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Growth delay

MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
Synonyms: Delayed growth; Growth deficiency; Growth retardation; Poor growth; Retarded growth; Very poor growth
 
HPO: HP:0001510

Definition

A deficiency or slowing down of growth pre- and postnatally. [from HPO]

Conditions with this feature

Congenital ocular coloboma
MedGen UID:
1046
Concept ID:
C0009363
Congenital Abnormality
Coloboma is an ocular birth defect resulting from abnormal development of the eye during embryogenesis. It is defined as a congenital defect in any ocular tissue, typically presenting as absent tissue or a gap, at a site consistent with aberrant closure of the optic fissure. Failure of fusion can lead to coloboma of one or multiple regions of the inferior portion of the eye affecting any part of the globe traversed by the fissure, from the iris to the optic nerve, including the ciliary body, retina, and choroid. Coloboma is also frequently associated with small (microphthalmic) or absent (anophthalmic) eyes as part of an interrelated spectrum of developmental eye anomalies, and can affect either one or both eyes (summary by Kelberman et al., 2014). Genetic Heterogeneity of Ocular Coloboma A recessive form of ocular coloboma (216820) is caused by mutation in the SALL2 gene (602219) on chromosome 14q11.
5p partial monosomy syndrome
MedGen UID:
41345
Concept ID:
C0010314
Disease or Syndrome
Cri-du-chat syndrome was first described by Lejeune et al. (1963) as a hereditary congenital syndrome associated with deletion of part of the short arm of chromosome 5. The deletions can vary in size from extremely small and involving only band 5p15.2 to the entire short arm. Although the majority of deletions arise as new mutations, approximately 12% result from unbalanced segregation of translocations or recombination involving a pericentric inversion in one of the parents.
Familial dysautonomia
MedGen UID:
41678
Concept ID:
C0013364
Congenital Abnormality
Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature perception, and cardiovascular instability. About 40% of individuals have autonomic crises. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Life expectancy is decreased.
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.
Hutchinson-Gilford syndrome
MedGen UID:
46123
Concept ID:
C0033300
Disease or Syndrome
Hutchinson-Gilford progeria syndrome (HGPS) is characterized by clinical features that typically develop in childhood and resemble some features of accelerated aging. Children with HGPS usually appear normal at birth. Profound failure to thrive occurs during the first year. Characteristic facial features include head that is disproportionately large for the face, narrow nasal ridge, narrow nasal tip, thin vermilion of the upper and lower lips, small mouth, and retro- and micrognathia. Common features include loss of subcutaneous fat, delayed eruption and loss of primary teeth, abnormal skin with small outpouchings over the abdomen and upper thighs, alopecia, nail dystrophy, coxa valga, and progressive joint contractures. Later findings include low-frequency conductive hearing loss, dental crowding, and partial lack of secondary tooth eruption. Motor and mental development is normal. Death occurs as a result of complications of severe atherosclerosis, either cardiac disease (myocardial infarction or heart failure) or cerebrovascular disease (stroke), generally between ages six and 20 years. Average life span is approximately 14.5 years.
Protein-losing enteropathy
MedGen UID:
19522
Concept ID:
C0033680
Disease or Syndrome
Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy is characterized by abdominal pain and diarrhea, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption. Some patients also exhibit bowel inflammation, recurrent infections associated with hypogammaglobulinemia, and/or angiopathic thromboembolic disease. Patient T lymphocytes show increased complement activation, causing surface deposition of complement and generating soluble C5a (Ozen et al., 2017).
Epidermolysis bullosa simplex Dowling-Meara type
MedGen UID:
38194
Concept ID:
C0079295
Disease or Syndrome
Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some cases) that results in non-scarring blisters and erosions caused by minor mechanical trauma. The current classification of epidermolysis bullosa (EB) includes two major types and 17 minor subtypes of EBS; all share the common feature of blistering above the dermal-epidermal junction at the ultrastructural level. The four most common subtypes of EBS are the focus of this GeneReview: EBS, localized (EBS-loc; previously known as Weber-Cockayne type). EBS, generalized intermediate (EBS-gen intermed; previously known as Koebner type). EBS-with mottled pigmentation (EBS-MP). EBS, generalized severe (EBS-gen sev; previously known as Dowling-Meara type). The phenotypes for these subtypes range from relatively mild blistering of the hands and feet to more generalized blistering, which can be fatal. In EBS-loc, blisters are rarely present or minimal at birth and may occur on the knees and shins with crawling or on the feet at approximately age 18 months; some individuals manifest the disease in adolescence or early adulthood. Blisters are usually confined to the hands and feet, but can occur anywhere if trauma is significant. In EBS, gen intermed, blisters may be present at birth or develop within the first few months of life. Involvement is more widespread than in EBS-loc, but generally milder than in EBS-gen sev. In EBS-MP, skin fragility is evident at birth and clinically indistinguishable from EBS-gen sev; over time, progressive brown pigmentation interspersed with hypopigmented spots develops on the trunk and extremities, with the pigmentation disappearing in adult life. Focal palmar and plantar hyperkeratoses may occur. In EBS-gen sev, onset is usually at birth; severity varies greatly, both among and within families. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical and hemorrhagic blisters are common. Improvement occurs during mid- to late childhood. Progressive hyperkeratosis of the palms and soles begins in childhood and may be the major complaint of affected individuals in adult life. Nail dystrophy and milia are common. Both hyper- and hypopigmentation can occur. Mucosal involvement in EBS-gen sev may interfere with feeding, especially in neonates and infants. Blistering can be severe enough to result in neonatal or infant death.
Recessive dystrophic epidermolysis bullosa
MedGen UID:
36311
Concept ID:
C0079474
Disease or Syndrome
Dystrophic epidermolysis bullosa (DEB) is a genetic skin disorder affecting skin and nails that usually presents at birth. DEB is divided into two major types depending on inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB). Each type is further divided into multiple clinical subtypes. Absence of a known family history of DEB does not preclude the diagnosis. Clinical findings in severe generalized RDEB include skin fragility manifest by blistering with minimal trauma that heals with milia and scarring. Blistering and erosions affecting the whole body may be present in the neonatal period. Oral involvement may lead to mouth blistering, fusion of the tongue to the floor of the mouth, and progressive diminution of the size of the oral cavity. Esophageal erosions can lead to webs and strictures that can cause severe dysphagia. Consequently, malnutrition and vitamin and mineral deficiency may lead to growth restriction in young children. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring fuses the digits into "mitten" hands and feet, with contractures and pseudosyndactyly. The lifetime risk of aggressive squamous cell carcinoma is higher than 90%. In contrast, the blistering in the less severe forms of RDEB may be localized to hands, feet, knees, and elbows with or without involvement of flexural areas and the trunk, and without the mutilating scarring seen in severe generalized RDEB. In DDEB, blistering is often mild and limited to hands, feet, knees, and elbows, but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common and may be the only manifestation of DDEB.
Thyroid hypoplasia
MedGen UID:
57720
Concept ID:
C0151516
Disease or Syndrome
Thyroid hypoplasia is a form of thyroid dysgenesis (see this term) characterized by incomplete development of the thyroid gland that results in primary congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth.
Cyclical vomiting syndrome
MedGen UID:
57509
Concept ID:
C0152164
Disease or Syndrome
A condition characterized by recurrent, self-limiting episodes of vomiting associated with intense nausea, pallor, and lethargy. It is commonly a migraine precursor.
Smith-Lemli-Opitz syndrome
MedGen UID:
61231
Concept ID:
C0175694
Disease or Syndrome
Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple-anomaly / cognitive impairment syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase. It is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide; individuals with normal development and only minor malformations have been described.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Miller syndrome
MedGen UID:
120522
Concept ID:
C0265257
Disease or Syndrome
Miller syndrome, or postaxial acrofacial dysostosis, is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (summary by Ng et al., 2010).
Ectopic thyroid
MedGen UID:
78591
Concept ID:
C0266283
Congenital Abnormality
Thyroid ectopia is a form of thyroid dysgenesis (see this term) characterized by an ectopic location of the thyroid gland that results in primary congenital hypothyroidism (see this term), a permanent thyroid deficiency that is present from birth.
Congenital secretory diarrhea, chloride type
MedGen UID:
78631
Concept ID:
C0267662
Disease or Syndrome
Congenital secretory chloride diarrhea is an autosomal recessive form of severe chronic diarrhea characterized by excretion of large amounts of watery stool containing high levels of chloride, resulting in dehydration, hypokalemia, and metabolic alkalosis. The electrolyte disorder resembles the renal disorder Bartter syndrome (see 607364), except that chloride diarrhea is not associated with calcium level abnormalities (summary by Choi et al., 2009). Genetic Heterogeneity of Diarrhea Other forms of diarrhea include DIAR2 (251850), caused by mutation in the MYO5B gene (606540) on 18q21; DIAR3 (270420), caused by mutation in the SPINT2 gene (605124) on 19q13; DIAR4 (610370), caused by mutation in the NEUROG3 gene (604882) on 10q21; DIAR5 (613217), caused by mutation in the EPCAM gene (185535) on 2p21; DIAR6 (614616), caused by mutation in the GUCY2C gene (601330) on 12p12; DIAR7 (615863) caused by mutation in the DGAT1 gene (604900) on 8q24; DIAR8 (616868), caused by mutation in the SLC9A3 gene (182307) on 5p15; DIAR9 (618168), caused by mutation in the WNT2B gene (601968) on 1p13; DIAR10 (618183), caused by mutation in the PLVAP gene (607647) on 19p13; DIAR11 (618662), caused by deletion of the intestine critical region (ICR) on chromosome 16p13, resulting in loss of expression of the flanking gene PERCC1 (618656); and DIAR12 (619445), caused by mutation in the STX3 gene (600876) on 11q12.
Combined molybdoflavoprotein enzyme deficiency
MedGen UID:
75652
Concept ID:
C0268119
Disease or Syndrome
Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive metabolic disorder characterized by onset in infancy of poor feeding, intractable seizures, and severe psychomotor retardation. Characteristic biochemical abnormalities include decreased serum uric acid and increased urine sulfite levels due to the combined enzymatic deficiency of xanthine dehydrogenase (XDH; 607633) and sulfite oxidase (SUOX; 606887), both of which use molybdenum as a cofactor. Most affected individuals die in early childhood (summary by Reiss, 2000; Reiss et al., 2011). Genetic Heterogeneity of Molybdenum Cofactor Deficiency See also MOCOD, complementation group B (MOCODB; 252160), caused by mutation in the MOCS2 gene (602708) on chromosome 5q11; and MOCOD, complementation group C (MOCODC; 615501), caused by mutation in the GPHN gene (603930) on chromosome 14q24.
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).
Xeroderma pigmentosum, group G
MedGen UID:
75657
Concept ID:
C0268141
Disease or Syndrome
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
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).
Corticosterone 18-monooxygenase deficiency
MedGen UID:
82784
Concept ID:
C0268293
Disease or Syndrome
CMO type I deficiency is an autosomal recessive disorder caused by a defect in the penultimate biochemical step of aldosterone biosynthesis, the 18-hydroxylation of corticosterone (B) to 18-hydroxycorticosterone (18-OHB). This enzymatic defect results in decreased aldosterone and salt-wasting. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal. These patients have an increased ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998). The CYP11B2 gene product also catalyzes the final step in aldosterone biosynthesis: the 18-oxidation of 18-OHB to aldosterone. A defect in that enzymatic step results in CMO type II deficiency (610600), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).
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.
Rowley-Rosenberg syndrome
MedGen UID:
120638
Concept ID:
C0268426
Disease or Syndrome
Familial hypokalemia-hypomagnesemia
MedGen UID:
75681
Concept ID:
C0268450
Disease or Syndrome
Gitelman syndrome is an autosomal recessive renal tubular salt-wasting disorder characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. It is the most common renal tubular disorder among Caucasians (prevalence of 1 in 40,000). Most patients have onset of symptoms as adults, but some can present in childhood. Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis (summary by Glaudemans et al., 2012). Gitelman syndrome is sometimes referred to as a mild variant of classic Bartter syndrome (607364). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
Dopa-responsive dystonia due to 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.
Tyrosinemia type II
MedGen UID:
75687
Concept ID:
C0268487
Disease or Syndrome
Tyrosinemia type II (TYRSN2) is an autosomal recessive disorder characterized by keratitis, painful palmoplantar hyperkeratosis, mental retardation, and elevated serum tyrosine levels. The disorder is caused by deficiency of hepatic tyrosine aminotransferase (Natt et al., 1992).
Hyperlysinuria with hyperammonemia
MedGen UID:
120650
Concept ID:
C0268555
Disease or Syndrome
Acetyl-CoA: carboxylase deficiency
MedGen UID:
124338
Concept ID:
C0268603
Disease or Syndrome
GLUTAMATE FORMIMINOTRANSFERASE DEFICIENCY
MedGen UID:
82823
Concept ID:
C0268609
Disease or Syndrome
Glutamate formiminotransferase deficiency is an autosomal recessive disorder and the second most common inborn error of folate metabolism. Features of a severe phenotype include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and mental retardation. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematologic abnormalities (summary by Hilton et al., 2003).
Vitamin D-dependent rickets, type 1
MedGen UID:
124344
Concept ID:
C0268689
Disease or Syndrome
Vitamin D-dependent rickets is a disorder of bone development that leads to softening and weakening of the bones (rickets). There are several forms of the condition that are distinguished primarily by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A). There is also evidence of a very rare form of the condition, called type 2B (VDDR2B), although not much is known about this form.\n\nThe signs and symptoms of vitamin D-dependent rickets begin within months after birth, and most are the same for all types of the condition. The weak bones often cause bone pain and delayed growth and have a tendency to fracture. When affected children begin to walk, they may develop abnormally curved (bowed) legs because the bones are too weak to bear weight. Impaired bone development also results in widening of the areas near the ends of bones where new bone forms (metaphyses), especially in the knees, wrists, and ribs. Some people with vitamin D-dependent rickets have dental abnormalities such as thin tooth enamel and frequent cavities. Poor muscle tone (hypotonia) and muscle weakness are also common in this condition, and some affected individuals develop seizures.\n\nIn vitamin D-dependent rickets, there is an imbalance of certain substances in the blood. An early sign in all types of the condition is low levels of the mineral calcium (hypocalcemia), which is essential for the normal formation of bones and teeth. Affected individuals also develop high levels of a hormone involved in regulating calcium levels called parathyroid hormone (PTH), which leads to a condition called secondary hyperparathyroidism. Low levels of a mineral called phosphate (hypophosphatemia) also occur in affected individuals. Vitamin D-dependent rickets types 1 and 2 can be grouped by blood levels of a hormone called calcitriol, which is the active form of vitamin D; individuals with VDDR1A and VDDR1B have abnormally low levels of calcitriol and individuals with VDDR2A and VDDR2B have abnormally high levels.\n\nHair loss (alopecia) can occur in VDDR2A, although not everyone with this form of the condition has alopecia. Affected individuals can have sparse or patchy hair or no hair at all on their heads. Some affected individuals are missing body hair as well.
