49 is an autosomal recessive complicated form of spastic paraplegia, a neurodegenerative disorder of the corticospinal tracts. It is characterized by delayed psychomotor development, mental retardation, and onset of spastic paraplegia in the first decade. Affected individuals also have dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, which may be fatal (summary by Oz-Levi et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.
Infantile Refsum disease
MedGen UID:
763607
Concept ID:
C3550693
Disease or Syndrome
Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a PEX gene defect regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.
BARATELA-SCOTT SYNDROME
MedGen UID:
763790
Concept ID:
C3550876
Disease or Syndrome
Cornelia de Lange syndrome 5
MedGen UID:
763817
Concept ID:
C3550903
Disease or Syndrome
Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; <5th centile throughout life), hirsutism, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched eyebrows, long eyelashes, short nose with anteverted nares, small widely spaced teeth, and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS.
Epileptic encephalopathy, early infantile, 36
MedGen UID:
763818
Concept ID:
C3550904
Disease or Syndrome
Early infantile epileptic encephalopathy-36 is an X-linked dominant neurodevelopmental disorder characterized by onset of seizures in infancy followed by delayed psychomotor development. Some patients may have dysmorphic features. Only females with this specific phenotype have been reported (summary by Dimassi et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see 308350. For a discussion of the classification of CDGs, see CDG1A (212065).
Mental retardation, X-linked, syndromic 32
MedGen UID:
763827
Concept ID:
C3550913
Disease or Syndrome
Linear skin defects with multiple congenital anomalies 2
MedGen UID:
763835
Concept ID:
C3550921
Disease or Syndrome
Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia and/or anophthalmia and linear skin defects, usually involving the face and neck, which are present at birth and heal with age, leaving minimal residual scarring. Other findings can include a wide variety of other ocular abnormalities (e.g., corneal anomalies, orbital cysts, cataracts), central nervous system involvement (e.g., structural anomalies, developmental delay, infantile seizures), cardiac concerns (e.g., hypertrophic or oncocytic cardiomyopathy, atrial or ventricular septal defects, arrhythmias), short stature, diaphragmatic hernia, nail dystrophy, hearing impairment, and genitourinary malformations. Inter- and intrafamilial variability is described.
Neurodegeneration with brain iron accumulation 5
MedGen UID:
763887
Concept ID:
C3550973
Disease or Syndrome
Beta-propeller protein-associated neurodegeneration (BPAN) is typically characterized by early-onset seizures, infantile-onset developmental delay, intellectual disability, absent to limited expressive language, motor dysfunction (ataxia), and abnormal behaviors often similar to autism spectrum disorder. Seizure types including generalized (absence, tonic, atonic, tonic-clonic and myoclonic), focal with impaired consciousness, and epileptic spasms, as well as epileptic syndromes (West syndrome and Lennox-Gastaut syndrome) can be seen. With age seizures tend to resolve or become less prominent, whereas cognitive decline and movement disorders (progressive parkinsonism and dystonia) emerge as characteristic findings.
Ayazi syndrome
MedGen UID:
763933
Concept ID:
C3551019
Disease or Syndrome
Hydrocephalus, sprengel anomaly, and costovertebral dysplasia
MedGen UID:
764174
Concept ID:
C3551260
Disease or Syndrome
Polymicrogyria, asymmetric
MedGen UID:
765150
Concept ID:
C3552236
Disease or Syndrome
Congenital fibrosis of the extraocular muscles (CFEOM) refers to at least eight genetically defined strabismus syndromes (CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, Tukel syndrome, and CFEOM3 with polymicrogyria) characterized by congenital non-progressive ophthalmoplegia (inability to move the eyes) with or without ptosis (droopy eyelids) affecting part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique). In general, affected individuals have severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze. Individuals with CFEOM frequently compensate for the ophthalmoplegia by maintaining abnormal head positions at rest and by moving their heads rather than their eyes to track objects. Individuals with CFEOM3A may also have intellectual disability, social disability, Kallmann syndrome, facial weakness, and vocal cord paralysis; and/or may develop a progressive sensorimotor axonal polyneuropathy. Individuals with Tukel syndrome also have postaxial oligodactyly or oligosyndactyly of the hands. Those with CFEOM3 with polymicrogyria also have microcephaly and intellectual disability.
Microphthalmia, syndromic 11
MedGen UID:
765991
Concept ID:
C3553077
Disease or Syndrome
Mental retardation, autosomal dominant 14
MedGen UID:
766161
Concept ID:
C3553247
Disease or Syndrome
Coffin-Siris syndrome is a congenital malformation syndrome characterized by developmental delay, intellectual disability, coarse facial features, feeding difficulties, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Other more variable features may also occur. Patients with ARID1A mutations have a wide spectrum of manifestations, from severe intellectual disability and serious internal complications that could result in early death to mild intellectual disability (summary by Kosho et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900). The chromosome 1p36.11 duplication syndrome, in which the ARID1A gene is duplicated, is characterized by impaired intellectual development, microcephaly, dysmorphic facial features, and hand and foot anomalies.
Mental retardation, autosomal dominant 15
MedGen UID:
766162
Concept ID:
C3553248
Disease or Syndrome
Coffin-Siris syndrome is a congenital malformation syndrome characterized by developmental delay, intellectual disability, coarse facial features, feeding difficulties, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Other more variable features may also occur. Patients with SMARCB1 mutations may have more severe neurodevelopmental deficits including severe intellectual disability, brain structural abnormalities, and no expressive words, as well as scoliosis (summary by Kosho et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
Mental retardation, autosomal dominant 16
MedGen UID:
766163
Concept ID:
C3553249
Disease or Syndrome
Coffin-Siris syndrome is a congenital malformation syndrome characterized by developmental delay, intellectual disability, coarse facial features, feeding difficulties, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Other more variable features may also occur. Patients with SMARCA4 mutations may have less coarse craniofacial appearances and fewer behavioral abnormalities than Coffin-Siris patients with mutations in other genes (summary by Kosho et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
Acrodysostosis 2, with or without hormone resistance
MedGen UID:
766164
Concept ID:
C3553250
Disease or Syndrome
Acrodysostosis-2 is a rare skeletal dysplasia characterized by brachydactyly, facial dysostosis, and spinal stenosis. Many patients have intellectual disability and some have hormone resistance (summary by Michot et al., 2012 and Lee et al., 2012). For a discussion of genetic heterogeneity of acrodysostosis, see ACRDYS1 (101800).
Joubert syndrome 17
MedGen UID:
766178
Concept ID:
C3553264
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Coenzyme Q10 deficiency, primary, 5
MedGen UID:
766288
Concept ID:
C3553374
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Pontocerebellar hypoplasia, type 1b
MedGen UID:
766363
Concept ID:
C3553449
Disease or Syndrome
EXOSC3-related pontocerebellar hypoplasia (PCH) is characterized by abnormalities in the posterior fossa and degeneration of the anterior horn cells. At birth, skeletal muscle weakness manifests as hypotonia (sometimes with congenital joint contractures) and poor feeding. In persons with prolonged survival, spasticity, dystonia, and seizures become evident. Within the first year of life respiratory insufficiency and swallowing difficulties are common. Intellectual disability is severe. Life expectancy ranges from a few weeks to adolescence. To date, 51 individuals with PCH from 36 families with mutation of EXOSC3 have been described.
Cornelia de Lange syndrome 4
MedGen UID:
766431
Concept ID:
C3553517
Disease or Syndrome
Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation (prenatal onset; <5th centile throughout life), hirsutism, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched eyebrows, long eyelashes, short nose with anteverted nares, small widely spaced teeth, and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS.
Combined oxidative phosphorylation deficiency 10
MedGen UID:
766443
Concept ID:
C3553529
Disease or Syndrome
COXPD10 is an autosomal recessive disorder resulting in variable defects of mitochondrial oxidative respiration. Affected individuals present in infancy with hypertrophic cardiomyopathy and lactic acidosis. The severity is variable, but can be fatal in the most severe cases (summary by Ghezzi et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Congenital disorder of glycosylation type 2k
MedGen UID:
766485
Concept ID:
C3553571
Disease or Syndrome
CDG2K is an autosomal recessive disorder with a variable phenotype. Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern (summary by Foulquier et al., 2012). For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066).
Seckel syndrome 6
MedGen UID:
766496
Concept ID:
C3553582
Disease or Syndrome
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
MedGen UID:
766511
Concept ID:
C3553597
Disease or Syndrome
MEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like) syndrome is characterized in neonates by hypoglycemia and a sepsis-like clinical picture for which no infectious agent can be found. During the first year of life feeding problems, failure to thrive, and/or truncal hypotonia become evident; many infants experience (transient) liver involvement ranging from undulating transaminases to prolonged hyperbilirubinemia and near-fatal liver failure. By age two years progressive deafness, dystonia, and spasticity prevent further psychomotor development and/or result in loss of acquired skills. Affected children are completely dependent on care for all activities of daily living; speech is absent.
Mitochondrial pyruvate carrier deficiency
MedGen UID:
766521
Concept ID:
C3553607
Disease or Syndrome
Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation (summary by Bricker et al., 2012).
Cerebellar ataxia, nonprogressive, with mental retardation
MedGen UID:
766575
Concept ID:
C3553661
Disease or Syndrome
Nonprogressive cerebellar ataxia with mental retardation is an autosomal dominant neurodevelopmental disorder characterized by mildly delayed psychomotor development, early onset of cerebellar ataxia, and intellectual disability later in childhood and adult life. Other features may include neonatal hypotonia, dysarthria, and dysmetria. Brain imaging in some patients shows cerebellar atrophy. Dysmorphic facial features are variable (summary by Thevenon et al., 2012).
