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Abnormal facial shape

MedGen UID:
505048
Concept ID:
CN001810
Finding
Synonyms: Craniofacial abnormalities; Craniofacial dysmorphism; craniofacial dysmorphism; Distinctive facies; Dysmorphic facial features; dysmorphic facial features; Dysmorphic facies; Facial dysmorphism; Unusual facial appearance; Unusual facies
 
HPO: HP:0001999

Definition

An abnormal morphology (form) of the face or its components. [from HPO]

Conditions with this feature

Crouzon syndrome
MedGen UID:
1162
Concept ID:
C0010273
Disease or Syndrome
The eight disorders comprising the FGFR-related craniosynostosis spectrum are Pfeiffer syndrome, Apert syndrome, Crouzon syndrome, Beare-Stevenson syndrome, FGFR2-related isolated coronal synostosis, Jackson-Weiss syndrome, Crouzon syndrome with acanthosis nigricans (AN), and Muenke syndrome (isolated coronal synostosis caused by the p.Pro250Arg mutation in FGFR3). Muenke syndrome and FGFR2-related isolated coronal synostosis are characterized only by uni- or bicoronal craniosynostosis; the remainder are characterized by bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot findings.
Diaphyseal dysplasia
MedGen UID:
4268
Concept ID:
C0011989
Congenital Abnormality
Camurati-Engelmann disease (CED) is characterized by hyperostosis of the long bones and the skull, proximal muscle weakness, severe limb pain, a wide-based, waddling gait, and joint contractures. Facial features such as frontal bossing, enlargement of the mandible, proptosis, and cranial nerve impingement resulting in facial palsy are seen in severely affected individuals later in life.
Endocardial fibroelastosis
MedGen UID:
4041
Concept ID:
C0014117
Disease or Syndrome
A condition characterized by the thickening of ENDOCARDIUM due to proliferation of fibrous and elastic tissue, usually in the left ventricle leading to impaired cardiac function (CARDIOMYOPATHY, RESTRICTIVE). It is most commonly seen in young children and rarely in adults. It is often associated with congenital heart anomalies (HEART DEFECTS CONGENITAL;) INFECTION; or gene mutation. Defects in the tafazzin protein, encoded by TAZ gene, result in a form of autosomal dominant familial endocardial fibroelastosis.
Pyruvate dehydrogenase complex deficiency
MedGen UID:
19610
Concept ID:
C0034345
Disease or Syndrome
Genetic defects in the pyruvate dehydrogenase complex are one of the most common causes of primary lactic acidosis in children. Most cases are caused by mutation in the E1-alpha subunit gene on the X chromosome. X-linked PDH deficiency is one of the few X-linked diseases in which a high proportion of heterozygous females manifest severe symptoms. The clinical spectrum of PDH deficiency is broad, ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis (Robinson et al., 1987; Brown et al., 1994). Genetic Heterogeneity of Pyruvate Dehydrogenase Complex Deficiency PDH deficiency can also be caused by mutation in other subunits of the PDH complex, including a form (PDHXD; 245349) caused by mutation in the component X gene (PDHX; 608769) on chromosome 11p; a form (PDHBD; 614111) caused by mutation in the PDHB gene (179060) on chromosome 3p; a form (PDHDD; 245348) caused by mutation in the DLAT gene (608770) on chromosome 11q; a form (PDHPD; 608782) caused by mutation in the PDP1 gene (605993) on chromosome 8q22; and a form (PDHLD; 614462) caused by mutation in the LIAS gene (607031) on chromosome 4p14.
Femoral hypoplasia - unusual facies syndrome
MedGen UID:
120523
Concept ID:
C0265263
Disease or Syndrome
Femoral-facial syndrome (FFS), also known as femoral hypoplasia-unusual facies syndrome (FHUFS), is a rare and sporadic multiple congenital anomaly syndrome comprising bilateral femoral hypoplasia and characteristic facial features, such as long philtrum, thin upper lip, micrognathia with or without cleft palate, upward-slanting palpebral fissures, and a short nose with broad tip. Other features, such as renal anomalies, are more variable (summary by Nowaczyk et al., 2010).