Pituitary dwarfism with large sella turcica
MedGen UID:
78778
Concept ID:
C0271575
Disease or Syndrome
Progressive osseous heteroplasia
MedGen UID:
137714
Concept ID:
C0334041
Disease or Syndrome
Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues.
Congenital microvillous atrophy
MedGen UID:
137954
Concept ID:
C0341306
Disease or Syndrome
Diarrhea-2 with microvillus atrophy (DIAR2) is characterized by onset of intractable life-threatening watery diarrhea during infancy. Two forms are recognized: early-onset microvillus inclusion disease (MVID) with diarrhea beginning in the neonatal period, and late-onset, with first symptoms appearing after 3 or 4 months of life. Definite diagnosis is made by transmission electron microscopy demonstrating shortening or absence of apical microvilli with pathognomonic microvillus inclusions in mature enterocytes and peripheral accumulation of periodic acid-Schiff (PAS)-positive granules or vesicles in immature enterocytes (Muller et al., 2008). The natural course of MVID is often fatal, but partial or total weaning from parenteral nutrition has been described. For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (214700).
Iodotyrosine deiodination defect
MedGen UID:
87429
Concept ID:
C0342195
Disease or Syndrome
Presumed loss-of-function mutation(s) in the IYD gene, resulting in reduced activity of the enzyme iodotyrosine deiodinase.
Thyroglobulin synthesis defect
MedGen UID:
87430
Concept ID:
C0342196
Disease or Syndrome
Vitamin D-dependent rickets type II with alopecia
MedGen UID:
90989
Concept ID:
C0342646
Disease or Syndrome
Vitamin D-dependent rickets type 2A (VDDR2A) is caused by a defect in the vitamin D receptor gene. This defect leads to an increase in the circulating ligand, 1,25-dihydroxyvitamin D3. Most patients have total alopecia in addition to rickets. VDDR2B (600785) is a form of vitamin D-dependent rickets with a phenotype similar to VDDR2A but a normal vitamin D receptor, in which end-organ resistance to vitamin D has been shown to be caused by a nuclear ribonucleoprotein that interferes with the vitamin D receptor-DNA interaction. For a general phenotypic description and discussion of genetic heterogeneity of rickets due to disorders in vitamin D metabolism or action, see vitamin D-dependent rickets type 1A (VDDR1A; 264700).
D-Glyceric aciduria
MedGen UID:
452447
Concept ID:
C0342765
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).
Dihydropyrimidinase deficiency
MedGen UID:
83353
Concept ID:
C0342803
Disease or Syndrome
DPYS deficiency is an autosomal recessive disease characterized by the presence of dihydropyrimidinuria. The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU) (summary by Nakajima et al., 2017). See also dihydropyrimidine dehydrogenase deficiency (274270), a similar disorder.
Finnish congenital nephrotic syndrome
MedGen UID:
98011
Concept ID:
C0403399
Disease or Syndrome
The nephrotic syndrome is characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. Approximately 20% of affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure (summary by Fuchshuber et al., 1996). Nephrotic syndrome type 1 (NPHS1) is characterized by prenatal onset of massive proteinuria followed by severe steroid-resistant nephrotic syndrome apparent at birth with rapid progression to end-stage renal failure (Kestila et al., 1998). Because of confusion in the literature regarding use of the terms 'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see NOMENCLATURE section), these disorders in OMIM are classified as NPHS or FSGS according to how they were first designated in the literature. Genetic Heterogeneity of Nephrotic Syndrome and Focal Segmental Glomerulosclerosis Nephrotic syndrome and FSGS are genetically heterogeneous disorders representing a spectrum of hereditary renal diseases. See also NPHS2 (600995), caused by mutation in the podocin gene (604766); NPHS3 (610725), caused by mutation in the PLCE1 gene (608414); NPHS4 (256370), caused by mutation in the WT1 gene (607102); NPHS5 (614199), caused by mutation in the LAMB2 gene (150325); NPHS6 (614196), caused by mutation in the PTPRO gene (600579); NPHS7 (615008), caused by mutation in the DGKE gene (601440); NPHS8 (615244), caused by mutation in the ARHGDIA gene (601925); NPHS9 (615573), caused by mutation in the COQ8B gene (615567); NPHS10 (615861), caused by mutation in the EMP2 gene (602334); NPHS11 (616730), caused by mutation in the NUP107 gene (607617); NPHS12 (616892), caused by mutation in the NUP93 gene (614351); NPHS13 (616893), caused by mutation in the NUP205 gene (614352); NPHS14 (617575), caused by mutation in the SGPL1 gene (603729); NPHS15 (617609), caused by mutation in the MAGI2 gene (606382); NPHS16 (617783), caused by mutation in the KANK2 gene (614610), NPHS17 (618176), caused by mutation in the NUP85 gene (170285); NPHS18 (618177), caused by mutation in the NUP133 gene (607613); NPHS19 (618178), caused by mutation in the NUP160 gene (607614); NPHS20 (301028), caused by mutation in the TBC1D8B gene (301027); NPHS21 (618594) caused by mutation in the AVIL gene (613397); NPHS22 (619155), caused by mutation in the NOS1AP gene (605551); NPHS23 (619201), caused by mutation in the KIRREL1 gene (607428); and NPHS24 (619263), caused by mutation in the DAAM2 gene (606627). See also FSGS1 (603278), caused by mutation in the ACTN4 gene (604638); FSGS2 (603965), caused by mutation in the TRPC6 gene (603652); FSGS3 (607832), associated with variation in the CD2AP gene (604241); FSGS4 (612551), mapped to chromosome 22q12; FSGS5 (613237), caused by mutation in the INF2 gene (610982); FSGS6 (614131), caused by mutation in the MYO1E gene (601479); FSGS7 (616002), caused by mutation in the PAX2 gene (167409); FSGS8 (616032), caused by mutation in the ANLN gene (616027); and FSGS9 (616220), caused by mutation in the CRB2 gene (609720).
GAPO syndrome
MedGen UID:
98034
Concept ID:
C0406723
Disease or Syndrome
GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy (Tipton and Gorlin, 1984). Ilker et al. (1999) and Bayram et al. (2014) noted that optic atrophy is not a consistent feature of the disorder.
Chronic infantile neurological, cutaneous and articular syndrome
MedGen UID:
98370
Concept ID:
C0409818
Disease or Syndrome
Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is a severe chronic inflammatory disease of early onset, characterized by cutaneous symptoms, central nervous system involvement, and arthropathy (Feldmann et al., 2002). See also familial cold autoinflammatory syndrome-1 (FCAS1, CAPS1; 120100), an allelic disorder with a less severe phenotype.
Trichorhinophalangeal dysplasia type I
MedGen UID:
140929
Concept ID:
C0432233
Disease or Syndrome
Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features; ectodermal features (fine, sparse, depigmented, and slow growing hair; dystrophic nails; and small breasts); and skeletal findings (short stature; short feet; brachydactyly with ulnar or radial deviation of the fingers; and early, marked hip dysplasia). TRPS II is characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.
3-Methylglutaconic aciduria type 2
MedGen UID:
107893
Concept ID:
C0574083
Disease or Syndrome
Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies.
Microphthalmia with limb anomalies
MedGen UID:
154638
Concept ID:
C0599973
Disease or Syndrome
Ophthalmo-acromelic syndrome is a condition that results in malformations of the eyes, hands, and feet. The features of this condition are present from birth. The eyes are often absent or severely underdeveloped (anophthalmia), or they may be abnormally small (microphthalmia). Usually both eyes are similarly affected in this condition, but if only one eye is small or missing, the other eye may have a defect such as a gap or split in its structures (coloboma).\n\nThe most common hand and foot malformation seen in ophthalmo-acromelic syndrome is missing fingers or toes (oligodactyly). Other frequent malformations include fingers or toes that are fused together (syndactyly) or extra fingers or toes (polydactyly). These skeletal malformations are often described as acromelic, meaning that they occur in the bones that are away from the center of the body. Additional skeletal abnormalities involving the long bones of the arms and legs or the spinal bones (vertebrae) can also occur. Affected individuals may have distinctive facial features, an opening in the lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate), or intellectual disability.
Inflammatory bowel disease 1
MedGen UID:
146259
Concept ID:
C0678202
Disease or Syndrome
Thyroid agenesis
MedGen UID:
155447
Concept ID:
C0749420
Congenital Abnormality
A rare form of thyroid dysgenesis characterized by complete absence of thyroid tissue that results in primary congenital hypothyroidism, a permanent thyroid deficiency that is present from birth.
Recombinant 8 syndrome
MedGen UID:
167070
Concept ID:
C0795822
Disease or Syndrome
Recombinant chromosome 8 syndrome (Rec8 syndrome) is a chromosomal disorder found among individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have impaired intellectual development, congenital heart defects, seizures, a characteristic facial appearance with hypertelorism, thin upper lip, anteverted nares, wide face, and abnormal hair whorl, and other manifestations (Sujansky et al., 1993, summary by Graw et al., 2000).
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.
Subaortic stenosis-short stature syndrome
MedGen UID:
167085
Concept ID:
C0795947
Disease or Syndrome
A rare genetic multiple congenital anomalies/dysmorphic syndrome with the association of short stature and progressive discrete subaortic stenosis. Additional variable manifestations include upturned nose, voice and vocal cord abnormalities, obstructive lung disease, inguinal hernia, kyphoscoliosis and occasionally epicanthus, strabismus, microphthalmos and widely spaced teeth. There have been no further descriptions in the literature since 1984.
Chylomicron retention disease
MedGen UID:
208651
Concept ID:
C0795956
Disease or Syndrome
Chylomicron retention disease is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy (Dannoura et al., 1999).
Cholestasis-pigmentary retinopathy-cleft palate syndrome
MedGen UID:
208652
Concept ID:
C0795969
Disease or Syndrome
MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). 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. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders.
Johnson neuroectodermal syndrome
MedGen UID:
167092
Concept ID:
C0796002
Disease or Syndrome
Johnson neuroectodermal syndrome has characteristics of alopecia, anosmia or hyposmia, conductive deafness with malformed ears and microtia and/or atresia of the external auditory canal and hypogonadotropic hypogonadism. So far, less than 30 cases have been described in the literature. Other variable features include a congenital heart defect, facial asymmetry, intellectual deficit, cleft palate, choanal stenosis and an increased tendency for dental caries. The syndrome is transmitted as an autosomal dominant trait. The combination of developmental anomalies present in patients with this syndrome is suggestive of an embryological defect in the formation of the neuroectodermal derivatives of cephalic neural crest.
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.
Lenz microphthalmia syndrome
MedGen UID:
162898
Concept ID:
C0796016
Congenital Abnormality
Syndromic microphthalmia-1 (MCOPS1) is an X-linked disorder characterized by unilateral or bilateral microphthalmia or anophthalmia. The most common extraocular features are impaired intellectual development, large and dysplastic ears with skin tags, high-arched or cleft palate, dental anomalies, urogenital anomalies, and skeletal manifestations including lordosis or scoliosis, clinodactyly, syndactyly, brachydactyly, and abnormal thumbs. There is considerable variation in severity among reported families (Slavotinek et al., 2005). Genetic Heterogeneity Other forms of syndromic microphthalmia include MCOPS2 (300166), caused by the BCOR gene (300485) on chromosome Xp11; MCOPS3 (206900), caused by mutation in the SOX2 gene (184429) on chromosome 3q26; MCOPS5 (610125), caused by mutation in the OTX2 gene (600037) on chromosome 14q22; MCOPS6 (607932), caused by mutation in the BMP4 gene (112262) on chromosome 14q22; MCOPS7 (309801), caused by mutation in the HCCS gene (300056) on chromosome Xp22; MCOPS9 (601186), caused by mutation in the STRA6 gene (610745) on chromosome 15q24; MCOPS11 (614402), caused by mutation in the VAX1 gene (604294) on chromosome 10q25; MCOPS12 (615524), caused by mutation in the RARB gene (180220) on chromosome 3p24; MCOPS13 (300915), caused by mutation in the HMGB3 gene (300193) on chromosome Xq28; MCOPS14 (615877), caused by mutation in the MAB21L2 gene (604357) on chromosome 4q31; and MCOPS15 (615145), caused by mutation in the TENM3 gene (610083) on chromosome 4q. A form of syndromic microphthalmia also maps to chromosome 6q21 (MCOPS8; 601349). A form of microphthalmia associated with progressive brain atrophy has been reported (MCOPS10; 611222). A form of syndromic microphthalmia, formerly designated MCOPS4, has been found to be the same entity as MCOPS1. Williamson and FitzPatrick (2014) reviewed genes associated with microphthalmia, anophthalmia, and/or coloboma phenotypes. They noted that when exon sequencing is combined with detection of gene deletions via aCGH and high-resolution analysis of intragenic microdeletions and microduplications, approximately 75% of cases of bilateral anophthalmia or severe microphthalmia are found to carry heterozygous mutations in the SOX2 (184429) or OTX2 (600037) genes, or biallelic mutations in the STRA6 gene (610745) (see also MCOPS5, 610125 and MCOPS9, 601186).
Lysine malabsorption syndrome
MedGen UID:
167097
Concept ID:
C0796023
Disease or Syndrome
Lysine malabsorption with severe malnourishment, extreme flaccidity, and psychomotor retardation.
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.
3MC syndrome 3
MedGen UID:
208657
Concept ID:
C0796032
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).
3MC syndrome 1
MedGen UID:
167100
Concept ID:
C0796059
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). Genetic Heterogeneity of 3MC Syndrome Also see 3MC syndrome-2 (3MC2; 265050), caused by mutation in the COLEC11 gene (612502), and 3MC syndrome-3 (3MC3; 248340), caused by mutation in the COLEC1 gene (607620).
Acrocallosal syndrome
MedGen UID:
162915
Concept ID:
C0796147
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.
Salla disease
MedGen UID:
203368
Concept ID:
C1096903
Disease or Syndrome
Free sialic acid storage disorders (FSASDs) are a spectrum of neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. Historically, FSASD was divided into separate allelic disorders: Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD). The mildest type was Salla disease, characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures. Salla disease was named for a municipality in Finnish Lapland where a specific founder variant is relatively prevalent. However, the term Salla has been used in the literature to refer to less severe FSASD. More severe FSASD is historically referred to as ISSD, and is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood.
Deficiency of 3-hydroxyacyl-CoA dehydrogenase
MedGen UID:
266222
Concept ID:
C1291230
Disease or Syndrome
3-hydroxyacyl-CoA dehydrogenase deficiency is an inherited condition that prevents the body from converting certain fats to energy, particularly during prolonged periods without food (fasting).\n\nInitial signs and symptoms of this disorder typically occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, and lack of energy (lethargy). Affected individuals can also have muscle weakness (hypotonia), liver problems, low blood sugar (hypoglycemia), and abnormally high levels of insulin (hyperinsulinism). Insulin controls the amount of sugar that moves from the blood into cells for conversion to energy. Individuals with 3-hydroxyacyl-CoA dehydrogenase deficiency are also at risk for complications such as seizures, life-threatening heart and breathing problems, coma, and sudden death. This condition may explain some cases of sudden infant death syndrome (SIDS), which is defined as unexplained death in babies younger than 1 year.\n\nProblems related to 3-hydroxyacyl-CoA dehydrogenase 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.
Nicolaides-Baraitser syndrome
MedGen UID:
220983
Concept ID:
C1303073
Disease or Syndrome
Nicolaides-Baraitser syndrome (NCBRS) is characterized by sparse scalp hair, prominence of the inter-phalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, and developmental delay / intellectual disability. Seizures are of various types and can be difficult to manage. Developmental delay / intellectual disability (ID) is severe in nearly a half, moderate in a third, and mild in the remainder. Nearly a third never develop speech or language skills.
Trichothiodystrophy, nonphotosensitive 1
MedGen UID:
272036
Concept ID:
C1313961
Disease or Syndrome
A subtype of trichothiodystrophy caused by mutation(s) in the MPLKIP gene, encoding M-phase-specific PLK1-interacting protein.
Thyroid dysgenesis
MedGen UID:
289647
Concept ID:
C1563716
Congenital Abnormality