Adams-Oliver syndrome 3
MedGen UID:
766662
Concept ID:
C3553748
Disease or Syndrome
Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies.
Alternating hemiplegia of childhood 2
MedGen UID:
766702
Concept ID:
C3553788
Disease or Syndrome
ATP1A3-related neurologic disorders represent a clinical continuum in which at least three distinct phenotypes have been delineated: rapid-onset dystonia-parkinsonism (RDP); alternating hemiplegia of childhood (ACH); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). However, some affected individuals have intermediate phenotypes or only a few features that do not fit well into one of these major phenotypes. RDP has been characterized by: abrupt onset of dystonia over days to weeks with parkinsonism (primarily bradykinesia and postural instability); common bulbar involvement; and absence or minimal response to an adequate trial of L-dopa therapy, with few exceptions. Often fever, physiologic stress, or alcoholic binges trigger the onset of symptoms. After their initial appearance, symptoms often stabilize with little improvement; occasionally second episodes occur with abrupt worsening of symptoms. Rarely, affected individuals have reported a more gradual onset of symptoms over weeks to months. Anxiety, depression, and seizures have been reported. Age of onset ranges from four to 55 years, although a childhood variation of RDP with onset between ages nine and 14 months has been reported. AHC is a complex neurodevelopmental syndrome most frequently manifesting in infancy or early childhood with paroxysmal episodic neurologic dysfunction including alternating hemiparesis or dystonia, quadriparesis, seizure-like episodes, and oculomotor abnormalities. Episodes can last for minutes, hours, days, or even weeks. Remission of symptoms occurs with sleep and immediately after awakening. Over time, persistent neurologic deficits including oculomotor apraxia, ataxia, choreoathetosis, dystonia, parkinsonism, and cognitive and behavioral dysfunction develop in the majority of those affected; more than 50% develop epilepsy in addition to their episodic movement disorder phenotype. CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) syndrome is characterized by episodes of ataxic encephalopathy and/or weakness during and after a febrile illness. Onset is between ages six months and four years. Some acute symptoms resolve; progression of sensory losses and severity vary.
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8
MedGen UID:
766727
Concept ID:
C3553813
Disease or Syndrome
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. The phenotype includes the alternative clinical designation Walker-Warburg syndrome (WWS). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Manzini et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).
Spinocerebellar ataxia, autosomal recessive 13
MedGen UID:
766730
Concept ID:
C3553816
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-13 is an autosomal recessive neurologic disorder characterized by delayed psychomotor development beginning in infancy. Affected individuals show mild to profound mental retardation with poor or absent speech as well as gait and stance ataxia and hyperreflexia. Most individuals also have eye movement abnormalities. Brain MRI shows cerebellar atrophy and ventriculomegaly (summary by Guergueltcheva et al., 2012).
METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblJ TYPE
MedGen UID:
766829
Concept ID:
C3553915
Disease or Syndrome
Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous metabolic disorder of cobalamin (cbl; vitamin B12) metabolism, which is essential for hematologic and neurologic function. Biochemically, the defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). The cblJ type is phenotypically and biochemically similar to the cblF type (MAHCF; 277380) (summary by Coelho et al., 2012).
Peroxisome biogenesis disorder 4B
MedGen UID:
766851
Concept ID:
C3553937
Disease or Syndrome
Peroxisome biogenesis disorder-4B (PBD4B) includes the overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders (PBDs). The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX6 gene have cells of complementation group 4 (CG4, equivalent to CG6 and CGC). For information on the history of PBD complementation groups, see 214100.
Peroxisome biogenesis disorder 5a (zellweger)
MedGen UID:
766854
Concept ID:
C3553940
Disease or Syndrome
The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 5 (CG5, equivalent to CG10 and CGF) have mutations in the PEX2 gene. For information on the history of PBD complementation groups, see 214100.
Peroxisome biogenesis disorder 6B
MedGen UID:
766862
Concept ID:
C3553948
Disease or Syndrome
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood. Some patients with PEX10 mutations have a milder disorder characterized by childhood-onset cerebellar ataxia and neuropathy without mental retardation (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX10 gene have cells of complementation group 7 (CG7, equivalent to CGB). For information on the history of PBD complementation groups, see 214100.
Peroxisome biogenesis disorder 7B
MedGen UID:
766865
Concept ID:
C3553951
Disease or Syndrome
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX26 gene have cells of complementation group 8 (CG8, equivalent to CGA). For information on the history of PBD complementation groups, see 214100.
Peroxisome biogenesis disorder 8B
MedGen UID:
766874
Concept ID:
C3553960
Disease or Syndrome
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX16 gene have cells of complementation group 9 (CG9, equivalent to CGD). For information on the history of PBD complementation groups, see 214100.
Peroxisome biogenesis disorder 11A
MedGen UID:
766914
Concept ID:
C3554000
Disease or Syndrome
Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 13 (CG13, equivalent to CGH) have mutations in the PEX13 gene. For information on the history of PBD complementation groups, see 214100.
Peroxisome biogenesis disorder 12A
MedGen UID:
766916
Concept ID:
C3554002
Disease or Syndrome
Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 14 (CG14, equivalent to CGJ) have mutations in the PEX19 gene. For information on the history of PBD complementation groups, see 214100.
Combined oxidative phosphorylation deficiency 11
MedGen UID:
766981
Concept ID:
C3554067
Disease or Syndrome
COXPD11 is a severe multisystemic autosomal recessive disorder characterized by neonatal hypotonia and lactic acidosis. Affected individuals may have respiratory insufficiency, foot deformities, or seizures, and all reported patients have died in infancy. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes (summary by Garcia-Diaz et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation deficiency 12
MedGen UID:
766993
Concept ID:
C3554079
Disease or Syndrome
COXPD12 is an autosomal recessive mitochondrial neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability (summary by Steenweg et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Pontocerebellar hypoplasia type 8
MedGen UID:
767123
Concept ID:
C3554209
Disease or Syndrome
Pontocerebellar hypoplasia type 8 is an autosomal recessive neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects. Brain MRI shows pontocerebellar hypoplasia, decreased cerebral white matter, and a thin corpus callosum (summary by Mochida et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Joubert syndrome 20
MedGen UID:
767149
Concept ID:
C3554235
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Carpenter syndrome 2
MedGen UID:
767161
Concept ID:
C3554247
Disease or Syndrome
Carpenter syndrome-2 is an autosomal recessive multiple congenital malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet, in association with abnormal left-right patterning and other features, most commonly obesity, umbilical hernia, cryptorchidism, and congenital heart disease (summary by Twigg et al., 2012). For a discussion of genetic heterogeneity of Carpenter syndrome, see 201000.
Early infantile epileptic encephalopathy 15
MedGen UID:
767230
Concept ID:
C3554316
Disease or Syndrome
Schuurs-hoeijmakers syndrome
MedGen UID:
767257
Concept ID:
C3554343
Disease or Syndrome
Schuurs-Hoeijmakers syndrome is an autosomal dominant disorder characterized by mental retardation, distinct craniofacial features, and variable additional congenital abnormalities (summary by Schuurs-Hoeijmakers et al., 2016).
Congenital disorder of glycosylation type 1u
MedGen UID:
767299
Concept ID:
C3554385
Disease or Syndrome
Osteogenesis imperfecta, type xiv
MedGen UID:
767342
Concept ID:
C3554428
Disease or Syndrome
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most cases of OI are autosomal dominant with mutations in 1 of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Shaheen et al. (2012) described osteogenesis imperfecta type XIV (OI14), an autosomal recessive form of the disorder characterized by variable degrees of severity of multiple fractures and osteopenia, with normal teeth, sclerae, and hearing. Fractures first occur prenatally or by age 6 years.
Alazami syndrome
MedGen UID:
767353
Concept ID:
C3554439
Disease or Syndrome
Alazami syndrome is an autosomal recessive disorder characterized by severe growth restriction present at birth, severely impaired intellectual development, and distinctive facial features. Some patients have been reported with skeletal and behavioral features (summary by Imbert-Bouteille et al., 2019).
Mental retardation, autosomal dominant 18
MedGen UID:
767362
Concept ID:
C3554448
Disease or Syndrome
Autosomal dominant mental retardation-18 is characterized by severe intellectual disability, limited language development, motor delay, and dysmorphic features, including hypertelorism and narrow palpebral fissures (summary by Luo et al., 2017).
Mental retardation, autosomal dominant 19
MedGen UID:
767363
Concept ID:
C3554449
Disease or Syndrome
Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is characterized by global developmental delay, impaired intellectual development, axial hypotonia, and dysmorphic craniofacial features with microcephaly. Many patients have visual abnormalities, ranging from strabismus to optic nerve atrophy and retinal abnormalities. Affected individuals also develop spasticity, particularly of the lower limbs, and may have behavioral abnormalities (summary by Kuechler et al., 2015 and Kharbanda et al., 2017).
Steel syndrome
MedGen UID:
767508
Concept ID:
C3554594
Disease or Syndrome
Steel syndrome is characterized by characteristic facies, dislocated hips and radial heads, carpal coalition (fusion of carpal bones), short stature, scoliosis, and cervical spine anomalies. The dislocated hips are resistant to surgical intervention (summary by Flynn et al., 2010).