Leprechaunism syndrome
MedGen UID:
82708
Concept ID:
C0265344
Disease or Syndrome
Donohue syndrome is a rare disorder characterized by severe insulin resistance, a condition in which the body's tissues and organs do not respond properly to the hormone insulin. Insulin normally helps regulate blood sugar levels by controlling how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy. Severe insulin resistance leads to problems with regulating blood sugar levels and affects the development and function of organs and tissues throughout the body. Severe insulin resistance underlies the varied signs and symptoms of Donohue syndrome. Individuals with Donohue syndrome are unusually small starting before birth, and affected infants experience failure to thrive, which means they do not grow and gain weight at the expected rate. Additional features that become apparent soon after birth include a lack of fatty tissue under the skin (subcutaneous fat); wasting (atrophy) of muscles; excessive body hair growth (hirsutism); multiple cysts on the ovaries in females; and enlargement of the nipples, genitalia, kidneys, heart, and other organs. Most affected individuals also have a skin condition called acanthosis nigricans, in which the skin in body folds and creases becomes thick, dark, and velvety. Distinctive facial features in people with Donohue syndrome include bulging eyes, thick lips, upturned nostrils, and low-set ears. Affected individuals develop recurrent, life-threatening infections beginning in infancy. Donohue syndrome is one of a group of related conditions described as inherited severe insulin resistance syndromes. These disorders, which also include Rabson-Mendenhall syndrome and type A insulin resistance syndrome, are considered part of a spectrum. Donohue syndrome represents the most severe end of the spectrum; children with this condition do not survive beyond age 2.
Dysmorphic sialidosis with renal involvement
MedGen UID:
82778
Concept ID:
C0268232
Congenital Abnormality
Deficiency of glycerol kinase
MedGen UID:
82803
Concept ID:
C0268418
Disease or Syndrome
Francke et al. (1987) noted that there are 3 clinically distinct forms of glycerol kinase deficiency: infantile, juvenile, and adult. The infantile form is associated with severe developmental delay, and those with the adult form have no symptoms and are often detected fortuitously. The infantile form of GK deficiency, or the 'GK complex,' results from the Xp21 contiguous gene deletion syndrome (300679) with congenital adrenal hypoplasia (300200) and/or Duchenne muscular dystrophy (DMD; 310200), whereas the juvenile and adult forms have isolated GK deficiency (Walker et al., 1996).
Prolidase deficiency
MedGen UID:
120647
Concept ID:
C0268532
Disease or Syndrome
Prolidase deficiency is a rare autosomal recessive multisystem disorder associated with massive imidodipeptiduria and lack of or reduced prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts. The disorder is clinically heterogeneous and severity varies widely. Features include chronic, slowly healing ulcerations, mainly on the legs and feet. The ulcers are often preceded by other dermatologic manifestations that may occur anywhere and include erythematous papular eruptions, telangiectasias with pruritus and photosensitivity, impetigo-like eruptions, pruritic eczematous lesions, and necrotic papules. Mild to severe mental retardation is often a feature, and recurrent respiratory tract infections, sometimes fatal, are common. Facial dysmorphism may include low hairline and hirsutism, saddle nose, ocular hypertelorism, micrognathia, a high-arched palate, mandibular protrusion, and exophthalmos. Clinical manifestations are usually detectable after birth or in early childhood, but late-onset cases have been reported (summary by Lupi et al., 2008).
Glutaric aciduria, type 1
MedGen UID:
124337
Concept ID:
C0268595
Disease or Syndrome
The term "organic acidemia" or "organic aciduria" (OA) applies to a group of disorders characterized by the excretion of non-amino organic acids in urine. Most organic acidemias result from dysfunction of a specific step in amino acid catabolism, usually the result of deficient enzyme activity. The majority of the classic organic acid disorders are caused by abnormal amino acid catabolism of branched-chain amino acids or lysine. They include maple syrup urine disease (MSUD), propionic acidemia, methylmalonic acidemia (MMA), methylmalonic aciduria and homocystinuria, isovaleric acidemia, biotin-unresponsive 3-methylcrotonyl-CoA carboxylase deficiency, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency, ketothiolase deficiency, and glutaricacidemia type I (GA I). A neonate affected with an OA is usually well at birth and for the first few days of life. The usual clinical presentation is that of toxic encephalopathy and includes vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma. Outcome is enhanced by diagnosis and treatment in the first ten days of life. In the older child or adolescent, variant forms of the OAs can present as loss of intellectual function, ataxia or other focal neurologic signs, Reye syndrome, recurrent ketoacidosis, or psychiatric symptoms.