A congenital condition characterized by hypoplasia, absence, or ectopic position of the thyroid gland. It is manifested with congenital hypoparathyroidism.
Anterior chamber cleavage disorder, cerebellar hypoplasia, hypothyroidism, and tracheal stenosis
MedGen UID:
316973
Concept ID:
C1832362
Disease or Syndrome
Deafness-epiphyseal dysplasia-short stature syndrome
MedGen UID:
371330
Concept ID:
C1832438
Disease or Syndrome
This syndrome has characteristics of sensorineural deafness, short stature, femoral epiphyseal dysplasia, umbilical and inguinal hernias and developmental delay (growth retardation and mild intellectual deficit). It has been described in two brothers born to consanguineous parents. They also have dysmorphic features (triangular face, pointed chin) and bilateral obstruction of lacrimal ducts. This syndrome is transmitted as an autosomal recessive trait.
Microspherophakia-metaphyseal dysplasia syndrome
MedGen UID:
322520
Concept ID:
C1834880
Disease or Syndrome
Microspherophakia - metaphyseal dysplasia is a very rare syndrome associating bone dysplasia with micromelic dwarfism and eye defects.
Mental and growth retardation with amblyopia
MedGen UID:
331885
Concept ID:
C1835028
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).
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.
Sudden infant death with dysgenesis of the testes syndrome
MedGen UID:
332428
Concept ID:
C1837371
Disease or Syndrome
Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is a rare condition that is fatal in the first year of life; its major features include abnormalities of the reproductive system in males, feeding difficulties, and breathing problems.\n\nInfants with SIDDT who are genetically male, with one X chromosome and one Y chromosome in each cell, have underdeveloped or abnormal testes. They may also have external genitalia that appear female or that do not look clearly male or clearly female (ambiguous genitalia). In affected infants who are genetically female, with two X chromosomes in each cell, development of the internal and external reproductive organs is normal.\n\nSIDDT is associated with abnormal development of the brain, particularly the brainstem, which is the part of the brain that is connected to the spinal cord. The brainstem regulates many basic body functions, including heart rate, breathing, eating, and sleeping. It also relays information about movement and the senses between the brain and the rest of the body. Many features of SIDDT appear to be related to brainstem malfunction, including a slow or uneven heart rate, abnormal breathing patterns, difficulty controlling body temperature, unusual tongue and eye movements, an exaggerated startle reflex to sudden lights or loud noises, and feeding difficulties. Affected infants also have an unusual cry that has been described as similar to the bleating of a goat, which is probably a result of abnormal nerve connections between the brain and the voicebox (larynx).\n\nThe brainstem abnormalities lead to death in the first year of life, when affected infants suddenly stop breathing or their heart stops beating (cardiorespiratory arrest).
Cleft palate, cardiac defect, genital anomalies, and ectrodactyly
MedGen UID:
324947
Concept ID:
C1838121
Disease or Syndrome
A rare genetic disorder characterised by split-hand/split-foot malformation (SHFM), facial anomalies, cleft lip/palate, congenital heart defect (CHD), genital anomalies, and intellectual deficit.
Toriello-Lacassie-Droste 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).
Disorder of sex development-intellectual disability syndrome
MedGen UID:
325469
Concept ID:
C1838611
Disease or Syndrome
A rare syndrome with 46,XY disorder of sex development characterized by variable degrees of intellectual disability, short stature, severe genital anomalies resulting in sexual ambiguity (such as pseudovaginal perineoscrotal hypospadias and persistence of Müllerian structures), and ocular anomalies (microphthalmia, coloboma). Craniofacial peculiarities (coarse features, deep set eyes), spina bifida, imperforate anus, and sensorineural hearing loss were also described. No new cases have been reported since 1994.
Vitamin d hydroxylation-deficient rickets, type 1b
MedGen UID:
374020
Concept ID:
C1838657
Disease or Syndrome
Vitamin D hydroxylation-deficient rickets type 1B (VDDR1B) is caused by a defect in vitamin D 25-hydroxylation (Molin et al., 2017). The major function of vitamin D is to maintain calcium and phosphate levels in the normal range to support metabolic functions, neuromuscular transmission, and bone mineralization. Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (summary by Liberman and Marx, 2001).
Mitochondrial complex I deficiency
MedGen UID:
374101
Concept ID:
C1838979
Disease or Syndrome
Isolated complex I deficiency is a rare inborn error of metabolism due to mutations in nuclear or mitochondrial genes encoding subunits or assembly factors of the human mitochondrial complex I (NADH: ubiquinone oxidoreductase) and is characterized by a wide range of manifestations including marked and often fatal lactic acidosis, cardiomyopathy, leukoencephalopathy, pure myopathy and hepatopathy with tubulopathy. Among the numerous clinical phenotypes observed are Leigh syndrome, Leber hereditary optic neuropathy and MELAS syndrome (see these terms).
X-linked intellectual disability, Schimke type
MedGen UID:
374193
Concept ID:
C1839320
Disease or Syndrome
X-linked mental retardation, Schimke type, is characterised by intellectual deficit, growth retardation with short stature, deafness and ophthalmoplegia. Choreoathetosis with muscle spasticity generally appears during childhood. It has been described in four boys, three of whom were from the same family. Transmission is X-linked.
Heme oxygenase 1 deficiency
MedGen UID:
333882
Concept ID:
C1841651
Disease or Syndrome
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. See also Radio-Tartaglia syndrome (RATARS; 619312), caused by mutation in the SPEN gene (613484) on chromosome 1p36, which shows overlapping features.
Contractures-ectodermal dysplasia-cleft lip/palate syndrome
MedGen UID:
375546
Concept ID:
C1844935
Disease or Syndrome
Contractures - ectodermal dysplasia - cleft lip/palate is an ectodermal dyplasia syndrome characterized by severe arthrogryposis, multiple ectodermal dysplasia features, cleft lip/palate, facial dysmorphism, growth deficiency and a moderate delay of psychomotor development. Ectodermal dysplasia manifestations include sparse, brittle and hypopigmented hair, xerosis, multiple nevi, small conical shaped teeth and hypodontia, and facial dysmorphism with blepharophimosis, deep-set eyes and micrognathia.
Alpha thalassemia-X-linked intellectual disability syndrome
MedGen UID:
337145
Concept ID:
C1845055
Disease or Syndrome
Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants.
Fanconi anemia, complementation group B
MedGen UID:
336901
Concept ID:
C1845292
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/or 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, and genitourinary tract – are more common in individuals with FA.
Lathosterolosis
MedGen UID:
375885
Concept ID:
C1846421
Disease or Syndrome
Lathosterolosis (LATHOS) is an autosomal recessive disorder characterized by a recognizable pattern of multiple congenital anomalies involving axial and appendicular skeleton, liver, central nervous and urogenital systems, and lysosomal storage. It is caused by a defect of cholesterol biosynthesis due to sterol C5-desaturase deficiency (summary by Rossi et al., 2007).
Nephronophthisis 4
MedGen UID:
339667
Concept ID:
C1847013
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).
Seckel syndrome 2
MedGen UID:
338264
Concept ID:
C1847572
Disease or Syndrome
Seckel syndrome is a rare autosomal recessive disorder characterized by growth retardation, microcephaly with mental retardation, and a characteristic facial appearance (Borglum et al., 2001). For a general phenotypic description and a discussion of genetic heterogeneity of Seckel syndrome, see SCKL1 (210600).
Wolman disease with hypolipoproteinemia and acanthocytosis
MedGen UID:
336342
Concept ID:
C1848436
Disease or Syndrome
Vitiligo, progressive, with mental retardation and urethral duplication
MedGen UID:
336363
Concept ID:
C1848532
Disease or Syndrome
T-substance anomaly
MedGen UID:
338528
Concept ID:
C1848724
Finding
Thyroid dyshormonogenesis 1
MedGen UID:
336422
Concept ID:
C1848805
Disease or Syndrome
Approximately 10% of patients with congenital hypothyroidism harbor inborn errors of metabolism in one of the steps for thyroid hormone synthesis in thyrocytes (Vono-Toniolo et al., 2005). Dyshormonogenesis can be caused by recessive defects at any of the steps required for normal thyroid hormone synthesis. In untreated patients thyroid dyshormonogenesis is typically associated with goitrous enlargement of the thyroid secondary to long-term thyrotropin (TSH; see 188540) stimulation. Park and Chatterjee (2005) reviewed the genetics of primary congenital hypothyroidism, summarizing the different phenotypes associated with known genetic defects and proposing an algorithm for investigating the genetic basis of the disorder. Genetic Heterogeneity of Thyroid Dyshormonogenesis Other forms of thyroid hormone dysgenesis include TDH2A (274500), caused by mutation in the thyroid peroxidase gene (TPO; 606765) on 2p25; Pendred syndrome, a form of thyroid hormone dysgenesis associated with deafness (TDH2B; 274600) and caused by mutation in the SLC26A4 gene (605646) on 7q31; TDH3 (274700), caused by mutation in the thyroglobulin gene (TG; 188450) on 8q24; TDH4 (274800), caused by mutation in the iodotyrosine deiodinase gene (IYD; 612025) on 6q25; TDH5 (274900), caused by mutation in the DUOXA2 gene (612772) on 15q21; and TDH6 (607200), caused by mutation in the DUOX2 gene (606759) on 15q21.
Threoninemia
MedGen UID:
336439
Concept ID:
C1848861
Finding
An increased concentration of threonine in the blood.
Short stature due to growth hormone qualitative anomaly
MedGen UID:
340412
Concept ID:
C1849779
Disease or Syndrome
Kowarski syndrome, or short stature associated with bioinactive growth hormone, is characterized clinically by normal or slightly increased GH secretion, pathologically low IGF1 (147440) levels, and normal catch-up growth on GH replacement therapy (Besson et al., 2005).
Osteodysplasty, precocious, of Danks, Mayne, and Kozlowski
MedGen UID:
337989
Concept ID:
C1850185
Disease or Syndrome
Nathalie syndrome
MedGen UID:
338087
Concept ID:
C1850626
Disease or Syndrome
Nathalie syndrome has characteristics of deafness, cataract, muscular atrophy, skeletal abnormalities, growth retardation, underdeveloped secondary sexual characteristics and electrocardiographic abnormalities. It has been described in a Dutch family: in three sisters (one named Nathalie) and their brother.
Myopathy with giant abnormal mitochondria
MedGen UID:
376864
Concept ID:
C1850717
Disease or Syndrome
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 2
MedGen UID:
342799
Concept ID:
C1853102
Disease or Syndrome
Autosomal recessive hypophosphatemic bone disease
MedGen UID:
501133
Concept ID:
C1853271
Disease or Syndrome
Hereditary hypophosphatemic rickets with hypercalciuria is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (summary by Bergwitz et al., 2006).
Neonatal intrahepatic cholestasis caused by citrin deficiency
MedGen UID:
340091
Concept ID:
C1853942
Disease or Syndrome
Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). Often citrin deficiency is characterized by strong preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. NICCD. Children younger than age one year have a history of low birth weight with growth restriction and transient intrahepatic cholestasis, hepatomegaly, diffuse fatty liver, and parenchymal cellular infiltration associated with hepatic fibrosis, variable liver dysfunction, hypoproteinemia, decreased coagulation factors, hemolytic anemia, and/or hypoglycemia. NICCD is generally not severe and symptoms often resolve by age one year with appropriate treatment, although liver transplantation has been required in rare instances. FTTDCD. Beyond age one year, many children with citrin deficiency develop a protein-rich and/or lipid-rich food preference and aversion to carbohydrate-rich foods. Clinical abnormalities may include growth restriction, hypoglycemia, pancreatitis, severe fatigue, anorexia, and impaired quality of life. Laboratory changes are dyslipidemia, increased lactate-to-pyruvate ratio, higher levels of urinary oxidative stress markers, and considerable deviation in tricarboxylic acid (TCA) cycle metabolites. One or more decades later, some individuals with NICCD or FTTDCD develop CTLN2. CTLN2. Presentation is sudden and usually between ages 20 and 50 years. Manifestations are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. Symptoms are often provoked by alcohol and sugar intake, medication, and/or surgery. Affected individuals may or may not have a prior history of NICCD or FTTDCD.
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, broad 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 A
MedGen UID:
381530
Concept ID:
C1854988
Disease or Syndrome
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.\n\nBecause of the serious health problems caused by molybdenum cofactor deficiency, affected individuals usually do not survive past early childhood.\n\nMolybdenum 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."
Molybdenum cofactor deficiency, complementation group B
MedGen UID:
340760
Concept ID:
C1854989
Disease or Syndrome
Molybdenum cofactor deficiency is a rare autosomal recessive metabolic disorder characterized by neonatal onset of intractable seizures, opisthotonus, and facial dysmorphism associated with hypouricemia and elevated urinary sulfite levels. Affected individuals show severe neurologic damage and often die in early childhood (summary by Reiss et al., 1999). For a general phenotypic description and a discussion of genetic heterogeneity of MOCOD, see MOCODA (252150), which is clinically indistinguishable from MOCODB.
Mitochondrial myopathy-lactic acidosis-deafness syndrome
MedGen UID:
343245
Concept ID:
C1855033
Disease or Syndrome
Mitochondrial myopathy-lactic acidosis-deafness is a type of metabolic myopathy described only in two sisters to date, presenting during childhood, and characterized clinically by growth failure, severe muscle weakness, and moderate sensorineural deafness and biochemically by metabolic acidosis, elevated serum pyruvate concentration, hyperalaninemia and hyperalaninuria. There have been no further descriptions in the literature since 1973.
Frank-Ter Haar syndrome
MedGen UID:
383652
Concept ID:
C1855305
Disease or Syndrome
The primary characteristics of the Frank-ter Haar syndrome are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (summary by Maas et al., 2004). Borrone syndrome was described as a severe progressive multisystem disorder with features overlapping those of FTHS, including thick skin, acne conglobata, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. Although it was initially thought to be a distinct phenotype, mutations in the FTHS-associated gene SH3PXD2B have been identified in patients diagnosed with Borrone syndrome. The earlier differential description was attributed to phenotypic variability as well as to differences in the ages at which patients were examined (Wilson et al., 2014).
Leukomelanoderma, infantilism, mental retardation, hypodontia, hypotrichosis
MedGen UID:
383698
Concept ID:
C1855504
Disease or Syndrome
Leukomelanoderma-infantilism-intellectual disability-hypodontia-hypotrichosis syndrome is a rare ectodermal dysplasia syndrome characterized by congenital generalized melanoleukoderma, hypodontia and hypotrichosis associated with infantilism, intellectual disability and growth delay. There have been no further descriptions in the literature since 1961.
Keratoconus posticus circumscriptus
MedGen UID:
340922
Concept ID:
C1855645
Disease or Syndrome
Intrinsic factor and r binder, combined congenital deficiency of
MedGen UID:
340942
Concept ID:
C1855721
Disease or Syndrome
Immunodeficiency with defective T-cell response to interleukin 1
MedGen UID:
340948
Concept ID:
C1855735
Disease or Syndrome
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).
Cardiocranial syndrome, Pfeiffer type
MedGen UID:
346598
Concept ID:
C1857495
Disease or Syndrome
An extremely rare disorder found in less than ten patients worldwide with characteristics of congenital heart defect, sagittal craniosynostosis and severe developmental delay. Genital and renal anomalies, and various dysmorphic features may be present. Joint and palpebral abnormalities may also occur. The occurrence of the syndrome in a brother-sister sibship supports the hypothesis of autosomal recessive inheritance. Autosomal dominant inheritance and submicroscopic deletions have also been proposed as possible causes.
Citrulline transport defect
MedGen UID:
349092
Concept ID:
C1859084
Disease or Syndrome
Sengers syndrome
MedGen UID:
395228
Concept ID:
C1859317
Disease or Syndrome
Sengers syndrome is an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).
Thyrotropin-releasing hormone resistance, generalized
MedGen UID:
349957
Concept ID:
C1861106
Disease or Syndrome