Mitochondrial complex III deficiency, nuclear type 2
MedGen UID:
767519
Concept ID:
C3554605
Disease or Syndrome
Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life (summary by Ghezzi et al., 2011). The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances (Morino et al., 2014; Atwal, 2014; Nogueira et al., 2013). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Mitochondrial complex III deficiency, nuclear type 4
MedGen UID:
767521
Concept ID:
C3554607
Disease or Syndrome
Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and the muscles used for movement (skeletal muscles). Signs and symptoms of mitochondrial complex III deficiency usually begin in infancy but can appear later.The severity of mitochondrial complex III deficiency varies widely among affected individuals. People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise intolerance). More severely affected individuals have problems with multiple body systems, such as liver disease that can lead to liver failure, kidney abnormalities (tubulopathy), and brain dysfunction (encephalopathy). Encephalopathy can cause delayed development of mental and motor skills (psychomotor delay), movement problems, weak muscle tone (hypotonia), and difficulty with communication. Some affected individuals have a form of heart disease called cardiomyopathy, which can lead to heart failure. Most people with mitochondrial complex III deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis). Some affected individuals also have buildup of molecules called ketones (ketoacidosis) or high blood sugar levels (hyperglycemia). Abnormally high levels of these chemicals in the body can be life-threatening.Mitochondrial complex III deficiency can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood.
Mental retardation, autosomal recessive 35
MedGen UID:
767523
Concept ID:
C3554609
Disease or Syndrome
Dyskeratosis congenita, autosomal recessive, 5
MedGen UID:
767570
Concept ID:
C3554656
Disease or Syndrome
Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. The classic triad may not be present in all individuals. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include: abnormal pigmentation changes not restricted to the upper chest and neck, eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), and dental abnormalities (caries, periodontal disease, taurodauntism). Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome). Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
Osteosclerotic metaphyseal dysplasia
MedGen UID:
767579
Concept ID:
C3554665
Disease or Syndrome
Osteosclerotic metaphyseal dysplasia is a rare condition characterized by developmental delay, hypotonia, and distinctive radiographic changes, including osteosclerosis localized predominantly to the metaphyses of the long bones. The shafts of the long bones are osteopenic. The skull appears to be spared. Seizures and later-onset spastic paraplegia have been reported. Laboratory abnormalities include elevated alkaline phosphatase levels in some, but not all, patients. Elevated urinary pyridinoline and deoxypyridinoline levels, markers of osteoclastic activity, have also been reported (summary by Nishimura and Kozlowski, 1993 and Kasapkara et al., 2013).
Ohdo syndrome, X-linked
MedGen UID:
785805
Concept ID:
C3698541
Disease or Syndrome
The phenotypic spectrum of MED12-related disorders, which is still being defined, includes at a minimum the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), and X-linked Ohdo syndrome. FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. X-linked Ohdo syndrome (referred to as XLOS in this GeneReview) is characterized by intellectual disability, blepharophimosis, and facial coarsening. A number of individuals with nonsyndromic intellectual disability – including some affected females – have been described.
Bardet-Biedl syndrome 17
MedGen UID:
811538
Concept ID:
C3714980
Disease or Syndrome
BBS17 is an autosomal recessive ciliopathy characterized by retinitis pigmentosa, cognitive impairment, obesity, renal dysfunction, and hypogenitalism. Polydactyly, most often postaxial, is also a primary feature of BBS; in BBS17 mesoaxial polydactyly, with fused or Y-shaped metacarpals, is a distinct manifestation (Deffert et al., 2007; Schaefer et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).
Craniosynostosis 3
MedGen UID:
811568
Concept ID:
C3715051
Disease or Syndrome
Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by Fitzpatrick, 2013). Craniosynostosis-3 includes coronal, sagittal, and multisuture forms (Sharma et al., 2013). For discussion of genetic heterogeneity of craniosynostosis, see CRS1 (123100).
Epilepsy, focal, with speech disorder and with or without mental retardation
MedGen UID:
812732
Concept ID:
C3806402
Disease or Syndrome
GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.
Macrocephaly/megalencephaly syndrome, autosomal recessive
MedGen UID:
812742
Concept ID:
C3806412
Disease or Syndrome
Macrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by Olney, 2007 and Williams et al., 2008). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by Alfaiz et al., 2014).
Chromosome Xq28 deletion syndrome
MedGen UID:
812964
Concept ID:
C3806634
Disease or Syndrome
Deafness, dystonia, and cerebral hypomyelination is an X-linked recessive mental retardation syndrome characterized by almost no psychomotor development, dysmorphic facial features, sensorineural deafness, dystonia, pyramidal signs, and hypomyelination on brain imaging (summary by Cacciagli et al., 2013).
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIm
MedGen UID:
813018
Concept ID:
C3806688
Disease or Syndrome
Congenital disorder of glycosylation type IIm, or early infantile epileptic encephalopathy-22, is an X-linked dominant severe neurologic disorder characterized by infantile-onset seizures, hypsarrhythmia, hypotonia, and severe intellectual disability with lack of speech. Brain malformations include cerebral and cerebellar atrophy. Additionally, some patients had dysmorphic features or coarse facies (Ng et al., 2013; Kodera et al., 2013). For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Microphthalmia, syndromic 13
MedGen UID:
813072
Concept ID:
C3806742
Disease or Syndrome
Mental retardation, X-linked 99
MedGen UID:
813076
Concept ID:
C3806746
Disease or Syndrome
Epileptic encephalopathy Lennox-Gastaut type
MedGen UID:
813871
Concept ID:
C3807541
Disease or Syndrome
Lennox-Gastaut syndrome is a severe condition characterized by recurrent seizures (epilepsy) that begin early in life. Affected individuals have multiple types of seizures, a particular pattern of brain activity (called slow spike-and-wave) measured by a test called an electroencephalogram (EEG), and impaired mental abilities.In Lennox-Gastaut syndrome, epilepsy begins in early childhood, usually between ages 3 and 5. The most common seizure type is tonic seizures, which cause the muscles to stiffen (contract) uncontrollably. These seizures typically occur during sleep; they may also occur during wakefulness and cause sudden falls. Also common are atypical absence seizures, which cause a very brief partial or complete loss of consciousness. Additionally, many affected individuals have episodes called drop attacks, which cause sudden falls that can result in serious or life-threatening injuries. Drop attacks may be caused by sudden loss of muscle tone (described as atonic) or by abnormal muscle contraction (described as tonic). Other types of seizures have been reported less frequently in people with Lennox-Gastaut syndrome. Seizures associated with Lennox-Gastaut syndrome often do not respond well to therapy with anti-epileptic medications.Although each seizure episode associated with Lennox-Gastaut syndrome is usually brief, more than two-thirds of affected individuals experience prolonged periods of seizure activity (known as status epilepticus) or episodes of many seizures that occur in a cluster.Most children with Lennox-Gastaut syndrome have intellectual disability or learning problems even before seizures begin. These problems may worsen over time, particularly if seizures are very frequent or severe. Some affected children develop additional neurological abnormalities and behavioral problems. Many also have delayed development of motor skills such as sitting and crawling. As a result of their seizures and intellectual disability, most people with Lennox-Gastaut syndrome require help with the usual activities of daily living. However, a small percentage of affected adults live independently.People with Lennox-Gastaut syndrome have a higher risk of death than their peers of the same age. Although the increased risk is not fully understood, it is partly due to poorly controlled seizures and injuries from falls.
Mental retardation, autosomal dominant 22
MedGen UID:
814514
Concept ID:
C3808184
Disease or Syndrome
MRD22 is characterized by impaired intellectual development with frequent cooccurrence of corpus callosum anomalies, hypotonia, microcephaly, growth problems, and variable facial dysmorphism (summary by van der Schoot et al., 2018). Chromosome 1q43-q44 deletion syndrome is characterized by moderate to severe mental retardation, limited or no speech, and variable but characteristic facial features, including round face, prominent forehead, flat nasal bridge, hypertelorism, epicanthal folds, and low-set ears. Other features may include hypotonia, poor growth, microcephaly, agenesis of the corpus callosum, and seizures. The phenotype is variable, and not all features are observed in all patients, which may be explained in some cases by incomplete penetrance or variable expressivity (summary by Ballif et al., 2012).
Cortical dysplasia, complex, with other brain malformations 1
MedGen UID:
814727
Concept ID:
C3808397
Disease or Syndrome
Complex cortical dysplasia with other brain malformations (CDCBM) is a disorder of aberrant neuronal migration and disturbed axonal guidance. Affected individuals have mild to severe mental retardation, strabismus, axial hypotonia, and spasticity. Brain imaging shows variable malformations of cortical development, including polymicrogyria, gyral disorganization, and fusion of the basal ganglia, as well as thin corpus callosum, hypoplastic brainstem, and dysplastic cerebellar vermis. Extraocular muscles are not involved (summary by Poirier et al., 2010). Mutation in the TUBB3 gene can also cause congenital fibrosis of extraocular muscles-3A (CFEOM3A; 600638), a milder and somewhat different neurologic phenotype. Genetic Heterogeneity of Complex Cortical Dysplasia With Other Brain Malformations See also CDCBM2 (615282), caused by mutation in the KIF5C gene (604593) on chromosome 2q23; CDCBM3 (615411), caused by mutation in the KIF2A gene (602591) on chromosome 5q12; CDCBM4 (615412), caused by mutation in the TUBG1 gene (191135) on chromosome 17q21; CDCBM5 (615763), caused by mutation in the TUBB2A gene (615101) on chromosome 6p25; CDCBM6 (615771), caused by mutation in the TUBB gene (191130) on chromosome 6p21; CDCBM7 (610031), caused by mutation in the TUBB2B gene (612850) on chromosome 6p25; CDCBM8 (613180), caused by mutation in the TUBA8 gene (605742) on chromosome 22q11; and CDCBM9 (618174), caused by mutation in the CTNNA2 gene (114025) on chromosome 2p12. See also lissencephaly (e.g., LIS1, 607432), which shows overlapping features and may result from mutation in tubulin genes.