Glutaric aciduria, type 2
MedGen UID:
75696
Concept ID:
C0268596
Disease or Syndrome
Glutaric aciduria II (GA II) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I (231670) in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. GA II results from deficiency of any 1 of 3 molecules: the alpha (ETFA) and beta (ETFB) subunits of electron transfer flavoprotein, and electron transfer flavoprotein dehydrogenase (ETFDH). The clinical picture of GA II due to the different defects appears to be indistinguishable; each defect can lead to a range of mild or severe cases, depending presumably on the location and nature of the intragenic lesion, i.e., mutation, in each case (Goodman, 1993; Olsen et al., 2003). The heterogeneous clinical features of patients with MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in patients with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress (summary by Frerman and Goodman, 2001). Importantly, riboflavin treatment has been shown to ameliorate the symptoms and metabolic profiles in many MADD patients, particularly those with type III, the late-onset and mildest form (Liang et al., 2009).
Laron-type isolated somatotropin defect
MedGen UID:
78776
Concept ID:
C0271568
Disease or Syndrome
Laron syndrome is an autosomal recessive disorder characterized by marked short stature that results from failure to generate insulin-like growth factor I (IGF1; 147440) in response to growth hormone (GH; 139250). GH levels are normal or increased. The disorder is caused by dysfunction of the growth hormone receptor. A Laron syndrome-like phenotype associated with immunodeficiency (245590) is caused by postreceptor defect, i.e. mutation in the STAT5B gene (604260). Patients with mutations in the GHR gene that cause only partial insensitivity to growth hormone have a form of short stature (604271).
Neonatal adrenoleucodystrophy
MedGen UID:
129184
Concept ID:
C0282525
Disease or Syndrome
Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD, ZSS) is a continuum of three phenotypes — Zellweger syndrome (ZS), the most severe; neonatal adrenoleukodystrophy (NALD); and infantile Refsum disease (IRD), the least severe — that were originally described before the biochemical and molecular bases of these disorders had been fully determined. Individuals with PBD, ZSS usually come to clinical attention in the newborn period or later in childhood. In the newborn period, affected children are hypotonic, feed poorly, and have distinctive facies, seizures, and liver cysts with hepatic dysfunction. Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones may occur. Infants with ZS are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Older children have retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction. The clinical courses of NALD and IRD are variable and may include developmental delays, hearing loss, vision impairment, liver dysfunction, episodes of hemorrhage, and intracranial bleeding. While some children can be very hypotonic, others learn to walk and talk. The condition is often slowly progressive.
Infantile Refsum's disease
MedGen UID:
79470
Concept ID:
C0282527
Disease or Syndrome
Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD, ZSS) is a continuum of three phenotypes — Zellweger syndrome (ZS), the most severe; neonatal adrenoleukodystrophy (NALD); and infantile Refsum disease (IRD), the least severe — that were originally described before the biochemical and molecular bases of these disorders had been fully determined. Individuals with PBD, ZSS usually come to clinical attention in the newborn period or later in childhood. In the newborn period, affected children are hypotonic, feed poorly, and have distinctive facies, seizures, and liver cysts with hepatic dysfunction. Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones may occur. Infants with ZS are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Older children have retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction. The clinical courses of NALD and IRD are variable and may include developmental delays, hearing loss, vision impairment, liver dysfunction, episodes of hemorrhage, and intracranial bleeding. While some children can be very hypotonic, others learn to walk and talk. The condition is often slowly progressive.
3-Hydroxyisobutyric aciduria
MedGen UID:
90996
Concept ID:
C0342737
Disease or Syndrome
Beta-hydroxyisobutyryl-CoA deacylase deficiency
MedGen UID:
83349
Concept ID:
C0342738
Disease or Syndrome
3-Hydroxyisobutyrl-CoA hydrolase deficiency is an autosomal recessive inborn error of metabolism characterized by severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia (summary by Ferdinandusse et al., 2013).