Brachmann-de Lange-like facial changes with microcephaly, metatarsus adductus, and developmental delay
MedGen UID:
396307
Concept ID:
C1862171
Disease or Syndrome
Majeed syndrome
MedGen UID:
351273
Concept ID:
C1864997
Disease or Syndrome
Majeed syndrome is a rare condition characterized by recurrent episodes of fever and inflammation in the bones and skin.\n\nOne of the major features of Majeed syndrome is an inflammatory bone condition known as chronic recurrent multifocal osteomyelitis (CRMO). This condition causes recurrent episodes of pain and joint swelling beginning in infancy or early childhood. These symptoms persist into adulthood, although they may improve for short periods. CRMO can lead to complications such as slow growth and the development of joint deformities called contractures, which restrict the movement of certain joints.\n\nAnother feature of Majeed syndrome is a blood disorder called congenital dyserythropoietic anemia. This disorder is one of many types of anemia, all of which involve a shortage of red blood cells. Without enough of these cells, the blood cannot carry an adequate supply of oxygen to the body's tissues. The resulting symptoms can include tiredness (fatigue), weakness, pale skin, and shortness of breath. Complications of congenital dyserythropoietic anemia can range from mild to severe.\n\nMost people with Majeed syndrome also develop inflammatory disorders of the skin, most often a condition known as Sweet syndrome. The symptoms of Sweet syndrome include fever and the development of painful bumps or blisters on the face, neck, back, and arms.
Phosphoglycerate dehydrogenase deficiency
MedGen UID:
400935
Concept ID:
C1866174
Disease or Syndrome
Phosphoglycerate dehydrogenase deficiency is an autosomal recessive inborn error of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures (summary by Jaeken et al., 1996).
Hypothyroidism, congenital, nongoitrous
MedGen UID:
358389
Concept ID:
C1869118
Congenital Abnormality
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).
Dihydropyrimidine dehydrogenase deficiency
MedGen UID:
409522
Concept ID:
C1959620
Disease or Syndrome
Dihyropyrimidine dehydrogenase deficiency shows large phenotypic variability, ranging from no symptoms to a convulsive disorder with motor and mental retardation in homozygous patients. In addition, homozygous and heterozygous mutation carriers can develop severe toxicity after the administration of the antineoplastic drug 5-fluorouracil (5FU), which is also catabolized by the DPYD enzyme. This is an example of a pharmacogenetic disorder (Van Kuilenburg et al., 1999). Since there is no correlation between genotype and phenotype in DPD deficiency, it appears that the deficiency is a necessary, but not sufficient, prerequisite for the development of clinical abnormalities (Van Kuilenburg et al., 1999; Enns et al., 2004).
Osteopetrosis, autosomal recessive 5
MedGen UID:
409627
Concept ID:
C1968603
Disease or Syndrome
Autosomal recessive osteopetrosis-5 is a form of infantile malignant osteopetrosis, characterized by defective osteoclast function resulting in decreased bone resorption and generalized osteosclerosis. Defective resorption causes development of densely sclerotic fragile bones and progressive obliteration of the marrow spaces and cranial foramina. Marrow obliteration is associated with extramedullary hematopoiesis and hepatosplenomegaly, and results in anemia and thrombocytopenia, whereas nerve entrapment accounts for progressive blindness and hearing loss. Other major manifestations include failure to thrive, pathologic fractures, and increased infection rate. Most affected children succumb to severe bone marrow failure and overwhelming infection in the first few years of life (Quarello et al., 2004).
Autosomal recessive osteopetrosis 4
MedGen UID:
370598
Concept ID:
C1969106
Disease or Syndrome
The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII, Albers-Schönberg disease). Onset of ARO is in infancy. Findings may include: fractures; poor growth; sclerosis of the skull base (with or without choanal stenosis or hydrocephalus) resulting in optic nerve compression, facial palsy, and hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, and risk for mandibular osteomyelitis; and hypocalcemia with tetanic seizures and secondary hyperparathyroidism. Without treatment maximal life span in ARO is ten years. Onset of IAO is in childhood. Findings may include fractures after minor trauma, characteristic skeletal radiographic changes found incidentally, mild anemia, and occasional visual impairment secondary to optic nerve compression. Life expectancy in IAO is usually normal. Onset of ADOII is usually late childhood or adolescence. Findings may include: fractures (in any long bone and/or the posterior arch of a vertebra), scoliosis, hip osteoarthritis, and osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare.
Mental retardation, autosomal recessive 9
MedGen UID:
369678
Concept ID:
C1970195
Disease or Syndrome
Renal tubular acidosis, proximal, with ocular abnormalities and mental retardation
MedGen UID:
370883
Concept ID:
C1970309
Disease or Syndrome
Autosomal recessive proximal renal tubular acidosis (AR pRTA) is a rare form of proximal renal tubular acidosis (pRTA; see this term) characterized by an isolated defect in the proximal tubule leading to the decreased reabsorption of bicarbonate and consequentially to urinary bicarbonate wastage along with additional characteristic clinical features.
Hypothyroidism, congenital, nongoitrous, 5
MedGen UID:
388687
Concept ID:
C2673630
Disease or Syndrome
Combined oxidative phosphorylation deficiency 5
MedGen UID:
435972
Concept ID:
C2673642
Disease or Syndrome
This syndrome is characterised by severe hypotonia, lactic academia and congenital hyperammonaemia.
Chromosome 22q11.2 microduplication syndrome
MedGen UID:
436417
Concept ID:
C2675369
Disease or Syndrome
22q11.2 duplication is a condition caused by an extra copy of a small piece of chromosome 22. The duplication occurs near the middle of the chromosome at a location designated q11.2.\n\nThe features of this condition vary widely, even among members of the same family. Affected individuals may have developmental delay, intellectual disability, slow growth leading to short stature, and weak muscle tone (hypotonia). Many people with the duplication have no apparent physical or intellectual disabilities.
Diamond-Blackfan anemia 8
MedGen UID:
390817
Concept ID:
C2675511
Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency 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 or 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.
Diamond-Blackfan anemia 7
MedGen UID:
436451
Concept ID:
C2675512
Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency 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 or 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.
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).
Diamond-Blackfan anemia 4
MedGen UID:
393906
Concept ID:
C2675860
Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency 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 or 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.
Autosomal recessive osteopetrosis 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.\n\nAutosomal 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.\n\nOther 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).\n\nAutosomal 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.\n\nA 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.\n\nRarely, 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 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.
Diamond-Blackfan anemia 10
MedGen UID:
412873
Concept ID:
C2750080
Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency 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 or 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.
Diamond-Blackfan anemia 9
MedGen UID:
412874
Concept ID:
C2750081
Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency 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 or 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.
Bile acid malabsorption, primary
MedGen UID:
412875
Concept ID:
C2750087
Disease or Syndrome
Primary bile acid malabsorption (PBAM) is an intestinal disorder associated with chronic watery diarrhea, excess fecal bile acids, and steatorrhea. Bile acid malabsorption has been classified into 3 main types depending on the etiology. Types 1 and 3 are secondary disorders: type 1 is due to ileal dysfunction resulting from Crohn disease or ileal resection, and type 3 is secondary to other conditions, including cholecystectomy, post-vagotomy, celiac disease, and pancreatic insufficiency. Type 2 bile acid malabsorption is a primary congenital disorder, including the rare type due to mutations in the SLC10A2 gene (review by Pattni and Walters, 2009). Genetic Heterogeneity of Primary Bile Acid Malabsorption Also see PBAM2 (619481), caused by mutation in the SLC51B gene (612085).
Cutis laxa with severe pulmonary, gastrointestinal, and urinary abnormalities
MedGen UID:
442566
Concept ID:
C2750804
Disease or Syndrome
LTBP4-related cutis laxa is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective tissue disorder such as inguinal hernias and hollow visceral diverticula (e.g., intestine, bladder). Other manifestations can include pyloric stenosis, diaphragmatic hernia, rectal prolapse, gastrointestinal elongation/tortuosity, cardiovascular abnormality, pulmonary hypertension, hypotonia and frequent pulmonary infections. Bladder diverticula and hydronephrosis are common. Early demise has been associated with pulmonary emphysema.
Inflammatory bowel disease 28, autosomal recessive
MedGen UID:
442630
Concept ID:
C2751053
Disease or Syndrome
An autosomal recessive condition caused by mutation(s) in the IL10RA gene, encoding interleukin-10 receptor subunit alpha. It is characterized by early-onset chronic relapsing intestinal inflammation.
Nijmegen breakage syndrome-like disorder
MedGen UID:
442700
Concept ID:
C2751318
Disease or Syndrome
Nijmegen breakage syndrome-like disorder (NBSLD) is an autosomal recessive disorder characterized by severe prenatal growth retardation and persistent postnatal growth restriction, congenital microcephaly, borderline to mildly impaired intellectual development, normal sexual development, and radioresistant DNA synthesis with no immunodeficiency, myelodysplasia, or early neurodegeneration (summary by Ragamin et al., 2020).
Glycogen storage disease IXc
MedGen UID:
442778
Concept ID:
C2751643
Disease or Syndrome
Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that patients need to be monitored for long-term complications such as liver fibrosis and cirrhosis.
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.\n\nAdditional 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.
COG7 congenital disorder of glycosylation
MedGen UID:
419311
Concept ID:
C2931010
Disease or Syndrome
CDG IIe is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways. For a general discussion of CDGs, see CDG1A (212065).
Nephropathic cystinosis
MedGen UID:
419735
Concept ID:
C2931187
Disease or Syndrome
Cystinosis comprises three allelic phenotypes: Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years. The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.
Leber congenital amaurosis 1
MedGen UID:
419026
Concept ID:
C2931258
Disease or Syndrome
Oculocerebral hypopigmentation syndrome of preus
MedGen UID:
419131
Concept ID:
C2931646
Disease or Syndrome
A rare congenital syndrome characterized 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, anemia, and/or nystagmus.
Diamond-Blackfan anemia 6
MedGen UID:
419918
Concept ID:
C2931850
Disease or Syndrome
Diamond-Blackfan anemia (DBA) is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50%, and growth deficiency 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 or 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.
Cross syndrome
MedGen UID:
423639
Concept ID:
C2936910
Disease or Syndrome
Oculocerebral hypopigmentation syndrome, Cross type is a rare congenital syndrome characterized by cutaneous and ocular hypopigmentation, various ocular anomalies (e.g. corneal and lens opacity, spastic ectropium, and/or nystagmus), growth deficiency, intellectual deficit and other progressive neurologic anomalies such as spastic tetraplegia, hyperreflexia, and/or athetoid movements. The clinical picture varies among patients and may also include other anomalies such as urinary tract abnormalities, Dandy-Walker malformations, and/or bilateral inguinal hernia.
Thyroid hormone resistance, generalized, autosomal dominant
MedGen UID:
424846
Concept ID:
C2937288
Disease or Syndrome
Thyroid hormone resistance syndrome
MedGen UID:
424854
Concept ID:
C2940786
Disease or Syndrome
Reduced sensitivity of end organs to thyroid hormone characterized by elevated serum levels of free thyroid hormone with nonsuppressed thyroid stimulating hormone.
Chromosome 14q11-q22 deletion syndrome
MedGen UID:
462057
Concept ID:
C3150707
Disease or Syndrome
14q11.2 microdeletion syndrome is a recently described syndrome characterized by developmental delay, hypotonia and facial dysmorphism.
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).
Myopathy, lactic acidosis, and sideroblastic anemia 2
MedGen UID:
462152
Concept ID:
C3150802
Disease or Syndrome
Myopathy, lactic acidosis, and sideroblastic anemia-2 is an autosomal recessive disorder of the mitochondrial respiratory chain. The disorder shows marked phenotypic variability: some patients have a severe multisystem disorder from infancy, including cardiomyopathy and respiratory insufficiency resulting in early death, whereas others present in the second or third decade of life with sideroblastic anemia and mild muscle weakness (summary by Riley et al., 2013). For a discussion of genetic heterogeneity of MLASA, see MLASA1 (600462).
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
Rajab interstitial lung disease with brain calcifications
MedGen UID:
462260
Concept ID:
C3150910
Disease or Syndrome
Rajab interstitial lung disease with brain calcifications-1 (RILCBC1) is an autosomal recessive multisystem disorder with a highly variable phenotype. Most patients present in infancy or early childhood with poor growth and interstitial lung disease, which may lead to death. Some may also have liver, skeletal, and renal abnormalities, and most have intracranial calcifications on brain imaging. Some may have early impaired motor development, but most have normal cognitive development (summary by Xu et al., 2018). Genetic Heterogeneity of Rajab Interstitial Lung Disease with Brain Calcifications Also see Rajab interstitial disease with brain calcifications-2 (RILDBC2; 619013), caused by mutation in the FARSA gene (602918).
Noonan syndrome 7
MedGen UID:
462320
Concept ID:
C3150970
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.
LEOPARD syndrome 3
MedGen UID:
462321
Concept ID:
C3150971
Disease or Syndrome
Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features, including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (HCM) (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth retardation resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th percentile for age. Sensorineural hearing deficits, present in approximately 20%, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.
Dyskeratosis congenita, autosomal recessive 2
MedGen UID:
462791
Concept ID:
C3151441
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.
Dyskeratosis congenita, autosomal dominant, 3
MedGen UID:
462795
Concept ID:
C3151445
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).
Mitochondrial DNA depletion syndrome 9 (encephalomyopathic with methylmalonic aciduria)
MedGen UID:
462826
Concept ID:
C3151476
Disease or Syndrome
SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized in the majority of affected newborns by hypotonia, muscle atrophy, feeding difficulties, and lactic acidosis. Affected infants commonly manifest developmental delay / cognitive impairment, growth retardation / failure to thrive, hepatopathy, sensorineural hearing impairment, dystonia, and hypertonia. Notable findings in some affected individuals include hypertrophic cardiomyopathy, epilepsy, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, and/or hypoglycemia. Life span is shortened, with median survival of 20 months.
Mitochondrial DNA-depletion syndrome 3, hepatocerebral
MedGen UID:
462863
Concept ID:
C3151513
Disease or Syndrome
The two forms of deoxyguanosine kinase (DGUOK) deficiency are a neonatal multisystem disorder and an isolated hepatic disorder that presents later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation) evident within weeks of birth. Those with isolated liver disease may also have renal involvement and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms.
Immunodeficiency-centromeric instability-facial anomalies syndrome 2
MedGen UID:
481378
Concept ID:
C3279748
Disease or Syndrome
Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disorder characterized by facial dysmorphism, immunoglobulin deficiency resulting in recurrent infections, and mental retardation. Laboratory studies of patient cells show hypomethylation of satellite regions of chromosomes 1, 9, and 16, as well as pericentromeric chromosomal instability in response to phytohemagglutinin stimulation (summary by de Greef et al., 2011). For a discussion of genetic heterogeneity of immunodeficiency-centromeric instability-facial anomalies syndrome, see ICF1 (242860).