Osteogenesis imperfecta, type xv
MedGen UID:
815174
Concept ID:
C3808844
Disease or Syndrome
Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Keupp et al. (2013) and Pyott et al. (2013) described osteogenesis imperfecta type XV, an autosomal recessive form of the disorder characterized by early-onset recurrent fractures, bone deformity, significant reduction of bone density, short stature, and, in some patients, blue sclera. Tooth development and hearing are normal. Learning and developmental delays and brain anomalies have been observed in some patients.
Congenital disorder of deglycosylation
MedGen UID:
815321
Concept ID:
C3808991
Disease or Syndrome
Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.
Cardiofaciocutaneous syndrome 2
MedGen UID:
815335
Concept ID:
C3809005
Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Cardiofaciocutaneous syndrome 3
MedGen UID:
815336
Concept ID:
C3809006
Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Cardiofaciocutaneous syndrome 4
MedGen UID:
815337
Concept ID:
C3809007
Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Cortical dysplasia, complex, with other brain malformations 2
MedGen UID:
815343
Concept ID:
C3809013
Disease or Syndrome
Severe congenital neutropenia 5, autosomal recessive
MedGen UID:
815361
Concept ID:
C3809031
Disease or Syndrome
Severe congenital neutropenia-5 is an autosomal recessive primary immunodeficiency disorder characterized primarily by neutropenia and neutrophil dysfunction, a lack of response to G-CSF, life-threatening infections, bone marrow fibrosis, and renal extramedullary hematopoiesis (summary by Vilboux et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700).
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 13
MedGen UID:
815372
Concept ID:
C3809042
Disease or Syndrome
Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is a autosomal recessive disorder associated with severe neurologic defects and resulting in early infantile death. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as dystroglycanopathies (summary by Buysse et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).
Ehlers-Danlos syndrome, progeroid type, 2
MedGen UID:
815540
Concept ID:
C3809210
Disease or Syndrome
The features of Ehlers-Danlos syndrome spondylodysplastic type 2 include an aged appearance, developmental delay, short stature, craniofacial disproportion, generalized osteopenia, defective wound healing, hypermobile joints, hypotonic muscles, and loose but elastic skin (Okajima et al., 1999). For a discussion of genetic heterogeneity of the spondylodysplastic type of Ehlers-Danlos syndrome, see 130070.
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 14
MedGen UID:
815546
Concept ID:
C3809216
Disease or Syndrome
Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type b, 14
MedGen UID:
815551
Concept ID:
C3809221
Disease or Syndrome
MDDGB14 is an autosomal recessive congenital muscular dystrophy characterized by severe muscle weakness apparent in infancy and mental retardation. Some patients may have additional features, such as microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia. It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Carss et al., 2013). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).
Epileptic encephalopathy, childhood-onset
MedGen UID:
815608
Concept ID:
C3809278
Disease or Syndrome
CHD2-related neurodevelopmental disorders are characterized by early-onset epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity). Seizure onset is typically between ages six months and four years. Seizure types typically include drop attacks, myoclonus, and a rapid onset of multiple seizure types associated with generalized spike-wave on EEG, atonic-myoclonic-absence seizures, and clinical photosensitivity. Intellectual disability and/or autism spectrum disorders are common. To date only 32 individuals with a CHD2-related neurodevelopmental disorder have been reported; thus, better understanding of the phenotypic spectrum of CHD2-related neurodevelopmental disorders is likely to evolve over time.
Spinocerebellar ataxia, autosomal recessive 14
MedGen UID:
815657
Concept ID:
C3809327
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-14 is a neurologic disorder characterized by delayed psychomotor development, severe early-onset gait ataxia, eye movement abnormalities, cerebellar atrophy on brain imaging, and intellectual disability (summary by Lise et al., 2012).
Multiple congenital anomalies-hypotonia-seizures syndrome 3
MedGen UID:
815686
Concept ID:
C3809356
Disease or Syndrome
Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Immunodeficiency 8
MedGen UID:
815713
Concept ID:
C3809383
Disease or Syndrome
Cortical dysplasia, complex, with other brain malformations 3
MedGen UID:
815744
Concept ID:
C3809414
Disease or Syndrome
Cortical dysplasia, complex, with other brain malformations 4
MedGen UID:
815750
Concept ID:
C3809420
Disease or Syndrome
Specific language impairment 5
MedGen UID:
815813
Concept ID:
C3809483
Disease or Syndrome
Specific language impairment-5 is characterized by a delay in early speech acquisition and is usually associated with cerebral white matter abnormalities on brain MRI. Some individuals may show disorders in communication, consistent with autism spectrum disorder, or global developmental delay, although others ultimately show normal cognitive function. Penetrance is incomplete and expressivity is variable. This type of disorder is observed most commonly among individuals of East Asian descent (summary by Wiszniewski et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of specific language impairment, see SLI1 (602081).
Infantile liver failure syndrome 1
MedGen UID:
815852
Concept ID:
C3809522
Disease or Syndrome
Combined oxidative phosphorylation deficiency 17
MedGen UID:
815856
Concept ID:
C3809526
Disease or Syndrome
Combined oxidative phosphorylation deficiency-17 is an autosomal recessive disorder of mitochondrial dysfunction characterized by onset of severe hypertrophic cardiomyopathy in the first year of life. Other features include hypotonia, poor growth, lactic acidosis, and failure to thrive. The disorder may be fatal in early childhood (summary by Haack et al., 2013).
Early infantile epileptic encephalopathy 17
MedGen UID:
815936
Concept ID:
C3809606
Disease or Syndrome
Early infantile epileptic encephalopathy-17 is a severe neurologic disorder characterized by onset of intractable seizures in the first weeks or months of life and usually associated with EEG abnormalities. Affected infants have very poor psychomotor development and may have brain abnormalities, such as cerebral atrophy or thin corpus callosum. Some patients may show involuntary movements (summary by Nakamura et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Primary aldosteronism, seizures, and neurologic abnormalities
MedGen UID:
815939
Concept ID:
C3809609
Disease or Syndrome
Early infantile epileptic encephalopathy 18
MedGen UID:
815954
Concept ID:
C3809624
Disease or Syndrome
Early infantile epileptic encephalopathy-18 is a severe autosomal recessive neurologic disorder characterized by lack of psychomotor development apparent from birth, dysmorphic facial features, early onset of refractory seizures, and thick corpus callosum and persistent cavum septum pellucidum on brain imaging (summary by Basel-Vanagaite et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).
Mental retardation, autosomal dominant 21
MedGen UID:
816016
Concept ID:
C3809686
Disease or Syndrome
Alacrima, achalasia, and mental retardation syndrome
MedGen UID:
816068
Concept ID:
C3809738
Disease or Syndrome
Alacrima, achalasia, and mental retardation syndrome (AAMR) is an autosomal recessive disorder characterized by onset of these 3 main features at birth or in early infancy. More variable features include hypotonia, gait abnormalities, anisocoria, and visual or hearing deficits. The disorder shows similarity to the triple A syndrome (231550), but patients with AAMR do not have adrenal insufficiency (summary by Koehler et al., 2013). See also 300858 for a phenotypically similar disorder that shows X-linked inheritance.
Mental retardation, autosomal recessive 38
MedGen UID:
816083
Concept ID:
C3809753
Disease or Syndrome
Chromosome 22q13 duplication syndrome
MedGen UID:
816174
Concept ID:
C3809844
Disease or Syndrome
Mental retardation, autosomal recessive 39
MedGen UID:
816183
Concept ID:
C3809853
Disease or Syndrome
Periventricular nodular heterotopia 6
MedGen UID:
816202
Concept ID:
C3809872
Disease or Syndrome
Schaaf-yang syndrome
MedGen UID:
816207
Concept ID:
C3809877
Disease or Syndrome
SHFYNG syndrome is an autosomal dominant multisystem disorder characterized by delayed psychomotor development, impaired intellectual development, hypotonia, and behavioral abnormalities. Additional features include contractures, feeding difficulties, and variable dysmorphic facial features. The severity of the disorder is highly variable: some patients may die in utero with fetal akinesia, whereas others can live with moderate disability. Individuals are affected only if the mutation occurs on the paternal allele, since MAGEL2 is a maternally imprinted gene (summary by Fountain et al., 2017)
Arthrogryposis, mental retardation, and seizures
MedGen UID:
816240
Concept ID:
C3809910
Disease or Syndrome
Common variable immunodeficiency 10
MedGen UID:
816321
Concept ID:
C3809991
Disease or Syndrome
Common variable immunodeficiency-10 is an autosomal dominant primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency (summary by Chen et al., 2013). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).
Verheij syndrome
MedGen UID:
816353
Concept ID:
C3810023
Disease or Syndrome
Verheij syndrome is characterized by growth retardation, delayed psychomotor development, dysmorphic facial features, and skeletal, mainly vertebral, abnormalities. Additional variable features may include coloboma, renal defects, and cardiac defects (summary by Verheij et al., 2009 and Dauber et al., 2013).
Congenital disorder of glycosylation type 1w
MedGen UID:
816392
Concept ID:
C3810062
Disease or Syndrome
A form of congenital disorders of N-linked glycosylation with characteristics of developmental delay, intellectual disability, failure to thrive, hypotonia and seizures. Caused by mutations in the gene STT3A (11q23.3).
Mental retardation, autosomal recessive 40
MedGen UID:
816410
Concept ID:
C3810080
Disease or Syndrome
Joubert syndrome 21
MedGen UID:
816542
Concept ID:
C3810212
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Mental retardation, autosomal recessive 41
MedGen UID:
816555
Concept ID:
C3810225
Disease or Syndrome
Neurodegeneration with brain iron accumulation 6
MedGen UID:
816560
Concept ID:
C3810230
Disease or Syndrome
Neurodegeneration with brain iron accumulation refers to a group of neurodegenerative disorders characterized by progressive motor and cognitive dysfunction beginning in childhood or young adulthood. Patients show extrapyramidal motor signs, such as spasticity, dystonia, and parkinsonism. Brain imaging shows iron accumulation in the basal ganglia (summary by Dusi et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).