Dihydropyrimidinase deficiency
MedGen UID:
83353
Concept ID:
C0342803
Disease or Syndrome
DPYS deficiency is an autosomal recessive inborn error of pyrimidine metabolism. Less than a dozen affected individuals have been reported. About half are asymptomatic, but rare patients with neurologic abnormalities have been reported. It is unclear whether or not these abnormalities are related to the enzymatic defect. Affected individuals theoretically could have severe toxicity after the administration of the antineoplastic drug 5-fluorouracil (5FU), although no cases have been reported (Hamajima et al., 1998; van Kuilenburg et al., 2007). See also dihydropyrimidine dehydrogenase deficiency (274270), a similar disorder.
Beta-D-mannosidosis
MedGen UID:
87462
Concept ID:
C0342849
Disease or Syndrome
Beta-mannosidosis is an autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of lysosomal beta-mannosidase activity. The most severely affected patients show developmental delay and mental retardation, but there are differing levels of severity and some patients may have comparatively mild disease (Bedilu et al., 2002) The disorder was first described in goats (Jones and Dawson, 1981), who have a more severe neurodegenerative disorder than that seen in humans.
Bifunctional peroxisomal enzyme deficiency
MedGen UID:
137982
Concept ID:
C0342870
Pathologic Function
D-bifunctional protein deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also peroxisomal acyl-CoA oxidase deficiency (264470), caused by mutation in the ACOX1 gene (609751) on chromosome 17q25. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including X-linked adrenoleukodystrophy (ALD; 300100), Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (NALD; see 601539) (Watkins et al., 1995). DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. McMillan et al. (2012) proposed a type IV deficiency on the basis of less severe features; these patients have a phenotype reminiscent of Perrault syndrome (PRLTS1; 233400). Pierce et al. (2010) noted that Perrault syndrome and DBP deficiency overlap clinically and suggested that DBP deficiency may be underdiagnosed.
Ochoa syndrome
MedGen UID:
98015
Concept ID:
C0403555
Disease or Syndrome
Urofacial syndrome (UFS) is characterized by prenatal or infantile onset of urinary bladder voiding dysfunction, abnormal facial movement with expression (resulting from abnormal co-contraction of the corners of the mouth and eyes), and often bowel dysfunction (constipation and/or encopresis). Bladder voiding dysfunction increases the risk for urinary incontinence, megacystis, vesicoureteric reflux, hydroureteronephrosis, urosepsis, and progressive renal impairment.
Familial focal facial dermal dysplasia
MedGen UID:
98155
Concept ID:
C0432353
Disease or Syndrome
Pseudoaminopterin syndrome
MedGen UID:
163196
Concept ID:
C0795939
Disease or Syndrome
The pseudoaminopterin syndrome (aminopterin syndrome sine aminopterin; ASSA) is a multiple congenital anomaly disorder characterized by ossification defects of the skull, dysmorphic facial features, delayed development, and variable limb defects. The clinical features resemble the embryopathy caused by maternal treatment with the folic acid antagonist aminopterin, which has been recognized since 1952 (Thiersch, 1952) when aminopterin was used as an abortifacient. The characteristic phenotype of the children who survived infancy after having been exposed to aminopterin or its methyl derivative, methotrexate, in early pregnancy included a very unusual facies, skull anomalies, and skeletal defects (summary by Fraser et al., 1987).
Harrod Doman Keele syndrome
MedGen UID:
162895
Concept ID:
C0795970
Disease or Syndrome
A rare syndrome of microcephaly with a long thin face and pointed chin, small mouth, malformed ears, hypotelorism, arachnodactyly, hypogenitalism and mental retardation.
Hypospadias mental retardation Goldblatt type
MedGen UID:
162896
Concept ID:
C0795989
Disease or Syndrome
Hypospadias, retarded mental development, microcephaly, craniofacial dysmorphism, joint laxity, and beaked nails.
McDonough syndrome
MedGen UID:
162902
Concept ID:
C0796038
Disease or Syndrome
A syndrome of psychomotor retardation, characteristic facies, kyphoscoliosis, diastasis recti, cryptorchidism, and congenital heart defect. Named after Dr. Kenneth B. McDonough, who referred to the authors the original family affected with this syndrome
Renal hamartomas nephroblastomatosis and fetal gigantism
MedGen UID:
162909
Concept ID:
C0796113
Disease or Syndrome
Perlman syndrome is an autosomal recessive congenital overgrowth syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650). Affected children are large at birth, are hypotonic, and show organomegaly, characteristic facial dysmorphisms (inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad and flat nasal bridge, and low-set ears), renal anomalies (nephromegaly and hydronephrosis), frequent neurodevelopmental delay, and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumor, with a 64% incidence in infants surviving beyond the neonatal period. The tumor is diagnosed at an earlier age in these individuals compared with sporadic cases (less than 2 years and 3-4 years of age, respectively), and there is a high frequency of bilateral tumors (55%). Histologic examination of the kidneys in children with Perlman syndrome shows frequent nephroblastomatosis, which is a precursor lesion for Wilms tumor (summary by Astuti et al., 2012).