Mosaic variegated aneuploidy syndrome 2
MedGen UID:
481473
Concept ID:
C3279843
Disease or Syndrome
Mosaic variegated aneuploidy syndrome is an autosomal recessive disorder characterized by poor growth and variable phenotypic manifestations, such as facial dysmorphism and congenital heart defects, associated with mosaic aneuploidies resulting from defects in cell division (summary by Snape et al., 2011). See also MVA1 (257300), caused by mutation in the BUB1B gene (602860) on chromosome 15q15.
Immunodeficiency 31C
MedGen UID:
481620
Concept ID:
C3279990
Disease or Syndrome
IMD31C is disorder of immunologic dysregulation with highly variable manifestations resulting from autosomal dominant gain-of-function mutations in STAT1 (600555). Most patients present in infancy or early childhood with chronic mucocutaneous candidiasis (CMC). Other highly variable features include recurrent bacterial, viral, fungal, and mycoplasmal infections, disseminated dimorphic fungal infections, enteropathy with villous atrophy, and autoimmune disorders, such as hypothyroidism or diabetes mellitus. A subset of patients show apparently nonimmunologic features, including osteopenia, delayed puberty, and intracranial aneurysms. Laboratory studies show increased activation of gamma-interferon (IFNG; 147570)-mediated inflammation (summary by Uzel et al., 2013 and Sampaio et al., 2013).
Three M syndrome 3
MedGen UID:
481776
Concept ID:
C3280146
Disease or Syndrome
Three M syndrome is characterized by severe pre- and postnatal growth deficiency (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies, and normal intelligence. Additional features of three M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. Males with three M syndrome have hypogonadism and occasionally hypospadias.
Chromosome 15q25 deletion syndrome
MedGen UID:
481985
Concept ID:
C3280355
Disease or Syndrome
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
Mental retardation, autosomal recessive 30
MedGen UID:
482170
Concept ID:
C3280540
Disease or Syndrome
Mental retardation, autosomal recessive 24
MedGen UID:
482173
Concept ID:
C3280543
Disease or Syndrome
Microcephaly, cerebellar hypoplasia, and cardiac conduction defect syndrome
MedGen UID:
482322
Concept ID:
C3280692
Disease or Syndrome
The Zaki-Gleeson syndrome is an autosomal recessive neurodevelopmental disorder characterized by profound mental retardation, severe microcephaly, poor growth, cerebellar hypoplasia, and second-degree cardiac conduction defects (summary by Zaki et al., 2011).
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.
Hypothyroidism, congenital, nongoitrous, 6
MedGen UID:
482447
Concept ID:
C3280817
Disease or Syndrome
Any hypothyroidism, congenital, nongoitrous in which the cause of the disease is a mutation in the THRA gene.
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).
Pyruvate dehydrogenase lipoic acid synthetase deficiency
MedGen UID:
482517
Concept ID:
C3280887
Disease or Syndrome
Hyperglycinemia, lactic acidosis, and seizures is a severe autosomal recessive disorder characterized by onset of hypotonia and seizures associated with increased serum glycine and lactate in the first days of life. Affected individuals develop an encephalopathy or severely delayed psychomotor development, which may result in death 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 HGCLAS, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014).
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).
Corticosterone methyloxidase type 2 deficiency
MedGen UID:
483046
Concept ID:
C3463917
Disease or Syndrome
CMO type II deficiency is an autosomal recessive disorder caused by a defect in the final biochemical step of aldosterone biosynthesis, the 18-hydroxylation of 18-hydroxycorticosterone (18-OHB) to aldosterone. This enzymatic defect results in decreased aldosterone and salt-wasting associated with an increased serum ratio of 18-OHB to aldosterone. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998). The CYP11B2 gene product also catalyzes an earlier step in aldosterone biosynthesis: the 18-hydroxylation of corticosterone to 18-OHB. A defect in that enzymatic step results in CMO type I deficiency (204300), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal (Portrat-Doyen et al., 1998).
Fanconi anemia, complementation group G
MedGen UID:
854017
Concept ID:
C3469527
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/or 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, and genitourinary tract – are more common in individuals with FA.
Fanconi anemia, complementation group P
MedGen UID:
854020
Concept ID:
C3469542
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/or 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, and genitourinary tract – are more common in individuals with FA.
Neuropathy, hereditary sensory and autonomic, type VI
MedGen UID:
761278
Concept ID:
C3539003
Disease or Syndrome
Hereditary sensory and autonomic neuropathy type VI is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection (summary by Edvardson et al., 2012). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).
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).
Congenital disorder of glycosylation type 2L
MedGen UID:
766144
Concept ID:
C3553230
Disease or Syndrome
CDG2L is an autosomal recessive multisystem disorder apparent from birth or early infancy. It is characterized by poor growth, gastrointestinal and liver abnormalities, delayed psychomotor development, hypotonia, recurrent infections, hematologic abnormalities, increased bleeding tendency, and hyperhidrosis or hyperkeratosis. More variable features include nonspecific dysmorphic facial features and cardiac septal defects. The disorder often results in death in infancy or the first years of life (summary by Rymen et al., 2015). For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066).
Pontocerebellar hypoplasia, type 1b
MedGen UID:
766363
Concept ID:
C3553449
Disease or Syndrome
EXOSC3 pontocerebellar hypoplasia (EXOSC3-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, 82 individuals (from 58 families) with EXOSC3-PCH have been described.
Common variable immunodeficiency 8, with autoimmunity
MedGen UID:
766426
Concept ID:
C3553512
Disease or Syndrome
Common variable immunodeficiency-8 with autoimmunity is an autosomal recessive disorder of immune dysregulation. Affected individuals have early childhood onset of recurrent infections, particularly respiratory infections, and also develop variable autoimmune disorders, including idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and inflammatory bowel disease. The presentation and phenotype are highly variable, even within families (summary by Lopez-Herrera et al., 2012 and Alangari et al., 2012). Immunologic findings are also variable and may include decreased B cells, hypogammaglobulinemia, and deficiency of CD4+ T regulatory (Treg) cells (Charbonnier et al., 2015). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).
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).
Hyperphosphatasia with mental retardation syndrome 2
MedGen UID:
766551
Concept ID:
C3553637
Disease or Syndrome
Hyperphosphatasia with mental retardation syndrome-2 is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures (summary by Krawitz et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of hyperphosphatasia with mental retardation syndrome, see HPMRS1 (239300). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Methylmalonic acidemia with homocystinuria, type cblJ
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 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 13
MedGen UID:
767043
Concept ID:
C3554129
Disease or Syndrome
Combined oxidative phosphorylation deficiency-13 is an autosomal recessive multisystem disorder resulting from mitochondrial dysfunction. Affected individuals develop severe neurologic impairment in the first months of life, including hypotonia, abnormal dystonic movements, hearing loss, poor feeding, global developmental delay, and abnormal eye movements. Brain imaging shows signal abnormalities in putamen, basal ganglia, caudate nuclei, or corpus callosum, as well as delayed myelination. Analysis of patient tissues shows multiple defects in enzymatic activities of the mitochondrial respiratory chain, although some tissues may show normal values since tissue expression of the mitochondrial defect and metabolic needs of specific tissues are variable (summary by Vedrenne et al., 2012).
Combined oxidative phosphorylation deficiency 14
MedGen UID:
767082
Concept ID:
C3554168
Disease or Syndrome
The spectrum of FARS2 deficiency ranges from the infantile-onset phenotype, characterized by epileptic encephalopathy with lactic acidosis and poor prognosis (70% of affected individuals), to the later-onset phenotype, characterized by spastic paraplegia, less severe neurologic manifestations, and longer survival (30% of affected individuals). To date FARS2 deficiency has been reported in 37 individuals from 25 families. Infantile-onset phenotype. Seizures are difficult to control and may progress quickly at an early age to intractable seizures with frequent status epilepticus; some children have hypsarrhythmia on EEG. All have developmental delay; most are nonverbal and unable to walk. Feeding difficulties are common. More than half of affected children die in early childhood. Later-onset phenotype. All affected individuals have spastic paraplegia manifested by weakness, spasticity, and exaggerated reflexes of the lower extremities associated with walking difficulties; some have developmental delay/intellectual disability; some have brief seizures that resolve over time.
Glycogen storage disease type IXa1
MedGen UID:
854172
Concept ID:
C3694531
Disease or Syndrome
Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that patients need to be monitored for long-term complications such as liver fibrosis and cirrhosis.
Mental retardation, X-linked 98
MedGen UID:
813060
Concept ID:
C3806730
Disease or Syndrome
X-linked intellectual developmental disorder-98 (XLID98) is a neurodevelopmental disorder characterized by delayed psychomotor development, poor speech, behavioral abnormalities, poor overall growth, dysmorphic facial features, and often early-onset seizures. Some carrier females are unaffected, whereas other females with mutations are affected; males tend to be more severely affected than females. It is believed that the phenotypic variability and disease manifestations in female carriers results from skewed X-inactivation or cellular mosaicism (summary by de Lange et al., 2016).
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).
Hypochromic microcytic anemia with iron overload 2
MedGen UID:
815250
Concept ID:
C3808920
Disease or Syndrome
STEAP3/TSAP6-related sideroblastic anemia is a very rare severe non-syndromic hypochromic anemia, which is characterized by transfusion-dependent hypochromic, poorly regenerative anemia, iron overload, resembling non-syndromic sideroblastic anemia (see this term) except for increased erythrocyte protoporphyrin levels.
Fanconi anemia, complementation group Q
MedGen UID:
815318
Concept ID:
C3808988
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/or 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, and genitourinary tract – are more common in individuals with FA.
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).
Immunodeficiency 12
MedGen UID:
815913
Concept ID:
C3809583
Disease or Syndrome
Combined immunodeficiency due to MALT1 deficiency is a rare, genetic form of primary immunodeficiency characterized by growth retardation, early recurrent pulmonary infections leading to bronchiectasis, inflammatory gastrointestinal disease, and other symptoms, such as rash, dermatitis, skin infections.
Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)
MedGen UID:
815922
Concept ID:
C3809592
Disease or Syndrome
FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
Erythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper-ige
MedGen UID:
816049
Concept ID:
C3809719
Disease or Syndrome
A rare genetic epidermal disorder with characteristics of congenital erythroderma with severe psoriasiform dermatitis, ichthyosis, severe palmoplantar keratoderma, yellow keratosis on the hands and feet, elevated immunoglobulin E, multiple food allergies, and metabolic wasting. Other variable features may include hypotrichosis, nail dystrophy, recurrent infections, mild global developmental delay, eosinophilia, nystagmus, growth impairment and cardiac defects.
Van Maldergem syndrome 2
MedGen UID:
816205
Concept ID:
C3809875
Disease or Syndrome
Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia (summary by Cappello et al., 2013). For a discussion of genetic heterogeneity of Van Maldergem syndrome, see 601390.
Loeys-Dietz syndrome 5
MedGen UID:
816342
Concept ID:
C3810012
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.
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).
Fanconi renotubular syndrome 3
MedGen UID:
816430
Concept ID:
C3810100
Disease or Syndrome
Fanconi renotubular syndrome-3 (FRTS3) is an autosomal dominant disorder characterized by rickets, impaired growth, glucosuria, generalized aminoaciduria, phosphaturia, metabolic acidosis, and low molecular weight proteinuria (summary by Klootwijk et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of Fanconi renotubular syndrome, see FRTS1 (134600).
Congenital dyserythropoietic anemia type type 1B
MedGen UID:
816515
Concept ID:
C3810185
Disease or Syndrome
Congenital dyserythropoietic anemia type I (CDA I) is characterized by moderate-to-severe macrocytic anemia presenting occasionally in utero as severe anemia associated with hydrops fetalis but more commonly in neonates as hepatomegaly, early jaundice, and intrauterine growth restriction. Some individuals present in childhood or adulthood. After the neonatal period, most affected individuals have lifelong moderate anemia, usually accompanied by jaundice and splenomegaly. Secondary hemochromatosis develops with age as a result of increased iron absorption even in those who are not transfused. Distal limb anomalies occur in 4%-14% of affected individuals.
Chromosome 5q12 deletion syndrome
MedGen UID:
816612
Concept ID:
C3810282
Disease or Syndrome
PDE4D haploinsufficiency syndrome is a rare syndromic intellectual disability characterized by developmental delay, intellectual disability, low body mass index, long arms, fingers and toes, prominent nose and small chin.
Poikiloderma, hereditary fibrosing, with tendon contractures, myopathy, and pulmonary fibrosis
MedGen UID:
816655
Concept ID:
C3810325
Disease or Syndrome
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is characterized by the skin findings of poikiloderma (typically beginning in the first six months and mainly localized to the face), hypohidrosis with heat intolerance, mild lymphedema of the extremities, chronic erythematous and scaly skin lesions on the extremities, sclerosis of the digits, and mild palmoplantar keratoderma. Scalp hair, eyelashes, and/or eyebrows are typically sparse. Muscle contractures are usually seen in childhood and can be present as early as age two years. The majority of affected individuals develop progressive weakness of the proximal and distal muscles of all four limbs. Some adults develop progressive interstitial pulmonary fibrosis, which can be life threatening within three to four years after respiratory symptoms appear. Other features are exocrine pancreatic insufficiency, liver impairment, hematologic abnormalities, relative short stature, and cataract.
Hyperphosphatasia with mental retardation syndrome 4
MedGen UID:
816684
Concept ID:
C3810354
Disease or Syndrome
Hyperphosphatasia with mental retardation syndrome-4 is an autosomal recessive neurologic disorder characterized by severely delayed psychomotor development, mental retardation, lack of speech acquisition, seizures, and dysmorphic facial features. Laboratory studies show increased serum alkaline phosphatase (summary by Howard et al., 2014). 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).
Apparent mineralocorticoid excess
MedGen UID:
854657
Concept ID:
C3887949
Disease or Syndrome
Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone (review by Ferrari, 2010).
Autosomal recessive congenital ichthyosis 2
MedGen UID:
854762
Concept ID:
C3888093
Disease or Syndrome
Autosomal recessive congenital ichthyosis (ARCI) encompasses several forms of nonsyndromic ichthyosis. Although most neonates with ARCI are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE). These phenotypes are now recognized to fall on a continuum; however, the phenotypic descriptions are clinically useful for clarification of prognosis and management. Infants with harlequin ichthyosis are usually born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection. Collodion babies are born with a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks. LI and CIE are seemingly distinct phenotypes: classic, severe LI with dark brown, plate-like scale with no erythroderma and CIE with finer whiter scale and underlying generalized redness of the skin. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar keratoderma. Besides these major forms of nonsyndromic ichthyosis, a few rare subtypes have been recognized, such as bathing suit ichthyosis, self-improving collodion ichthyosis, or ichthyosis-prematurity syndrome.