Joubert syndrome 22
MedGen UID:
816608
Concept ID:
C3810278
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Chromosome 5q12 deletion syndrome
MedGen UID:
816612
Concept ID:
C3810282
Disease or Syndrome
Bosch-Boonstra-Schaaf optic atrophy syndrome
MedGen UID:
816693
Concept ID:
C3810363
Disease or Syndrome
Bosch-Boonstra-Schaaf optic atrophy syndrome is an autosomal dominant disorder characterized by delayed development, moderate intellectual disability, and optic atrophy. Most patients also have evidence of cerebral visual impairment. Dysmorphic facial features are variable and nonspecific (summary by Bosch et al., 2014).
Epileptic encephalopathy, early infantile, 19
MedGen UID:
816730
Concept ID:
C3810400
Disease or Syndrome
An autosomal dominant form of early infantile epileptic encephalopathy, caused by mutation(s) in the GABRA1 gene, encoding gamma-aminobutyric acid receptor subunit alpha-1.
Carbonic anhydrase VA deficiency, hyperammonemia due to
MedGen UID:
816734
Concept ID:
C3810404
Disease or Syndrome
The four children with carbonic anhydrase VA (CA-VA) deficiency reported to date presented between day two of life and age 20 months with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma). Data on long-term follow up are limited (the oldest known patient is age 7 years). Two of the four children showed normal psychomotor development and two showed mild learning difficulties and delayed motor skills. Seven additional children diagnosed with CA-VA deficiency (but not yet published) presented similarly.
Mental retardation, autosomal dominant 23
MedGen UID:
816736
Concept ID:
C3810406
Disease or Syndrome
X-Linked Mental Retardation 41
MedGen UID:
854647
Concept ID:
C3887939
Disease or Syndrome
Nonsyndromic mental retardation.
Hermansky-Pudlak syndrome 6
MedGen UID:
854714
Concept ID:
C3888007
Disease or Syndrome
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Aicardi-Goutieres syndrome 7
MedGen UID:
854829
Concept ID:
C3888244
Disease or Syndrome
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Bardet-Biedl syndrome 16
MedGen UID:
855172
Concept ID:
C3889474
Disease or Syndrome
Bardet-Biedl syndrome (BBS) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.
Mental retardation, X-linked 101
MedGen UID:
855517
Concept ID:
C3890168
Disease or Syndrome
Seckel syndrome 8
MedGen UID:
856014
Concept ID:
C3891452
Disease or Syndrome
Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance (summary by Shanske et al., 1997). For a discussion of genetic heterogeneity of Seckel syndrome, see SCKL1 (210600).
Congenital disorder of glycosylation type 1y
MedGen UID:
860832
Concept ID:
C4012395
Disease or Syndrome
A form of congenital disorders of N-linked glycosylation with characteristics of neurologic abnormalities (global developmental delay in language, social skills and fine and gross motor development, intellectual disability, hypotonia, microcephaly, seizures/epilepsy), facial dysmorphism (deep set eyes, large ears, hypoplastic vermillion of upper lip, large mouth with widely spaced teeth), feeding problems often due to chewing difficulties and aversion to food with certain textures, failure to thrive, gastrointestinal abnormalities (reflux or vomiting) and strabismus. The disease is caused by mutations in the gene SSR4 (Xq28).
Pancreatic agenesis and congenital heart disease
MedGen UID:
860891
Concept ID:
C4012454
Disease or Syndrome
Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1
MedGen UID:
861164
Concept ID:
C4012727
Disease or Syndrome
The MPPH syndrome is a developmental brain disorder characterized by megalencephaly (brain overgrowth) with the cortical malformation bilateral perisylvian polymicrogyria (BPP). At birth the occipital frontal circumference (OFC) ranges from normal to 6 standard deviations (SD) above the mean for age, sex, and gestational age; in older individuals the range is from 3 to 10 SD above the mean. A variable degree of ventriculomegaly is seen in almost all children with MPPH syndrome; nearly 50% of those have frank hydrocephalus. Neurologic problems associated with BPP include oromotor dysfunction (100%), epilepsy (50%), and mild to severe intellectual disability (100%). Postaxial hexadactyly occurs in 50% of individuals with MPPH syndrome.
Desbuquois dysplasia 2
MedGen UID:
862731
Concept ID:
C4014294
Disease or Syndrome
Desbuquois dysplasia, which belongs to the multiple dislocation group of disorders, is characterized by dislocations of large joints, severe pre- and postnatal growth retardation, joint laxity, and flat face with prominent eyes. Radiologic features include short long bones with an exaggerated trochanter that gives a 'monkey wrench' appearance to the proximal femur, and advanced carpal and tarsal ossification (summary by Bui et al., 2014). For a discussion of genetic heterogeneity of Desbuquois dysplasia, see DBQD1 (251450).
Mental retardation, autosomal recessive 42
MedGen UID:
862780
Concept ID:
C4014343
Disease or Syndrome
Autosomal recessive mental retardation-42 is a neurodevelopmental disorder characterized by severely delayed psychomotor development. Additional features are variable and include nonspecific dysmorphic facial features, hypotonia, structural brain abnormalities, and cortical visual impairment (summary by Bosch et al., 2015). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Immunodeficiency 23
MedGen UID:
862808
Concept ID:
C4014371
Disease or Syndrome
IMD23 is an autosomal recessive primary immunodeficiency syndrome characterized by recurrent respiratory and skin infections beginning in early childhood. Laboratory studies are notable for increased serum IgE. Affected individuals also show developmental delay or cognitive impairment of varying severity (summary by Zhang et al., 2014).
Mental retardation, autosomal recessive 43
MedGen UID:
862823
Concept ID:
C4014386
Disease or Syndrome
Mitochondrial complex III deficiency, nuclear type 7
MedGen UID:
862845
Concept ID:
C4014408
Disease or Syndrome
Mitochondrial complex III deficiency is a genetic condition that can affect several parts of the body, including the brain, kidneys, liver, heart, and the muscles used for movement (skeletal muscles). Signs and symptoms of mitochondrial complex III deficiency usually begin in infancy but can appear later.The severity of mitochondrial complex III deficiency varies widely among affected individuals. People who are mildly affected tend to have muscle weakness (myopathy) and extreme tiredness (fatigue), particularly during exercise (exercise intolerance). More severely affected individuals have problems with multiple body systems, such as liver disease that can lead to liver failure, kidney abnormalities (tubulopathy), and brain dysfunction (encephalopathy). Encephalopathy can cause delayed development of mental and motor skills (psychomotor delay), movement problems, weak muscle tone (hypotonia), and difficulty with communication. Some affected individuals have a form of heart disease called cardiomyopathy, which can lead to heart failure. Most people with mitochondrial complex III deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis). Some affected individuals also have buildup of molecules called ketones (ketoacidosis) or high blood sugar levels (hyperglycemia). Abnormally high levels of these chemicals in the body can be life-threatening.Mitochondrial complex III deficiency can be fatal in childhood, although individuals with mild signs and symptoms can survive into adolescence or adulthood.
Mental retardation, autosomal dominant 24
MedGen UID:
862851
Concept ID:
C4014414
Disease or Syndrome
Xia-Gibbs syndrome
MedGen UID:
862856
Concept ID:
C4014419
Disease or Syndrome
Xia-Gibbs syndrome is a neurological disorder characterized by weak muscle tone (hypotonia), mild to severe intellectual disability and delayed development. Expressive language skills (vocabulary and the production of speech) are particularly affected; children with this condition usually do not speak their first word, a milestone typically achieved within the first year, until age two or later, and some never learn to talk. Development of motor skills, such as crawling and walking, can also be delayed.Other signs and symptoms of Xia-Gibbs syndrome vary among affected individuals. Additional neurological features include poor coordination and balance (ataxia) and seizures. Feeding problems and sleep abnormalities can also occur in people with the condition, and many affected individuals experience short pauses in breathing while they sleep (obstructive sleep apnea). In some people with Xia-Gibbs syndrome, imaging tests of the brain show abnormalities in the brain's structure. For example, the tissue connecting the left and right halves of the brain (the corpus callosum) can be abnormally thin.Xia-Gibbs syndrome can also affect physical development. Growth is usually impaired, and many affected individuals are shorter than their peers. Side-to-side curvature of the spine (scoliosis) is also a common feature. Some people with Xia-Gibbs syndrome have unusual facial features, such as a broad forehead, low-set ears or ears that stick out, widely space eyes (hypertelorism), eye openings that slant up or down (upslanting palpebral fissures or downslanting palpebral fissures), a flat bridge of the nose, or a thin upper lip. Other, less-common abnormalities involving the bones and skin include premature fusion of certain skull bones (craniosynostosis), unusually loose (lax) joints, and loose skin.Behavior problems can also occur in Xia-Gibbs syndrome. Some affected individuals have features of autism spectrum disorder, which is characterized by impaired communication and social interactions, or of attention-deficit/hyperactivity disorder (ADHD). Other problems can include aggression, anxiety, poor impulse control, and self-injury.