Mental retardation, X-linked 14
MedGen UID:
163231
Concept ID:
C0796220
Disease or Syndrome
Nonsyndromic mental retardation with inconsistent abnormalities.
Ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism
MedGen UID:
330396
Concept ID:
C1832167
Disease or Syndrome
Traboulsi syndrome is characterized by dislocated crystalline lenses and anterior segment abnormalities in association with a distinctive facies involving flat cheeks and a beaked nose. Some affected individuals develop highly unusual nontraumatic conjunctival cysts (filtering blebs), presumably caused by abnormal thinning of the sclera (Patel et al., 2014).
46,XY agonadism with mental retardation, short stature, retarded bone age, and multiple extragenital malformations
MedGen UID:
318801
Concept ID:
C1833162
Disease or Syndrome
Ectodermal dysplasia mental retardation syndactyly
MedGen UID:
322135
Concept ID:
C1833169
Disease or Syndrome
Intrauterine growth retardation with increased mitomycin C sensitivity
MedGen UID:
322242
Concept ID:
C1833615
Disease or Syndrome
Oculoectodermal syndrome
MedGen UID:
333068
Concept ID:
C1838329
Disease or Syndrome
Pyruvate dehydrogenase E1-alpha deficiency
MedGen UID:
326487
Concept ID:
C1839414
Disease or Syndrome
Multiple pterygium syndrome X-linked
MedGen UID:
374225
Concept ID:
C1839440
Disease or Syndrome
Corpus callosum, partial agenesis of, X-linked
MedGen UID:
374339
Concept ID:
C1839909
Disease or Syndrome
L1 syndrome is an inherited disorder that primarily affects the nervous system. L1 syndrome involves a variety of features that were once thought to be distinct disorders, but are now considered to be part of the same syndrome. The most common characteristics of L1 syndrome are muscle stiffness (spasticity) of the lower limbs, intellectual disability, increased fluid in the center of the brain (hydrocephalus), and thumbs bent toward the palm (adducted thumbs). People with L1 syndrome can also have difficulty speaking (aphasia), seizures, and underdeveloped or absent tissue connecting the left and right halves of the brain (agenesis of the corpus callosum). The symptoms of L1 syndrome vary widely among affected individuals, even among members of the same family. Because this disorder involves spasticity of the lower limbs, L1 syndrome is sometimes referred to as spastic paraplegia type 1 (SPG1).
Iridogoniodysgenesis, dominant type
MedGen UID:
330750
Concept ID:
C1842031
Disease or Syndrome
Craniosynostosis, calcification of basal ganglia, and facial dysmorphism
MedGen UID:
333981
Concept ID:
C1842058
Disease or Syndrome
Craniofacial abnormalities, cataracts, congenital heart disease, sacral neural tube defects, and growth and developmental retardation
MedGen UID:
330832
Concept ID:
C1842363
Disease or Syndrome
Mental retardation 91, X-linked
MedGen UID:
375592
Concept ID:
C1845142
Disease or Syndrome
Chromosome Xq28 deletion syndrome
MedGen UID:
336933
Concept ID:
C1845408
Disease or Syndrome
Deafness, dystonia, and cerebral hypomyelination is an X-linked recessive mental retardation syndrome characterized by almost no psychomotor development, dysmorphic facial features, sensorineural deafness, dystonia, pyramidal signs, and hypomyelination on brain imaging (summary by Cacciagli et al., 2013).
Cubitus valgus with mental retardation and unusual facies
MedGen UID:
336943
Concept ID:
C1845450
Disease or Syndrome
Macrocephaly with multiple epiphyseal dysplasia and distinctive facies
MedGen UID:
335505
Concept ID:
C1846722
Disease or Syndrome
Insulin-like growth factor 1 resistance to
MedGen UID:
338622
Concept ID:
C1849157
Disease or Syndrome
Rodrigues blindness
MedGen UID:
340297
Concept ID:
C1849332
Disease or Syndrome
Polysyndactyly with cardiac malformation
MedGen UID:
337895
Concept ID:
C1849719
Disease or Syndrome
Cousin syndrome
MedGen UID:
342400
Concept ID:
C1850040
Disease or Syndrome
Holoprosencephaly, recurrent infections, and monocytosis
MedGen UID:
343987
Concept ID:
C1853187
Disease or Syndrome
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having “microform” HPE.