Desbuquois dysplasia 1
MedGen UID:
860583
Concept ID:
C4012146
Disease or Syndrome
Desbuquois dysplasia (DBQD) is an autosomal recessive chondrodysplasia belonging to the multiple dislocation group and characterized by severe prenatal and postnatal growth retardation (stature less than -5 SD), joint laxity, short extremities, and progressive scoliosis. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advanced carpal and tarsal bone age with a delta phalanx (summary by Huber et al., 2009). Desbuquois dysplasia is clinically and radiographically heterogeneous, and had been classified into 2 types based on the presence (type 1) or absence (type 2) of characteristic hand anomalies, including an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and dislocation of the interphalangeal joints (Faivre et al., 2004). However, patients with and without these additional hand anomalies have been reported to have mutations in the same gene (see, e.g., CANT1); thus, these features are not distinctive criteria to predict the molecular basis of DBQD (Furuichi et al., 2011). In addition, Kim et al. (2010) described another milder variant of DBQD with almost normal outwardly appearing hands, but significant radiographic changes, including short metacarpals, elongated phalanges, and remarkably advanced carpal bone age. However, there is no accessory ossification center distal to the second metacarpal, and patients do not have thumb anomalies. Similar changes occur in the feet. These patients also tend to develop precocious osteoarthritis of the hand and spine with age. This phenotype is sometimes referred to as the 'Kim variant' of DBQD (Furuichi et al., 2011). Genetic Heterogeneity of Desbuquois Dysplasia DBQD2 (615777) is caused by mutation in the XYLT1 gene (608124) on chromosome 16p12. Two unrelated patients with immunodeficiency-23 (IMD23; 615816), due to mutation in the PGM3 gene (172100), were reported to have skeletal features reminiscent of DBQD.
Common variable immunodeficiency 11
MedGen UID:
862695
Concept ID:
C4014258
Disease or Syndrome
Common variable immune deficiency (CVID) is a disorder that impairs the immune system. People with CVID are highly susceptible to infection from foreign invaders such as bacteria, or more rarely, viruses and often develop recurrent infections, particularly in the lungs, sinuses, and ears. Pneumonia is common in people with CVID. Over time, recurrent infections can lead to chronic lung disease. Affected individuals may also experience infection or inflammation of the gastrointestinal tract, which can cause diarrhea and weight loss. Abnormal accumulation of immune cells causes enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly) in some people with CVID. Immune cells can accumulate in other organs, forming small lumps called granulomas.\n\nApproximately 25 percent of people with CVID have an autoimmune disorder, which occurs when the immune system malfunctions and attacks the body's tissues and organs. The blood cells are most frequently affected by autoimmune attacks in CVID; the most commonly occurring autoimmune disorders are immune thrombocytopenia, which is an abnormal bleeding disorder caused by a decrease in cells involved in blood clotting called platelets, and autoimmune hemolytic anemia, which results in premature destruction of red blood cells. Other autoimmune disorders such as rheumatoid arthritis can occur. Individuals with CVID also have a greater than normal risk of developing certain types of cancer, including a cancer of immune system cells called non-Hodgkin lymphoma and less frequently, stomach (gastric) cancer.\n\nPeople with CVID may start experiencing signs and symptoms of the disorder anytime between childhood and adulthood; most people with CVID are diagnosed in their twenties or thirties. The life expectancy of individuals with CVID varies depending on the severity and frequency of illnesses they experience. Most people with CVID live into adulthood.\n\nThere are many different types of CVID that are distinguished by genetic cause. People with the same type of CVID may have varying signs and symptoms.
Pontocerebellar hypoplasia, type 10
MedGen UID:
862784
Concept ID:
C4014347
Disease or Syndrome
Pontocerebellar hypoplasia type 10 is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy and delayed myelination. Some patients have dysmorphic features and an axonal sensorimotor neuropathy (summary by Karaca et al., 2014 and Schaffer et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Mental retardation, autosomal dominant 27
MedGen UID:
862965
Concept ID:
C4014528
Disease or Syndrome
Coffin-Siris syndrome 9 is characterized by mild intellectual disability, dysmorphic facial features, hypertrichosis, microcephaly, growth deficiency, and hypoplastic fifth toenails (Tsurusaki et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
Polyglucosan body myopathy 1 with or without immunodeficiency
MedGen UID:
863042
Concept ID:
C4014605
Disease or Syndrome
Polyglucosan body myopathy-1 is an autosomal recessive disorder characterized by onset in childhood of progressive proximal muscle weakness, resulting in difficulties in ambulation. Most patients also develop progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. A small subset of patients present with severe immunodeficiency and a hyperinflammatory state in very early childhood (summary by Boisson et al., 2012 and Nilsson et al., 2013). Genetic Heterogeneity of Polyglucosan Body Myopathy See also PGBM2 (616199), caused by mutation in the GYG1 gene (603942) on chromosome 3q24.
Immunodeficiency 36
MedGen UID:
863371
Concept ID:
C4014934
Disease or Syndrome
IMD36 is a primary immunodeficiency with a highly heterogeneous clinical phenotype, characterized primarily by recurrent respiratory tract infections, lymphoproliferation, and antibody deficiency. Other features include growth retardation, mild neurodevelopmental delay, and autoimmunity. The major complication is development of B-cell lymphoma (Elkaim et al., 2016).
Hennekam lymphangiectasia-lymphedema syndrome 2
MedGen UID:
863376
Concept ID:
C4014939
Disease or Syndrome
Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. Additional features of the disorder include facial dysmorphism and cognitive impairment (summary by Alders et al., 2014). For a discussion of genetic heterogeneity of Hennekam lymphangiectasia-lymphedema syndrome, see HKLLS1 (235510).
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).
Mitochondrial complex III deficiency, nuclear type 9
MedGen UID:
863690
Concept ID:
C4015253
Disease or Syndrome
Any mitochondrial complex III deficiency in which the cause of the disease is a mutation in the UQCC3 gene.
Mental retardation, autosomal recessive 46
MedGen UID:
863720
Concept ID:
C4015283
Disease or Syndrome
Peroxisomal fatty acyl-coa reductase 1 disorder
MedGen UID:
863781
Concept ID:
C4015344
Disease or Syndrome
Peroxisomal fatty acyl-CoA reductase-1 disorder (PFCRD) is an autosomal recessive disorder characterized by onset in infancy of severely delayed psychomotor development, growth retardation with microcephaly, and seizures. Some patients may have congenital cataracts and develop spasticity later in childhood. Biochemical studies tend to show decreased plasmalogen, consistent with a peroxisomal defect. The disorder is reminiscent of rhizomelic chondrodysplasia punctata (see, e.g., RCDP1, 215100), although the characteristic skeletal abnormalities observed in RCDP are absent (Buchert et al., 2014).
Microcephaly, short stature, and impaired glucose metabolism 2
MedGen UID:
906140
Concept ID:
C4225195
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).
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.
Seizures, cortical blindness, and microcephaly syndrome
MedGen UID:
894797
Concept ID:
C4225261
Disease or Syndrome
Seizures, cortical blindness, and microcephaly syndrome (SCBMS) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, severely delayed psychomotor development, and cortical blindness. Affected individuals also tend to show poor overall growth with short stature (summary by Ercan-Sencicek et al., 2015).
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).
3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia
MedGen UID:
907853
Concept ID:
C4225393
Disease or Syndrome
CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which range from severe to mild. To date, a total of 26 individuals from 16 families have been reported. In severe CLPB deficiency, death usually occurs at a few months of age as a result of significant neonatal neurologic involvement (hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy) and severe neutropenia associated with life-threatening infections. In moderate CLPB deficiency neurologic abnormalities in infancy are comparable to but less severe than those observed in the severe phenotype (e.g., hypotonia and feeding problems) and in later childhood can include spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability ranging from mild learning disability to limited development of all cognitive and motor functions. Neutropenia is variable, but not life threatening. In mild CLPB deficiency there is no neurologic involvement, intellect is normal, and neutropenia is mild and intermittent. Life expectancy is normal.
Ritscher-schinzel syndrome 2
MedGen UID:
897005
Concept ID:
C4225419
Disease or Syndrome
Ritscher-Schinzel syndrome (RSS) is a clinically recognizable condition that includes the cardinal findings of craniofacial features, cerebellar defects, and cardiovascular malformations resulting in the alternate diagnostic name of 3C syndrome. Dysmorphic facial features may include brachycephaly, hypotonic face with protruding tongue, flat appearance of the face on profile view, short midface, widely spaced eyes, downslanted palpebral fissures, low-set ears with overfolding of the upper helix, smooth or short philtrum, and high or cleft palate. Affected individuals also typically have a characteristic metacarpal phalangeal profile showing a consistent wavy pattern on hand radiographs. RSS is associated with variable degrees of developmental delay and intellectual disability. Eye anomalies and hypercholesterolemia may be variably present.
Mental retardation, X-linked 61
MedGen UID:
924419
Concept ID:
C4283894
Disease or Syndrome
Tonne-Kalscheuer syndrome (TOKAS) is an X-linked recessive multiple congenital anomaly disorder with 2 main presentations. Most patients exhibit global developmental delay apparent from early infancy, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait. Affected individuals also have dysmorphic facial features that evolve with age, anomalies of the hands, feet, and nails, and urogenital abnormalities with hypogenitalism. A subset of more severely affected males develop congenital diaphragmatic hernia in utero, which may result in perinatal or premature death. Carrier females may have very mild skeletal or hormonal abnormalities (summary by Frints et al., 2019). Also see Fryns syndrome (229850), an autosomal recessive disorder with overlapping features.
Fanconi anemia, complementation group R
MedGen UID:
924579
Concept ID:
C4284093
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/or 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, and genitourinary tract – are more common in individuals with FA.
Intellectual developmental disorder with dysmorphic facies and ptosis
MedGen UID:
934584
Concept ID:
C4310617
Disease or Syndrome
Intellectual developmental disorder with dysmorphic facies and ptosis is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, delayed language, and dysmorphic facial features, most notably ptosis/blepharophimosis. Additional features may include poor growth, hypotonia, and seizures (summary by Mattioli et al., 2017). See also chromosome 3p deletion syndrome (613792).
3-methylglutaconic aciduria, type VIII
MedGen UID:
934617
Concept ID:
C4310650
Disease or Syndrome
MGCA8 is an autosomal recessive metabolic disorder resulting in death in infancy. Features include hypotonia, abnormal movements, respiratory insufficiency with apneic episodes, and lack of developmental progress, often with seizures. Brain imaging is variable, but may show progressive cerebral atrophy. Laboratory studies show increased serum lactate and 3-methylglutaconic aciduria, suggesting a mitochondrial defect (summary by Mandel et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).
Fanconi anemia, complementation group U
MedGen UID:
934618
Concept ID:
C4310651
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/or 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, and genitourinary tract – are more common in individuals with FA.
Meier-gorlin syndrome 7
MedGen UID:
934705
Concept ID:
C4310738
Disease or Syndrome
Heart and brain malformation syndrome
MedGen UID:
934760
Concept ID:
C4310793
Disease or Syndrome
Heart and brain malformation syndrome is a severe autosomal recessive multiple congenital anomaly syndrome characterized by profoundly delayed psychomotor development, dysmorphic facial features, microphthalmia, cardiac malformations, mainly septal defects, and brain malformations, including Dandy-Walker malformation (summary by Shaheen et al., 2016).
Witteveen-kolk syndrome
MedGen UID:
934771
Concept ID:
C4310804
Disease or Syndrome
15q24 microdeletion is a chromosomal change in which a small piece of chromosome 15 is deleted in each cell. The deletion occurs on the long (q) arm of the chromosome at a position designated q24.\n\n15q24 microdeletion is associated with mild to moderate intellectual disability and delayed speech development. Other common signs and symptoms include short stature, weak muscle tone (hypotonia), and skeletal abnormalities including loose (lax) joints. Affected males may have genital abnormalities, which can include an unusually small penis (micropenis) and the opening of the urethra on the underside of the penis (hypospadias). Affected individuals also have distinctive facial features such as a high front hairline, broad eyebrows, widely set eyes (hypertelorism), outside corners of the eyes that point downward (downslanting palpebral fissures), a broad nasal bridge, a full lower lip, and a long, smooth space between the upper lip and nose (philtrum).
MENTAL RETARDATION, X-LINKED, SYNDROMIC, 35
MedGen UID:
1392054
Concept ID:
C4478383
Disease or Syndrome
Cerebroretinal microangiopathy with calcifications and cysts 2
MedGen UID:
1390862
Concept ID:
C4479220
Disease or Syndrome
CRMCC2 is an autosomal recessive multisystem disorder characterized by premature aging, pancytopenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding. Brain imaging shows intracranial calcifications and leukodystrophy, which may result in neurologic signs including spasticity, ataxia, or dystonia. Patients may also have retinal telangiectasia (summary by Simon et al., 2016). For a discussion of genetic heterogeneity of CRMCC, see CRMCC1 (612199).
Autoinflammation with arthritis and dyskeratosis
MedGen UID:
1380109
Concept ID:
C4479278
Disease or Syndrome
Autoinflammation with arthritis and dyskeratosis is characterized by recurrent fever, widespread skin dyskeratosis, arthritis, elevated biologic markers of inflammation, and mild autoimmunity with a high transitional B-cell level (summary by Grandemange et al., 2016).
Fanconi anemia, complementation group W
MedGen UID:
1621245
Concept ID:
C4521564
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/or 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, and genitourinary tract – are more common in individuals with FA.
Mosaic variegated aneuploidy syndrome 3
MedGen UID:
1616382
Concept ID:
C4539839
Disease or Syndrome
MVA3 is an autosomal recessive disorder resulting from errors in chromosome segregation. Most affected individuals develop early-onset Wilms tumor and show either aneuploidy or premature chromatid separation in cells. Some patients may have additional developmental features, such as microcephaly, growth retardation, or developmental delay (summary by Yost et al., 2017). For a discussion of genetic heterogeneity of MVA, see MVA1 (257300).
Early infantile epileptic encephalopathy 55
MedGen UID:
1622363
Concept ID:
C4539843
Disease or Syndrome
Developmental and epileptic encephalopathy-55 (DEE55) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first weeks or months of life. Affected individuals have an extremely poor outcome, with profoundly impaired intellectual development, absent speech, spastic quadriplegia, and dyskinetic movements. Most have cortical visual impairment and require a feeding tube. Brain imaging shows nonspecific abnormalities, including cerebral atrophy, thin corpus callosum, and abnormal signals in the white matter. Death in childhood may occur. Biochemically, the disorder is associated with impaired synthesis of GPI-anchored proteins (summary by Vetro et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Multiple mitochondrial dysfunctions syndrome 5
MedGen UID:
1623132
Concept ID:
C4539919
Disease or Syndrome