Mental retardation, autosomal dominant 26
MedGen UID:
862872
Concept ID:
C4014435
Disease or Syndrome
Mitochondrial complex III deficiency, nuclear type 8
MedGen UID:
862877
Concept ID:
C4014440
Disease or Syndrome
Mitochondrial complex III deficiency, nuclear type 8, is an autosomal recessive disorder characterized by progressive neurodegeneration with onset in childhood. Affected individuals may have normal or delayed early development, and often have episodic acute neurologic decompensation and regression associated with febrile illnesses. The developmental regression results in variable intellectual disability and motor deficits, such as hypotonia, axial hypertonia, and spasticity; some patients may lose the ability to walk independently. Laboratory studies show increased serum lactate and isolated deficiency of mitochondrial complex III in skeletal muscle and fibroblasts. Brain imaging shows a characteristic pattern of multifocal small cystic lesions in the periventricular and deep cerebral white matter (summary by Dallabona et al., 2016). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Culler-Jones syndrome
MedGen UID:
862916
Concept ID:
C4014479
Disease or Syndrome
Epileptic encephalopathy, early infantile, 23
MedGen UID:
862929
Concept ID:
C4014492
Disease or Syndrome
Helsmoortel-Van der Aa Syndrome
MedGen UID:
862975
Concept ID:
C4014538
Disease or Syndrome
ADNP-related intellectual disability and autism spectrum disorders (ADNP-related ID/ASD) are characterized by mild to severe intellectual disability and autism spectrum disorder (ASD). Of the 24 individuals reported to date, 23 were ascertained in cohorts with autism spectrum disorder (ASD) / intellectual disability (ID); one was identified in a clinical setting. The clinical information available on 12 of the 24 revealed: delayed developmental milestones (walking independently between 19 months and 4.5 years) and speech ranging from no words to sentences. ASD was characterized by stereotypic behavior and impaired social interaction. Other common findings include behavioral problems, sleep disturbance, hypotonia, seizures, feeding difficulties, visual problems (hypermetropia, strabismus, cortical visual impairment), and cardiac defects.
Epileptic encephalopathy, early infantile, 25
MedGen UID:
863058
Concept ID:
C4014621
Disease or Syndrome
Combined oxidative phosphorylation deficiency 20
MedGen UID:
863097
Concept ID:
C4014660
Disease or Syndrome
Combined oxidative phosphorylation deficiency 21
MedGen UID:
863105
Concept ID:
C4014668
Disease or Syndrome
Ataxia-telangiectasia-like disorder 2
MedGen UID:
863113
Concept ID:
C4014676
Disease or Syndrome
Ataxia-telangiectasia-like disorder-2 is an autosomal recessive syndrome resulting from defects in DNA excision repair. Affected individuals have a neurodegenerative phenotype characterized by developmental delay, ataxia, and sensorineural hearing loss. Other features include short stature, cutaneous and ocular telangiectasia, and photosensitivity (summary by Baple et al., 2014). For a discussion of genetic heterogeneity of ATLD, see ATLD1 (604391).
Mental retardation, autosomal recessive 44
MedGen UID:
863182
Concept ID:
C4014745
Disease or Syndrome
Epileptic encephalopathy, early infantile, 26
MedGen UID:
863556
Concept ID:
C4015119
Disease or Syndrome
Pontocerebellar hypoplasia, type 1c
MedGen UID:
863597
Concept ID:
C4015160
Disease or Syndrome
Pontocerebellar hypoplasia type 1C is a severe autosomal recessive neurodegenerative disorder characterized by severe muscle weakness and failure to thrive apparent in the first months of life. Affected infants showed delayed psychomotor development, often with visual and hearing impairment, and may die of respiratory failure. Brain imaging typically shows cerebellar hypoplasia, hypoplasia of the corpus callosum, and immature myelination (summary by Boczonadi et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).
Mental retardation, autosomal dominant 30
MedGen UID:
863604
Concept ID:
C4015167
Disease or Syndrome
Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay
MedGen UID:
863609
Concept ID:
C4015172
Disease or Syndrome
Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013).
Monocarboxylate transporter 1 deficiency
MedGen UID:
863623
Concept ID:
C4015186
Disease or Syndrome
Retinal dystrophy, juvenile cataracts, and short stature syndrome
MedGen UID:
863679
Concept ID:
C4015242
Disease or Syndrome
Mitochondrial complex III deficiency, nuclear type 9
MedGen UID:
863690
Concept ID:
C4015253
Disease or Syndrome
Mental retardation, autosomal recessive 46
MedGen UID:
863720
Concept ID:
C4015283
Disease or Syndrome
Spinocerebellar ataxia, autosomal recessive 17
MedGen UID:
863738
Concept ID:
C4015301
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-17 is a neurologic disorder characterized by onset of gait ataxia and cerebellar signs in early childhood. Patients also have variable intellectual disability (summary by Evers et al., 2016).
Epileptic encephalopathy, early infantile, 27
MedGen UID:
863753
Concept ID:
C4015316
Disease or Syndrome
GRIN2B-related neurodevelopmental disorder is characterized by mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties), as well as epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common. Other infantile- or childhood-onset findings include microcephaly; dystonic, dyskinetic, or choreiform movement disorder; and/or cortical visual impairment. Brain MRI reveals a malformation of cortical development in a minority of affected individuals. To date, fewer than 100 individuals with GRIN2B-related neurodevelopmental disorder have been reported.
Leukodystrophy, hypomyelinating, 9
MedGen UID:
863760
Concept ID:
C4015323
Disease or Syndrome
Hypomyelinating leukodystrophy-9 is an autosomal recessive neurologic disorder characterized by onset of delayed psychomotor development, spasticity, and nystagmus in the first year of life. Additional neurologic features such as ataxia and abnormal movements may also occur. Brain imaging shows diffuse hypomyelination affecting all regions of the brain (summary by Wolf et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.
Generalized epilepsy with febrile seizures plus, type 9
MedGen UID:
863832
Concept ID:
C4015395
Disease or Syndrome
Generalized epilepsy with febrile seizures plus-9 is an autosomal dominant neurologic disorder characterized by onset of febrile and/or afebrile seizures in early childhood, usually before age 3 years. Seizure types are variable and include generalized tonic-clonic, atonic, myoclonic, complex partial, and absence. Most patients have remission of seizures later in childhood with no residual neurologic deficits, but rare patients may show mild developmental delay or mild intellectual disabilities (summary by Schubert et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of GEFS+, see 604233.
Mental retardation, autosomal recessive 47
MedGen UID:
863881
Concept ID:
C4015444
Disease or Syndrome
Combined oxidative phosphorylation deficiency 23
MedGen UID:
863884
Concept ID:
C4015447
Disease or Syndrome
Combined oxidative phosphorylation deficiency-23 is an autosomal recessive disorder characterized by early childhood onset of hypertrophic cardiomyopathy and/or neurologic symptoms, including hypotonia and delayed psychomotor development. Laboratory investigations are consistent with a defect in mitochondrial function resulting in lactic acidosis, impaired activities of respiratory complexes I and IV, and defective translation of mitochondrial proteins. Brain imaging shows abnormal lesions in the basal ganglia, thalamus, and brainstem. The severity of the disorder is variable, ranging from death in early infancy to survival into the second decade (summary by Kopajtich et al., 2014). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Cerebellofaciodental syndrome
MedGen UID:
863932
Concept ID:
C4015495
Disease or Syndrome
Cerebellofaciodental syndrome is an autosomal recessive neurodevelopmental disorder characterized by delayed development, intellectual disability, abnormal facial and dental findings, and cerebellar hypoplasia (summary by Borck et al., 2015).
Spinocerebellar ataxia, autosomal recessive 18
MedGen UID:
863942
Concept ID:
C4015505
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-18 is a neurologic disorder characterized by delayed psychomotor development, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and intellectual disability. Brain imaging shows progressive cerebellar atrophy (summary by Hills et al., 2013).
Lissencephaly 6, with microcephaly
MedGen UID:
863962
Concept ID:
C4015525
Congenital Abnormality
Lissencephaly-6 is an autosomal recessive neurodevelopmental disorder characterized by severe microcephaly and developmental delay. Brain imaging shows variable malformations of cortical development, including lissencephaly, pachygyria, and hypoplasia of the corpus callosum (summary by Mishra-Gorur et al., 2014). For a general description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).
Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset
MedGen UID:
864165
Concept ID:
C4015728
Disease or Syndrome
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD) is an autosomal recessive multisystemic disorder with variable expressivity. The core features usually include global developmental delay with impaired intellectual development and speech delay, ataxia, sensorineural hearing loss, and pancreatic insufficiency. Additional features may include peripheral neuropathy, postnatal microcephaly, dysmorphic facial features, and cerebellar atrophy. However, some patients may not display all features (summary by Picker-Minh et al., 2016, Sharkia et al., 2017).
Congenital hyperammonemia, type I
MedGen UID:
907954
Concept ID:
C4082171
Disease or Syndrome
Carbamoyl phosphate synthetase I deficiency is an autosomal recessive inborn error of metabolism of the urea cycle which causes hyperammonemia. There are 2 main forms: a lethal neonatal type and a less severe, delayed-onset type (summary by Klaus et al., 2009). Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency (207800).
Joubert syndrome 23
MedGen UID:
900119
Concept ID:
C4084822
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Joubert syndrome 25
MedGen UID:
895764
Concept ID:
C4084842
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
Joubert syndrome 26
MedGen UID:
900415
Concept ID:
C4084843
Disease or Syndrome
Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.
MEND syndrome
MedGen UID:
905986
Concept ID:
C4085243
Disease or Syndrome
Male EBP disorder with neurologic defects is an X-linked recessive disorder representing a continuous phenotypic spectrum with variable manifestations associated with a defect in sterol biosynthesis. Features include intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities. Not all patients show all features, and the severity is highly variable. Molecular studies indicate that affected males are hemizygous for a nonmosaic hypomorphic EBP allele. Carrier females are generally clinically asymptomatic, but may show biochemical abnormalities (summary by Arnold et al., 2012 and Barboza-Cerda et al., 2014).