Mental retardation, microcephaly, growth retardation, joint contractures, and facial dysmorphism
MedGen UID:
342889
Concept ID:
C1853480
Disease or Syndrome
Lethal multiple pterygium syndrome
MedGen UID:
381473
Concept ID:
C1854678
Disease or Syndrome
Multiple pterygium syndrome is a condition that is evident before birth with webbing of the skin (pterygium) at the joints and a lack of muscle movement (akinesia) before birth. Akinesia frequently results in muscle weakness and joint deformities called contractures that restrict the movement of joints (arthrogryposis). As a result, multiple pterygium syndrome can lead to further problems with movement such as arms and legs that cannot fully extend. The two forms of multiple pterygium syndrome are differentiated by the severity of their symptoms. Multiple pterygium syndrome, Escobar type (sometimes referred to as Escobar syndrome) is the milder of the two types. Lethal multiple pterygium syndrome is fatal before birth or very soon after birth. In people with multiple pterygium syndrome, Escobar type, the webbing typically affects the skin of the neck, fingers, forearms, inner thighs, and backs of the knee. People with this type may also have arthrogryposis. A side-to-side curvature of the spine (scoliosis) is sometimes seen. Affected individuals may also have respiratory distress at birth due to underdeveloped lungs (lung hypoplasia). People with multiple pterygium syndrome, Escobar type usually have distinctive facial features including droopy eyelids (ptosis), outside corners of the eyes that point downward (downslanting palpebral fissures), skin folds covering the inner corner of the eyes (epicanthal folds), a small jaw, and low-set ears. Males with this condition can have undescended testes (cryptorchidism). This condition does not worsen after birth, and affected individuals typically do not have muscle weakness later in life. Lethal multiple pterygium syndrome has many of the same signs and symptoms as the Escobar type. In addition, affected fetuses may develop a buildup of excess fluid in the body (hydrops fetalis) or a fluid-filled sac typically found on the back of the neck (cystic hygroma). Individuals with this type have severe arthrogryposis. Lethal multiple pterygium syndrome is associated with abnormalities such as underdevelopment (hypoplasia) of the heart, lung, or brain; twisting of the intestines (intestinal malrotation); kidney abnormalities; an opening in the roof of the mouth (a cleft palate); and an unusually small head size (microcephaly). Affected individuals may also develop a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), a condition called a congenital diaphragmatic hernia. Lethal multiple pterygium syndrome is typically fatal in the second or third trimester of pregnancy.
Megaepiphyseal dwarfism
MedGen UID:
383654
Concept ID:
C1855310
Congenital Abnormality
Lichtenstein syndrome
MedGen UID:
340889
Concept ID:
C1855502
Disease or Syndrome
Al Gazali Hirschsprung syndrome
MedGen UID:
344653
Concept ID:
C1856110
Disease or Syndrome
Gonadal dysgenesis, xy type, with associated anomalies
MedGen UID:
344696
Concept ID:
C1856272
Disease or Syndrome
Gingival fibromatosis with distinctive facies
MedGen UID:
346437
Concept ID:
C1856761
Disease or Syndrome
Facial dysmorphism with multiple malformations
MedGen UID:
346465
Concept ID:
C1856892
Disease or Syndrome
Epilepsy telangiectasia
MedGen UID:
384017
Concept ID:
C1856929
Disease or Syndrome
Dextrocardia with unusual facies and microphthalmia
MedGen UID:
346559
Concept ID:
C1857298
Disease or Syndrome
Congenital Cataracts, Facial Dysmorphism, and Neuropathy
MedGen UID:
346973
Concept ID:
C1858726
Congenital Abnormality
Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils); mildly dysmorphic facial features apparent in late childhood; and a hypo/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade. Secondary scoliosis and foot deformities are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild non-progressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Roma/Gypsy population.