ISCA1-related multiple mitochondrial dysfunctions syndrome (ISCA1-MMDS) is a severe neurodegenerative condition typically characterized by either no attainment of developmental milestones or very early loss of achieved milestones, seizures in early infancy, development of spasticity with exaggerated deep tendon reflexes, nystagmus, and risk for sensorineural hearing loss. Affected individuals may also demonstrate elevated blood lactate levels with an elevated lipid-lactate peak on brain MR spectroscopy. Further brain MRI findings may include extensive cerebral and cerebellar deep white matter hyperintensities, marked dilatation of the cerebral ventricles, and pachygyria. Prognosis is poor and most individuals succumb to an intercurrent illness in early childhood.
Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay
MedGen UID:
1612119
Concept ID:
C4539968
Disease or Syndrome
CAKUTHED is an autosomal dominant highly pleiotropic developmental disorder characterized mainly by variable congenital anomalies of the kidney and urinary tract, sometimes resulting in renal dysfunction or failure, dysmorphic facial features, and abnormalities of the outer ear, often with hearing loss. Most patients have global developmental delay (summary by Heidet et al., 2017 and Slavotinek et al., 2017).
Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome
MedGen UID:
1620960
Concept ID:
C4540096
Disease or Syndrome
A rare genetic neurological disorder characterized by motor developmental delay (in infancy), growth impairment and muscle weakness associated with myopathic abnormalities on muscle biopsy and EMG, as well as tremor, dysmetry, adiadochokinesia and walking disturbances associated with global or partial cerebral atrophy on brain MRI (particularly cerebellar vermis and hemispheres), with or without mild intellectual disability. Some patients also show pigmentary retinopathy.
Immunodeficiency, developmental delay, and hypohomocysteinemia
MedGen UID:
1616061
Concept ID:
C4540293
Disease or Syndrome
IMDDHH is a multisystem disorder characterized by immunodeficiency, mildly delayed psychomotor development, poor overall growth from infancy, and hypohomocysteinemia. Additional features, such as congenital heart defects and liver involvement, are more variable (summary by Huppke et al., 2017).
Kleefstra syndrome 2
MedGen UID:
1623903
Concept ID:
C4540395
Disease or Syndrome
Kleefstra syndrome-2 is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, variable intellectual disability, and mild dysmorphic features (summary by Koemans et al., 2017). For a discussion of genetic heterogeneity of Kleefstra syndrome, see KLEFS1 (610253).
Wolfram syndrome 1
MedGen UID:
1641635
Concept ID:
C4551693
Disease or Syndrome
WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus (DM) and optic atrophy (OA) before age 16 years, and typically associated with other endocrine abnormalities, sensorineural hearing loss, and progressive neurologic abnormalities (cerebellar ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony). Although DM is mostly insulin-dependent, overall the course is milder (with lower prevalence of microvascular disease) than that seen in isolated DM. OA typically results in significantly reduced visual acuity in the first decade. Sensorineural hearing impairment ranges from congenital deafness to milder, sometimes progressive, hearing impairment.
Rubinstein-Taybi syndrome 1
MedGen UID:
1639327
Concept ID:
C4551859
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.
Van Maldergem syndrome 1
MedGen UID:
1644627
Concept ID:
C4551950
Disease or Syndrome
Van Maldergem syndrome is an autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia (summary by Cappello et al., 2013). Genetic Heterogeneity of Van Maldergem Syndrome See also VMLDS2 (615546), caused by mutation in the FAT4 gene (612411) on chromosome 4q28.
Nephronophthisis 1
MedGen UID:
1638799
Concept ID:
C4551979
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).
Epidermal nevus syndrome
MedGen UID:
1646345
Concept ID:
C4552097
Disease or Syndrome
Schimmelpenning-Feuerstein-Mims syndrome, also known as linear sebaceous nevus syndrome, is characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects (summary by Happle, 1991 and Ernst et al., 2007). The linear sebaceous nevi follow the lines of Blaschko (Hornstein and Knickenberg, 1974; Bouwes Bavinck and van de Kamp, 1985). All cases are sporadic. The syndrome is believed to be caused by an autosomal dominant lethal mutation that survives by somatic mosaicism (Gorlin et al., 2001).
Leukodystrophy, hypomyelinating, 14
MedGen UID:
1635255
Concept ID:
C4693535
Disease or Syndrome
Hypomyelinating leukodystrophy-14 is an autosomal recessive neurodevelopmental disorder characterized by hypotonia, almost complete lack of motor or cognitive skills, and absent language development. Additional features include spasticity and intractable seizures; many patients also have perceptive hearing loss and/or blindness. Most patients require tube feeding or ventilatory support, and most die in the first years of life. Brain imaging shows hypomyelination, small caudate and putamen, and cerebral and cerebellar atrophy (summary by Hamilton et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.
Impaired sensitivity to thyroid hormone
MedGen UID:
1654700
Concept ID:
C4722330
Disease or Syndrome
Decreased response to thyroid hormones in peripheral tissues and in the pituitary gland.
Proteasome-associated autoinflammatory syndrome 1
MedGen UID:
1648310
Concept ID:
C4746851
Disease or Syndrome
This autosomal recessive systemic autoinflammatory disorder is characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011). This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions. Genetic Heterogeneity of Proteasome-Associated Autoinflammatory Syndrome See also PRAAS2 (618048), caused by mutation in the POMP gene (613386) on chromosome 13q12; PRAAS3 (617591), caused by mutation in the PSMB4 gene (602177) on chromosome 1q21; PRAAS4 (619183), caused by mutation in the PSMG2 gene (609702) on chromosome 18p11; and PRAAS5 (619175), caused by mutation in the PSMB10 gene (176847) on chromosome 16q22.
Glycosylphosphatidylinositol biosynthesis defect 17
MedGen UID:
1648437
Concept ID:
C4747891
Disease or Syndrome
Glycosylphosphatidylinositol biosynthesis defect-17 is an autosomal recessive disorder characterized by variable neurologic deficits that become apparent in infancy or early childhood. Patients may present with early-onset febrile or afebrile seizures that tend to be mild or controllable. Other features may include learning disabilities, autism, behavioral abnormalities, hypotonia, and motor deficits. The phenotype is relatively mild compared to that of other GPIBDs (summary by Nguyen et al., 2018). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Neurodevelopmental disorder with spasticity and poor growth
MedGen UID:
1648309
Concept ID:
C4748081
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 21
MedGen UID:
1648383
Concept ID:
C4748792
Disease or Syndrome
Van Esch-O'Driscoll syndrome
MedGen UID:
1674293
Concept ID:
C5193012
Disease or Syndrome
Van Esch-O'Driscoll syndrome (VEODS) is characterized by varying degrees of intellectual disability, moderate to severe short stature, microcephaly, hypogonadism, and variable congenital malformations (Van Esch et al., 2019).
Spastic ataxia 9, autosomal recessive
MedGen UID:
1680026
Concept ID:
C5193100
Disease or Syndrome
Developmental and epileptic encephalopathy, 80
MedGen UID:
1684779
Concept ID:
C5231418
Disease or Syndrome
Developmental and epileptic encephalopathy-80 (DEE80) is an autosomal recessive neurologic disorder characterized by the onset of refractory seizures in the first year of life. Patients have severe global developmental delay and may have additional variable features, including dysmorphic or coarse facial features, distal skeletal abnormalities, and impaired hearing or vision. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Murakami et al., 2019). For a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies
MedGen UID:
1684792
Concept ID:
C5231448
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a global neurodevelopmental disorder with highly variable features. Patients often show poor feeding, poor overall growth, and hypotonia from early infancy, followed by mildly delayed motor development, poor language acquisition, and behavioral abnormalities. Intellectual development varies from severe with absent speech to mild with the ability to attend special schools. Common features include dysmorphic facial features with notable eye anomalies, joint hypermobility, and mild skeletal anomalies of the hands and feet (summary by Carapito et al., 2019).
Developmental and epileptic encephalopathy, 85, with or without midline brain defects
MedGen UID:
1708832
Concept ID:
C5393312
Disease or Syndrome
Developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85) is an X-linked neurologic disorder characterized by onset of severe refractory seizures in the first year of life, global developmental delay with impaired intellectual development and poor or absent speech, and dysmorphic facial features. The seizures tend to show a cyclic pattern with clustering. Many patients have midline brain defects on brain imaging, including thin corpus callosum and/or variable forms of holoprosencephaly (HPE). The severity and clinical manifestations are variable. Almost all reported patients are females with de novo mutations predicted to result in a loss of function (LOF). However, some patients may show skewed X inactivation, and the pathogenic mechanism may be due to a dominant-negative effect. The SMC1A protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; DEE85 can thus be classified as a 'cohesinopathy' (summary by Symonds et al., 2017 and Kruszka et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Developmental and epileptic encephalopathy, 88
MedGen UID:
1712195
Concept ID:
C5394553
Disease or Syndrome
Developmental and epileptic encephalopathy-88 (DEE88) is an autosomal recessive severe neurologic disorder characterized by global developmental delay, early-onset epilepsy, and progressive microcephaly. Brain MRI findings may include corpus callosum abnormalities, prominent ventricles, and mild hypoplasia of the inferior vermis and pons (Broeks et al., 2019). For a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see 308350.
Renal tubular acidosis, distal, autosomal recessive
MedGen UID:
1732975
Concept ID:
C5399980
Disease or Syndrome
Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with failure to thrive, although later presentations can occur, especially in individuals with autosomal dominant SLC4A1-dRTA. Initial clinical manifestations can also include emesis, polyuria, polydipsia, constipation, diarrhea, decreased appetite, and episodes of dehydration. Electrolyte manifestations include hyperchloremic non-anion gap metabolic acidosis and hypokalemia. Renal complications of dRTA include nephrocalcinosis, nephrolithiasis, medullary cysts, and impaired renal function. Additional manifestations include bone demineralization (rickets, osteomalacia), growth deficiency, sensorineural hearing loss (in ATP6V0A4-, ATP6V1B1-, and FOXI1-dRTA), and hereditary hemolytic anemia (in some individuals with SLC4A1-dRTA).
Joubert syndrome with hepatic defect
MedGen UID:
1769861
Concept ID:
C5435651
Disease or Syndrome
COACH syndrome is an autosomal recessive disorder characterized by impaired intellectual development, 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). Genetic Heterogeneity of COACH Syndrome Also see COACH syndrome-2 (COACH2; 619111), caused by mutation in in the CC2D2A gene (612013), and COACH syndrome-3 (COACH3; 619113), caused by mutation the RPGRIP1L gene (610937). Most cases of COACH syndrome are caused by mutation in the TMEM67 gene.
Rajab interstitial lung disease with brain calcifications 1
MedGen UID:
1750003
Concept ID:
C5436276
Disease or Syndrome
A rare, inherited disorder characterized by widespread calcifications of basal ganglia and cortex, developmental delay, small stature, retinopathy and microcephaly. The absence of progressive deterioration of the neurological functions is characteristic of the disease.
Arthrogryposis multiplex congenita 5
MedGen UID:
1731112
Concept ID:
C5436453
Disease or Syndrome
Arthrogryposis multiplex congenita-5 (AMC5) is an autosomal recessive disorder characterized by severe joint contractures apparent at birth. Affected individuals usually have hypertonia and abnormal movements suggestive of dystonia, as well as feeding and/or breathing difficulties. More variable features may include poor overall growth, strabismus, dysmorphic facies, and global developmental delay with impaired speech (summary by Kariminejad et al., 2017).
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
MedGen UID:
1736667
Concept ID:
C5436628
Disease or Syndrome
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA) is an autosomal recessive disorder characterized by impaired psychomotor development apparent in infancy. Affected individuals show poor overall growth, progressive microcephaly, and axial hypotonia, with later onset of spasticity. The disorder is progressive. Some patients show normal early development, but later have regression of motor, cognitive, and language skills. More variable features include seizures, joint contractures, ocular disturbances, episodic respiratory failure, and nonspecific dysmorphic facial features. The intellectual impairment is variable, ranging from poor visual contact with inability to walk or speak to milder intellectual disability with the ability to say some words. Brain imaging shows variable white matter abnormalities, including thin corpus callosum and poor myelination (summary by Husain et al., 2020).
Combined oxidative phosphorylation deficiency 51
MedGen UID:
1757992
Concept ID:
C5436703
Disease or Syndrome
Vitamin D-dependent rickets, type 3
MedGen UID:
1725534
Concept ID:
C5436733
Disease or Syndrome
Vitamin D-dependent rickets-3 (VDDR3) is characterized by early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to the parent molecule as well as activated forms of vitamin D (Roizen et al., 2018). For discussion of genetic heterogeneity of vitamin D-dependent rickets, see 264700.
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities
MedGen UID:
1750805
Concept ID:
C5436848
Disease or Syndrome
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB) is an autosomal recessive multisystemic disorder characterized by global neurodevelopmental delay, severely impaired intellectual development, poor overall growth, and spasticity of the lower limbs resulting in gait difficulties. Most affected individuals also develop progressive hypertrophic cardiomyopathy in childhood or have cardiac developmental anomalies. Additional more variable features include dysmorphic facies and axonal sensory peripheral neuropathy. Brain imaging tends to show thin corpus callosum and polymicrogyria (summary by Garcia-Cazorla et al., 2020).
Mitochondrial complex 2 deficiency, nuclear type 2
MedGen UID:
1742371
Concept ID:
C5436933
Disease or Syndrome
Mitochondrial complex II deficiency nuclear type 2 (MC2DN2) is an autosomal recessive multisystemic metabolic disorder with variable severity and features. Most patients present with neurologic deterioration in infancy or early childhood after normal early development. Features include loss of motor skills, spastic paresis, dystonia, and loss of speech associated with increased serum and CSF lactate. Some patients may have mental decline or visual loss. Skeletal muscle samples show isolated complex II deficiency, and proton MRS shows increased succinate levels in the CSF and brain white matter. Brain imaging usually shows progressive leukoencephalopathy. Although the pattern of brain involvement may not be characteristic of Leigh syndrome (see 256000), postmortem examination in 1 patient showed multifocal spongiform encephalomyelopathy consistent with a diagnosis of Leigh syndrome. The most severely affected patients die of multiorgan failure and lactic acidosis, whereas others who survive may stabilize and regain some skills. Treatment with riboflavin may offer clinical improvement (summary by Brockmann et al., 2002 and Bugiani et al., 2006). For a discussion of genetic heterogeneity of MC2DN, see MC2DN1 (252011).
Syndromic X-linked intellectual disability Lubs type
MedGen UID:
337496
Concept ID:
C1846058
Mental or Behavioral Dysfunction
MECP2 duplication syndrome is a severe neurodevelopmental disorder characterized by early-onset hypotonia, feeding difficulty, gastrointestinal manifestations including gastroesophageal reflux and constipation, delayed psychomotor development leading to severe intellectual disability, poor speech development, progressive spasticity, recurrent respiratory infections (in ~75% of affected individuals), and seizures (in ~50%). MECP2 duplication syndrome is 100% penetrant in males. Occasionally females have been described with a MECP2 duplication and a range of findings from mild intellectual disability to a phenotype similar to that seen in males. In addition to the core features, autistic behaviors, nonspecific neuroradiologic findings on brain MRI, mottled skin, and urogenital anomalies have been observed in several affected boys.
Xeroderma pigmentosum variant type
MedGen UID:
376352
Concept ID:
C1848410
Disease or Syndrome
Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