AL-RAQAD SYNDROME
MedGen UID:
897610
Concept ID:
C4085595
Disease or Syndrome
Chops syndrome
MedGen UID:
894554
Concept ID:
C4085597
Disease or Syndrome
CHOPS syndrome is a disorder involving multiple abnormalities that are present from birth (congenital). The name "CHOPS" is an abbreviation for a list of features of the disorder including cognitive impairment, coarse facial features, heart defects, obesity, lung (pulmonary) involvement, short stature, and skeletal abnormalities.Children with CHOPS syndrome have intellectual disability and delayed development of skills such as sitting and walking. Characteristic facial features include a round face; thick hair; thick eyebrows that grow together in the middle (synophrys); wide-set, bulging eyes with long eyelashes; a short nose; and down-turned corners of the mouth.Most affected individuals are born with a heart defect called patent ductus arteriosus (PDA). The ductus arteriosus is a connection between two major arteries, the aorta and the pulmonary artery. This connection is open during fetal development and normally closes shortly after birth. However, the ductus arteriosus remains open, or patent, in babies with PDA. If untreated, this heart defect causes infants to breathe rapidly, feed poorly, and gain weight slowly; in severe cases, it can lead to heart failure. Multiple heart abnormalities have sometimes been found in children with CHOPS syndrome. In addition to PDA, affected individuals may have ventricular septal defect, which is a defect in the muscular wall (septum) that separates the right and left sides of the heart's lower chamber.People with CHOPS syndrome have abnormalities of the throat and airways that cause momentary cessation of breathing while asleep (obstructive sleep apnea). These abnormalities can also cause affected individuals to breathe food or fluids into the lungs accidentally, which can lead to a potentially life-threatening bacterial lung infection (aspiration pneumonia) and chronic lung disease. Affected individuals are shorter than more than 97 percent of their peers and are overweight for their height. They also have skeletal differences including unusually short fingers and toes (brachydactyly) and abnormally-shaped spinal bones (vertebrae).Other features that can occur in CHOPS syndrome include a small head size (microcephaly); hearing loss; clouding of the lens of the eye (cataract); a single, horseshoe-shaped kidney; and, in affected males, undescended testes (cryptorchidism).
Luscan-lumish syndrome
MedGen UID:
898669
Concept ID:
C4085873
Disease or Syndrome
Luscan-Lumish syndrome is characterized by macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures (Luscan et al., 2014; Lumish et al., 2015)
Mental retardation, autosomal dominant 34
MedGen UID:
907277
Concept ID:
C4225156
Mental or Behavioral Dysfunction
Mental retardation, autosomal recessive 52
MedGen UID:
903181
Concept ID:
C4225168
Disease or Syndrome
Leukodystrophy, hypomyelinating, 13
MedGen UID:
896545
Concept ID:
C4225170
Disease or Syndrome
Hypomyelinating leukodystrophy-13 is an autosomal recessive neurodegenerative disorder characterized by infantile onset of delayed psychomotor development, axial hypotonia, and spasticity associated with delayed myelination and periventricular white matter abnormalities on brain imaging. More variable neurologic deficits, such as visual impairment, may also occur. Some patients may experience cardiac failure during acute illness (summary by Edvardson et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.
METABOLIC CRISES, RECURRENT, WITH RHABDOMYOLYSIS, CARDIAC ARRHYTHMIAS, AND NEURODEGENERATION
MedGen UID:
894196
Concept ID:
C4225171
Disease or Syndrome
Individuals with TANGO2-related metabolic encephalopathy and arrhythmias can present in acute metabolic crisis (hypoglycemia, elevated lactate, mild hyperammonemia) or with developmental delay, regression, and/or seizures. The acute presentation varies from profound muscle weakness, ataxia, and/or disorientation to a comatose state. Individuals can present with intermittent acute episodes of rhabdomyolysis. The first episode of myoglobinuria has been known to occur as early as age five months. Acute renal tubular damage due to myoglobinuria can result in acute kidney injury and renal failure. During acute illness, transient electrocardiogram changes can be seen; the most common is QT prolongation. Life-threatening recurrent ventricular tachycardia or torsade de pointes occurs primarily during times of acute illness. Individuals who do not present in metabolic crises may present with gait incoordination, progressively unsteady gait, difficulty with speech, or clumsiness. Intellectual disability of variable severity is observed in almost all individuals. Seizures are observed outside the periods of crises in more than 75% of individuals. Hypothyroidism has been reported in more than one third of individuals.
Cerebellar atrophy, visual impairment, and psychomotor retardation
MedGen UID:
905041
Concept ID:
C4225172
Disease or Syndrome
Spinal muscular atrophy with congenital bone fractures 2
MedGen UID:
907910
Concept ID:
C4225176
Disease or Syndrome
Spinal muscular atrophy with congenital bone fractures 1
MedGen UID:
896011
Concept ID:
C4225177
Disease or Syndrome
Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first months or years of life (summary by Knierim et al., 2016). Genetic Heterogeneity of Spinal Muscular Atrophy With Congenital Bone Fractures See also SMABF2 (616867), caused by mutation in the ASCC1 gene (614215) on chromosome 10q22.
Even-plus syndrome
MedGen UID:
904613
Concept ID:
C4225180
Disease or Syndrome
EVEN-PLUS syndrome is characterized by prenatal-onset short stature, vertebral and epiphyseal changes, microtia, midface hypoplasia with flat nose and triangular nares, cardiac malformations, and other findings including anal atresia, hypodontia, and aplasia cutis. The features overlap those reported in patients with CODAS syndrome (600373; Royer-Bertrand et al., 2015).
Lymphedema, hereditary, III
MedGen UID:
908120
Concept ID:
C4225184
Disease or Syndrome
Lymphatic malformation-6 is a form of generalized lymphatic dysplasia (GLD), which is characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. In LMPHM6, there is a high incidence of nonimmune hydrops fetalis (NIHF) with either death or complete resolution of the neonatal edema, but childhood onset of lymphedema with or without systemic involvement also occurs. Mild facial edema is often present. Patients have normal intelligence and no seizures (summary by Fotiou et al., 2015). For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.
Microcephaly, congenital cataract, and psoriasiform dermatitis
MedGen UID:
900653
Concept ID:
C4225189
Disease or Syndrome
SC4MOL deficiency represents an inborn error of cholesterol metabolism that is characterized by accumulation of a large amount of methylsterols, particularly dimethylsterols, in affected patients. The associated features of immune dysregulation, skin disease, and growth delay can be at least partially corrected with cholesterol and statin supplements (He et al., 2014).
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIp
MedGen UID:
895025
Concept ID:
C4225190
Disease or Syndrome
Congenital disorder of glycosylation type IIp (CDG2P) is an autosomal recessive metabolic disorder characterized by mild liver dysfunction, which may be found incidentally during adolescence. Laboratory abnormalities include elevated liver enzymes and alkaline phosphatase, coagulation factor deficiencies, hypercholesterolemia, and low ceruloplasmin. Serum isoelectric focusing of proteins shows a combined defect of N- and O-glycosylation, suggestive of a Golgi defect (summary by Jansen et al., 2016). For an overview of congenital disorders of glycosylation, see CDG1A (212065) and CDG2A (212066).
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIo
MedGen UID:
906792
Concept ID:
C4225191
Congenital Abnormality
Congenital disorder of glycosylation type IIo (CDG2O) is an autosomal recessive metabolic disorder characterized by infantile onset of progressive liver failure, hypotonia, and delayed psychomotor development. Laboratory abnormalities include elevated liver enzymes, coagulation factor deficiencies, hypercholesterolemia, and low ceruloplasmin. Serum isoelectric focusing of proteins shows a combined defect of N- and O-glycosylation, suggestive of a Golgi defect (summary by Jansen et al., 2016). For a general discussion of CDGs, see CDG1A (212065).
Corpus callosum, agenesis of, with facial anomalies and cerebellar ataxia
MedGen UID:
902346
Concept ID:
C4225193
Disease or Syndrome
Hypotonia, infantile, with psychomotor retardation
MedGen UID:
902080
Concept ID:
C4225196
Disease or Syndrome
Combined oxidative phosphorylation deficiency 29
MedGen UID:
901598
Concept ID:
C4225200
Disease or Syndrome
Hyperphosphatasia with mental retardation syndrome 6
MedGen UID:
906509
Concept ID:
C4225201
Disease or Syndrome
Hyperphosphatasia with mental retardation syndrome-6 (HPMRS6) is an autosomal recessive multisystem disorder characterized by global developmental delay, dysmorphic features, seizures, and congenital cataracts. Severity is variable, and the disorder may show a range of phenotypic and biochemical abnormalities, including increased serum alkaline phosphatase levels (summary by Ilkovski et al., 2015). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of HPMRS, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Lamb-shaffer syndrome
MedGen UID:
903542
Concept ID:
C4225202
Disease or Syndrome
Lamb-Shaffer syndrome is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, and mild dysmorphic facial features. Additional variable skeletal abnormalities may also be present (summary by Nesbitt et al., 2015).
Combined oxidative phosphorylation deficiency 28
MedGen UID:
907499
Concept ID:
C4225206
Disease or Syndrome
Combined oxidative phosphorylation deficiency-28 (COXPD28) is a complex autosomal recessive multisystem disorder associated with mitochondrial dysfunction. The phenotype is variable, but includes episodic metabolic decompensation beginning in infancy that can result in mild muscle weakness, cardiorespiratory insufficiency, developmental delay, or even death. Biochemical studies of patient tissues show variable mitochondrial defects, including decreased activities of respiratory chain enzymes (summary by Kishita et al., 2015). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Mental retardation and distinctive facial features with or without cardiac defects
MedGen UID:
900924
Concept ID:
C4225208
Disease or Syndrome
Mental retardation and distinctive facial features with or without cardiac defects (MRFACD) is an autosomal dominant, complex syndromic neurodevelopmental disorder characterized by delayed psychomotor development, poor speech acquisition, distinctive dysmorphic facial features, including frontal bossing, upslanting palpebral fissures, depressed nasal bridge with bulbous tip, and macrostomia. There is variable penetrance of cardiac malformations, ranging from no malformations to patent foramen ovale to septal defects and/or transposition of the great arteries (summary by Adegbola et al., 2015).