Charcot-Marie-Tooth disease, Guadalajara neuronal type
MedGen UID:
350075
Concept ID:
C1861673
Disease or Syndrome
BOD syndrome
MedGen UID:
350585
Concept ID:
C1862082
Disease or Syndrome
Aortic arch anomaly with peculiar facies and mental retardation
MedGen UID:
350734
Concept ID:
C1862682
Disease or Syndrome
Chromosome 16p13.3 deletion syndrome
MedGen UID:
350477
Concept ID:
C1864648
Disease or Syndrome
Holoprosencephaly 5
MedGen UID:
355304
Concept ID:
C1864827
Disease or Syndrome
Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having “microform” HPE.
Combined oxidative phosphorylation deficiency 2
MedGen UID:
400626
Concept ID:
C1864843
Disease or Syndrome
Arthrogryposis and ectodermal dysplasia
MedGen UID:
355714
Concept ID:
C1866427
Disease or Syndrome
Shprintzen omphalocele syndrome
MedGen UID:
356653
Concept ID:
C1866958
Disease or Syndrome
Scholte syndrome
MedGen UID:
401129
Concept ID:
C1866985
Disease or Syndrome
Noonan syndrome 5
MedGen UID:
370589
Concept ID:
C1969057
Disease or Syndrome
Noonan syndrome (NS) is characterized by 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, characteristic facies, 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 third of affected individuals have mild intellectual disability.
Birk Barel mental retardation dysmorphism syndrome
MedGen UID:
393583
Concept ID:
C2676770
Disease or Syndrome
15q13.3 microdeletion syndrome
MedGen UID:
393784
Concept ID:
C2677613
Disease or Syndrome
Individuals with 15q13.3 microdeletion are at increased risk for a wide range of clinical manifestations including intellectual disability, cardiac malformations, seizures, autism, and schizophrenia; however, the deletion itself does not seem to lead to a clinically recognizable syndrome and a subset of persons with the deletion have no obvious clinical findings. Behavioral problems are common and mainly comprise poor attention span, hyperactivity, mood disorder, and aggressive and/or impulsive behavior. Intellectual disability, observed in about half of the individuals with the common deletion at 15q13.3, is usually mild but can be moderate to severe.
Riddle syndrome
MedGen UID:
394368
Concept ID:
C2677792
Disease or Syndrome
Mental retardation and microcephaly with pontine and cerebellar hypoplasia
MedGen UID:
437070
Concept ID:
C2677903
Disease or Syndrome
Mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) is an X-linked disorder affecting females and characterized by severe intellectual disability, microcephaly, and variable degrees of pontocerebellar hypoplasia. Affected individuals have very poor psychomotor development, often without independent ambulation or speech, and axial hypotonia with or without hypertonia. Some may have sensorineural hearing loss or eye anomalies. Dysmorphic features include overall poor growth, severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism (summary by Moog et al., 2011).
Roifman-Chitayat syndrome
MedGen UID:
442377
Concept ID:
C2750068
Disease or Syndrome
Chromosome 16p12.1 deletion syndrome
MedGen UID:
460626
Concept ID:
C3149276
Disease or Syndrome
16p12.2 microdeletion is characterized by variable clinical findings that do not constitute a recognizable syndrome. Of note, the significant bias in ascertainment of individuals undergoing clinical chromosomal microarray analysis (i.e., children with intellectual disability and developmental delay; individuals with schizophrenia) makes it difficult to accurately associate specific phenotypes to the 16p12.2 microdeletion. Findings commonly observed in children (probands) with this deletion include: developmental delay, cognitive impairment (ranges from mild to profound), growth impairment (including short stature), cardiac malformations, epilepsy, and psychiatric and/or behavioral problems. Other findings can include: hearing loss, dental abnormalities, renal and genital anomalies (the latter in males), and cleft palate ± cleft lip.
Chromosome 17q23.1-q23.2 deletion syndrome
MedGen UID:
461957
Concept ID:
C3150607
Disease or Syndrome
Autoimmune disease, syndromic multisystem
MedGen UID:
461999
Concept ID:
C3150649
Disease or Syndrome
Congenital disorder of glycosylation type 2J
MedGen UID:
462086
Concept ID:
C3150736
Disease or Syndrome
Congenital disorders of N-linked glycosylation (abbreviated here as CDG-N-linked), are a group of disorders of N-linked oligosaccharides caused by deficiency in 42 different enzymes in the N-linked synthetic pathway. Most commonly, the disorders begin in infancy; manifestations range from severe developmental delay and hypotonia with multiple organ system involvement to hypoglycemia and protein-losing enteropathy with normal development. However, most types have been described in only a few individuals, and thus understanding of the phenotypes is limited. In PMM2-CDG (CDG-Ia), the most common type reported, the clinical presentation and course are highly variable, ranging from death in infancy to mild involvement in adults.