Recent clinical studies

Etiology

Galo IDC, Lima BE, Santos TG, Braoios A, Prado RP, Santos WGD
Braz J Biol 2021 Mar-May;81(2):370-376. doi: 10.1590/1519-6984.226473. PMID: 32490986
Nevado J, Ho KS, Zollino M, Blanco R, Cobaleda C, Golzio C, Beaudry-Bellefeuille I, Berrocoso S, Limeres J, Barrúz P, Serrano-Martín C, Cafiero C, Málaga I, Marangi G, Campos-Sánchez E, Moriyón-Iglesias T, Márquez S, Markham L, Twede H, Lortz A, Olson L, Sheng X, Weng C, Wassman ER 3rd, Newcomb T, Wassman ER, Carey JC, Battaglia A, López-Granados E; Wolf-Hirschhorn Spain's Working Group., Douglas D, Lapunzina P
Am J Med Genet A 2020 Jan;182(1):257-267. Epub 2019 Nov 25 doi: 10.1002/ajmg.a.61406. PMID: 31769173
Leung CN, Canter BS, Rajon D, Bäck TA, Fritton JC, Azzam EI, Howell RW
J Nucl Med 2020 Jan;61(1):89-95. Epub 2019 Sep 13 doi: 10.2967/jnumed.119.227835. PMID: 31519805Free PMC Article
Feichtinger M, Falcone V, Schoenleitner T, Stopp T, Husslein PW, Eppel W, Chalubinski KM, Göbl CS
Ultraschall Med 2020 Feb;41(1):52-59. Epub 2018 Oct 25 doi: 10.1055/a-0651-0424. PMID: 30360008
Ehounoux NZ, Zunzunegui MV, Séguin L, Nikiema B, Gauvin L; Quebec Longitudinal Study of Child Development Birth Cohort.
J Epidemiol Community Health 2009 Jan;63(1):45-9. Epub 2008 Sep 9 doi: 10.1136/jech.2007.072157. PMID: 18782808

Diagnosis

Wong K, Isaac DM, Wine E
Dig Dis Sci 2021 Apr;66(4):954-964. Epub 2021 Jan 12 doi: 10.1007/s10620-020-06759-5. PMID: 33433805
Liu X, Hu G, Ye J, Ye B, Shen N, Tao Y, Zhang X, Fan Y, Liu H, Zhang Z, Fang D, Gu X, Mo X, Yu Y
Hum Mutat 2020 May;41(5):1012-1024. Epub 2020 Mar 3 doi: 10.1002/humu.23990. PMID: 31981384
Grabeklis AR, Skalny AV, Ajsuvakova OP, Skalnaya AA, Mazaletskaya AL, Klochkova SV, Chang SJS, Nikitjuk DB, Skalnaya MG, Tinkov AA
Biol Trace Elem Res 2020 Aug;196(2):607-617. Epub 2019 Nov 11 doi: 10.1007/s12011-019-01938-6. PMID: 31713112
Berkun L, Slae M, Mor-Shaked H, Koplewitz B, Eventov-Friedman S, Harel T
Am J Med Genet A 2019 Dec;179(12):2454-2458. Epub 2019 Sep 9 doi: 10.1002/ajmg.a.61355. PMID: 31502381
Sakazume S, Kido Y, Murakami N, Matsubara T, Numabe H
Pediatr Int 2015 Oct;57(5):880-3. doi: 10.1111/ped.12742. PMID: 26114601

Therapy

Rothkamm K, Christiansen S, Rieckmann T, Horn M, Frenzel T, Brinker A, Schumacher U, Stein A, Petersen C, Burdak-Rothkamm S
Cancer Lett 2020 Nov 28;493:179-188. Epub 2020 Sep 4 doi: 10.1016/j.canlet.2020.08.038. PMID: 32891715
Leung CN, Canter BS, Rajon D, Bäck TA, Fritton JC, Azzam EI, Howell RW
J Nucl Med 2020 Jan;61(1):89-95. Epub 2019 Sep 13 doi: 10.2967/jnumed.119.227835. PMID: 31519805Free PMC Article
Zhumalina AK, Bekmukhambetov EZ, Tusupkaliev BT, Zharlikasinova MB
Environ Geochem Health 2019 Jun;41(3):1251-1265. Epub 2018 Nov 8 doi: 10.1007/s10653-018-0210-0. PMID: 30406898
Ismail R, Allaudin ZN, Abdullah R, Mohd Lila MA, Nik Abd Rahman NM, Abdul Rahman SO
BMC Cancer 2016 Jul 13;16:461. doi: 10.1186/s12885-016-2530-8. PMID: 27411985Free PMC Article
Ridnour LA, Cheng RY, Weiss JM, Kaur S, Soto-Pantoja DR, Basudhar D, Heinecke JL, Stewart CA, DeGraff W, Sowers AL, Thetford A, Kesarwala AH, Roberts DD, Young HA, Mitchell JB, Trinchieri G, Wiltrout RH, Wink DA
Cancer Res 2015 Jul 15;75(14):2788-99. Epub 2015 May 19 doi: 10.1158/0008-5472.CAN-14-3011. PMID: 25990221Free PMC Article

Prognosis

Grabeklis AR, Skalny AV, Ajsuvakova OP, Skalnaya AA, Mazaletskaya AL, Klochkova SV, Chang SJS, Nikitjuk DB, Skalnaya MG, Tinkov AA
Biol Trace Elem Res 2020 Aug;196(2):607-617. Epub 2019 Nov 11 doi: 10.1007/s12011-019-01938-6. PMID: 31713112
Johnson AE, Bruce J, Tarullo AR, Gunnar MR
Dev Psychopathol 2011 Aug;23(3):859-71. doi: 10.1017/S0954579411000356. PMID: 21756437Free PMC Article
Zandi R, Selivanova G, Christensen CL, Gerds TA, Willumsen BM, Poulsen HS
Clin Cancer Res 2011 May 1;17(9):2830-41. Epub 2011 Mar 17 doi: 10.1158/1078-0432.CCR-10-3168. PMID: 21415220
Wouters L, Rodriguez Rodriguez CM, Dapena EP, Poorten VV, Devriendt K, Van Esch H
Eur J Med Genet 2011 May-Jun;54(3):236-40. Epub 2011 Jan 22 doi: 10.1016/j.ejmg.2011.01.003. PMID: 21262397
Davis D, Davis S, Cotman K, Worley S, Londrico D, Kenny D, Harrison AM
Pediatr Cardiol 2008 Mar;29(2):328-33. Epub 2007 Aug 9 doi: 10.1007/s00246-007-9027-9. PMID: 17687586

Clinical prediction guides

Rothkamm K, Christiansen S, Rieckmann T, Horn M, Frenzel T, Brinker A, Schumacher U, Stein A, Petersen C, Burdak-Rothkamm S
Cancer Lett 2020 Nov 28;493:179-188. Epub 2020 Sep 4 doi: 10.1016/j.canlet.2020.08.038. PMID: 32891715
Grabeklis AR, Skalny AV, Ajsuvakova OP, Skalnaya AA, Mazaletskaya AL, Klochkova SV, Chang SJS, Nikitjuk DB, Skalnaya MG, Tinkov AA
Biol Trace Elem Res 2020 Aug;196(2):607-617. Epub 2019 Nov 11 doi: 10.1007/s12011-019-01938-6. PMID: 31713112
Leung CN, Canter BS, Rajon D, Bäck TA, Fritton JC, Azzam EI, Howell RW
J Nucl Med 2020 Jan;61(1):89-95. Epub 2019 Sep 13 doi: 10.2967/jnumed.119.227835. PMID: 31519805Free PMC Article
Feichtinger M, Falcone V, Schoenleitner T, Stopp T, Husslein PW, Eppel W, Chalubinski KM, Göbl CS
Ultraschall Med 2020 Feb;41(1):52-59. Epub 2018 Oct 25 doi: 10.1055/a-0651-0424. PMID: 30360008
Berkun L, Slae M, Mor-Shaked H, Koplewitz B, Eventov-Friedman S, Harel T
Am J Med Genet A 2019 Dec;179(12):2454-2458. Epub 2019 Sep 9 doi: 10.1002/ajmg.a.61355. PMID: 31502381

Recent systematic reviews

Waissi W, Paix A, Nicol A, Noël G, Burckel H
Crit Rev Oncol Hematol 2020 Sep;153:103060. Epub 2020 Jul 11 doi: 10.1016/j.critrevonc.2020.103060. PMID: 32707435
de Sousa Lima Strafacci A, Fernandes Camargo J, Bertapelli F, Guerra Júnior G
J Appl Genet 2020 May;61(2):205-212. Epub 2020 Mar 10 doi: 10.1007/s13353-020-00551-x. PMID: 32157657
Neale J, Pais SMA, Nicholls D, Chapman S, Hudson LD
J Adolesc Health 2020 Feb;66(2):144-156. Epub 2019 Nov 23 doi: 10.1016/j.jadohealth.2019.08.032. PMID: 31771922
Thaker V, Carter B, Putman M
Cochrane Database Syst Rev 2018 Dec 17;12:CD008901. doi: 10.1002/14651858.CD008901.pub4. PMID: 30557452Free PMC Article
Sagi-Dain L, Peleg A, Sagi S
Obstet Gynecol Surv 2017 Oct;72(10):603-609. doi: 10.1097/OGX.0000000000000490. PMID: 29059452

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