Seckel syndrome 9
MedGen UID:
907155
Concept ID:
C4225212
Disease or Syndrome
Leukodystrophy and acquired microcephaly with or without dystonia
MedGen UID:
908888
Concept ID:
C4225213
Disease or Syndrome
Spastic paraplegia and psychomotor retardation with or without seizures
MedGen UID:
897828
Concept ID:
C4225215
Disease or Syndrome
Spastic paraplegia and psychomotor retardation with or without seizures is an autosomal recessive complex neurodevelopmental disorder with onset in infancy. Affected children show hypotonia followed by severely impaired global development and significant motor disability. Most develop seizures in childhood and have speech delay. Other features, such as ocular abnormalities, foot deformities, hypoplasia of the corpus callosum, and decreased white matter, are more variable (summary by Hollstein et al., 2015).
Mental retardation, autosomal recessive 51
MedGen UID:
903243
Concept ID:
C4225220
Disease or Syndrome
Takenouchi-Kosaki syndrome
MedGen UID:
906646
Concept ID:
C4225222
Disease or Syndrome
Takenouchi-Kosaki syndrome is a highly heterogeneous autosomal dominant complex congenital developmental disorder affecting multiple organ systems. The core phenotype includes delayed psychomotor development with variable intellectual disability, dysmorphic facial features, and cardiac, genitourinary, and hematologic or lymphatic defects, including thrombocytopenia and lymphedema. Additional features may include abnormalities on brain imaging, skeletal anomalies, and recurrent infections. Some patients have a milder disease course reminiscent of Noonan syndrome (see, e.g., NS1, 163950) (summary by Martinelli et al., 2018).
Coenzyme Q10 deficiency, primary, 8
MedGen UID:
908648
Concept ID:
C4225226
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Nephrotic syndrome, type 11
MedGen UID:
898622
Concept ID:
C4225228
Disease or Syndrome
Nephrotic syndrome type 11 is an autosomal recessive disorder of the kidney with onset in the first decade of life. The disorder is progressive and usually results in end-stage renal disease necessitating renal transplantation, although some patients may have a slightly milder phenotype (summary by Miyake et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome, see NPHS1 (256300).
Cleft palate, psychomotor retardation, and distinctive facial features
MedGen UID:
895943
Concept ID:
C4225229
Disease or Syndrome
Rhizomelic chondrodysplasia punctata type 5
MedGen UID:
900333
Concept ID:
C4225237
Disease or Syndrome
Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life (summary by Wanders and Waterham, 2005). For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100.
Desanto-shinawi syndrome
MedGen UID:
908218
Concept ID:
C4225239
Disease or Syndrome
WAC-related intellectual disability (ID) is typically characterized by variable degrees of developmental delay and/or intellectual disability. Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder, and/or autism spectrum disorder are observed in the majority of older children and adults. Most affected infants have significant but nonspecific features at birth such as neonatal hypotonia and feeding problems. Some affected individuals come to medical attention with respiratory or vision problems. Facial features may be mildly dysmorphic, but are nonspecific. To date, 18 individuals have been identified with WAC-related ID.
Charcot-Marie-Tooth disease, axonal, type 2z
MedGen UID:
907298
Concept ID:
C4225243
Disease or Syndrome
Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an autosomal dominant peripheral neuropathy characterized by onset, usually in the first decade, of distal lower limb muscle weakness and sensory impairment. The disorder is progressive, and affected individuals tend to develop upper limb and proximal muscle involvement in an asymmetric pattern, resulting in severe disability late in adulthood (summary by Sevilla et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Seizures, scoliosis, and macrocephaly syndrome
MedGen UID:
909039
Concept ID:
C4225248
Disease or Syndrome
Seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from early infancy, impaired intellectual development, behavioral problems, poor or absent speech, seizures, dysmorphic facial features with macro- or microcephaly, and skeletal abnormalities, including scoliosis and delayed bone age. Other features may include hypotonia, gastrointestinal problems, and exostoses (summary by Gentile et al., 2019).
Microcephaly 16, primary, autosomal recessive
MedGen UID:
898705
Concept ID:
C4225249
Disease or Syndrome
Spastic paraplegia 75, autosomal recessive
MedGen UID:
896387
Concept ID:
C4225250
Disease or Syndrome
Spastic paraplegia-75 is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood (summary by Lossos et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).
Combined oxidative phosphorylation deficiency 27
MedGen UID:
908541
Concept ID:
C4225251
Disease or Syndrome
Yuan-Harel-Lupski syndrome
MedGen UID:
894862
Concept ID:
C4225255
Disease or Syndrome
Yuan-Harel-Lupski syndrome is a complex neurodevelopmental disorder characterized by global developmental delay and early-onset peripheral neuropathy. The disorder comprises features of both demyelinating Charcot-Marie-Tooth disease type 1A (CMT1A; 118220), which results from duplication of the PMP22 gene on 17p12, and Potocki-Lupski syndrome (PTLS; 610883), which results from duplication of a slightly proximal region on 17p11.2 that includes the RAI1 gene. These 2 loci are about 2.5 Mb apart. The resultant YUHAL phenotype may be more severe in comparison to the individual contributions of each gene, with particularly early onset of peripheral neuropathy and features of both central and peripheral nervous system involvement (summary by Yuan et al., 2015).
Epileptic encephalopathy, early infantile, 35
MedGen UID:
904159
Concept ID:
C4225256
Disease or Syndrome
Early infantile epileptic encephalopathy-35 is an autosomal recessive neurodegenerative disorder characterized by onset of seizures in the first months of life associated with essentially no normal development. Brain imaging shows a characteristic pattern consistent with lack of myelination of early structures, including the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices. Many patients die in early childhood (summary by Kevelam et al., 2015) For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see 308350.
Early infantile epileptic encephalopathy 34
MedGen UID:
899149
Concept ID:
C4225257
Disease or Syndrome
SLC12A5-related epilepsy of infancy with migrating focal seizures (SLC12A5-EIMFS), reported to date in nine children, is characterized by onset of seizures before age six months and either developmental delay or developmental regression with seizure onset. Of these nine children, six had severe developmental delay with no progress of abilities and three made notable neurodevelopmental progress. Eight had postnatal microcephaly and hypotonia. In most children epilepsy begins as focal motor seizures (typically involving head and eye deviation) that become multifocal and intractable to conventional antiepileptic drugs (AEDs).
Senior-Loken syndrome 9
MedGen UID:
899086
Concept ID:
C4225263
Disease or Syndrome
Senior-Loken syndrome-9 is an autosomal recessive disorder characterized by early-onset nephronophthisis and pigmentary retinopathy. Additional more variable features can include liver defects, skeletal anomalies, and obesity (summary by Bizet et al., 2015). For a phenotypic description and a discussion of genetic heterogeneity of Senior-Loken syndrome, see 266900.
Cutis laxa, autosomal dominant 3
MedGen UID:
899774
Concept ID:
C4225268
Disease or Syndrome
Autosomal dominant cutis laxa-3 is characterized by thin skin with visible veins and wrinkles, cataract or corneal clouding, clenched fingers, pre- and postnatal growth retardation, and moderate intellectual disability. In addition, patients exhibit a combination of muscular hypotonia with brisk muscle reflexes (Fischer-Zirnsak et al., 2015). For a general phenotypic description and discussion of genetic heterogeneity of autosomal dominant cutis laxa, see ARCL1 (123700).
Craniosynostosis 6
MedGen UID:
904675
Concept ID:
C4225269
Disease or Syndrome
Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by Fitzpatrick, 2013). Craniosynostosis-6 is a bicoronal form associated with bony defects in the sagittal, metopic, or lambdoid sutures (Twigg et al., 2015). For a discussion of genetic heterogeneity of craniosynostosis, see CRS1 (123100).
Spastic paraplegia 9b, autosomal recessive
MedGen UID:
909058
Concept ID:
C4225272
Disease or Syndrome
Autosomal recessive SPG9B is a neurologic disorder characterized by early-onset complex spastic paraplegia. Affected individuals had delayed psychomotor development, intellectual disability, and severe motor impairment. More variable features include dysmorphic facial features, tremor, and urinary incontinence (summary by Coutelier et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).
AU-KLINE SYNDROME
MedGen UID:
900671
Concept ID:
C4225274
Disease or Syndrome
Au-Kline syndrome is characterized by developmental delay and hypotonia with moderate-to-severe intellectual disability, and typical facial features that include long palpebral fissures, ptosis, shallow orbits, large and deeply grooved tongue, broad nose with a wide nasal bridge, and downturned mouth. There is frequently variable autonomic dysfunction (gastrointestinal dysmotility, high pain threshold, heat intolerance, recurrent fevers, abnormal sweating). Congenital heart disease, hydronephrosis, palate abnormalities, and oligodontia are also reported in the majority of affected individuals. Additional complications can include craniosynostosis, feeding difficulty, vision issues, osteopenia, and other skeletal anomalies.
Mental retardation, autosomal dominant 40
MedGen UID:
894460
Concept ID:
C4225275
Disease or Syndrome
Epilepsy, hearing loss, and mental retardation syndrome
MedGen UID:
895574
Concept ID:
C4225276
Disease or Syndrome
Epilepsy, hearing loss, and mental retardation syndrome is an autosomal recessive disorder characterized by severe neurologic impairment including intellectual disability, intractable epilepsy, microcephaly, abnormal muscle tone, and sensori