Beaulieu-Boycott-Innes syndrome
MedGen UID:
462289
Concept ID:
C3150939
Disease or Syndrome
Beaulieu-Boycott-Innes syndrome (BBIS) is an autosomal recessive neurodevelopmental disorder characterized by delayed development, moderate intellectual disability, and dysmorphic facial features. Other developmental anomalies, such as cardiac and renal defects, may also occur (summary by Beaulieu et al., 2013).
Hypermethioninemia with s-adenosylhomocysteine hydrolase deficiency
MedGen UID:
462408
Concept ID:
C3151058
Disease or Syndrome
Hypermethioninemia is an excess of a particular protein building block (amino acid), called methionine, in the blood. This condition can occur when methionine is not broken down (metabolized) properly in the body. People with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit intellectual disability and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage. Hypermethioninemia can occur with other metabolic disorders, such as homocystinuria, tyrosinemia and galactosemia, which also involve the faulty breakdown of particular molecules. It can also result from liver disease or excessive dietary intake of methionine from consuming large amounts of protein or a methionine-enriched infant formula.
Moyamoya disease 4 with short stature, hypergonadotropic hypogonadism, and facial dysmorphism
MedGen UID:
463207
Concept ID:
C3151857
Disease or Syndrome
This multisystem disorder is characterized by moyamoya disease, short stature, hypergonadotropic hypogonadism, and facial dysmorphism. Other variable features include dilated cardiomyopathy, premature graying of the hair, and early-onset cataracts. Moyamoya disease is a progressive cerebrovascular disorder characterized by stenosis or occlusion of the internal carotid arteries and the main branches, leading to the development of small collateral vessels (moyamoya vessels) at the base of the brain. Affected individuals can develop acute neurologic events due to stroke-like episodes (summary by Miskinyte et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350).
Macrocephaly, macrosomia, facial dysmorphism syndrome
MedGen UID:
481725
Concept ID:
C3280095
Disease or Syndrome
Psychomotor retardation, epilepsy, and craniofacial dysmorphism
MedGen UID:
482685
Concept ID:
C3281055
Disease or Syndrome
Congenital disorder of glycosylation type 1s
MedGen UID:
763818
Concept ID:
C3550904
Disease or Syndrome
Aplasia cutis congenita, reticulolinear, with microcephaly, facial dysmorphism, and other congenital anomalies
MedGen UID:
763835
Concept ID:
C3550921
Disease or Syndrome
Hypertelorism and other facial dysmorphism, brachydactyly, genital abnormalities, mental retardation, and recurrent inflammatory episodes
MedGen UID:
766379
Concept ID:
C3553465
Disease or Syndrome
Joubert syndrome 22
MedGen UID:
816608
Concept ID:
C3810278
Disease or Syndrome
Anhidrosis
MedGen UID:
1550
Concept ID:
C0003028
Disease or Syndrome
Metaphyseal dysplasia without hypotrichosis
MedGen UID:
320444
Concept ID:
C1834821
Disease or Syndrome
The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes: Metaphyseal dysplasia without hypotrichosis (MDWH), Cartilage-hair hypoplasia (CHH), and Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature which is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility and often fine silky hair, immunodeficiency, anemia, impaired spermatogenesis, gastrointestinal dysfunction, and increased risk for malignancy. The most severe phenotype (AD), which has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
Spondylometaphyseal dysplasia with cone-rod dystrophy
MedGen UID:
324684
Concept ID:
C1837073
Disease or Syndrome
Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction (summary by Hoover-Fong et al., 2014). Yamamoto et al. (2014) reviewed 16 reported cases of SMDCRD, noting that all affected individuals presented uniform skeletal findings, with rhizomelia and bowed lower limbs observed in the first year of life, whereas retinal dystrophy had a more variable age of onset. There was severe disproportionate short stature, with a final height of less than 100 cm; scoliosis was usually mild. Visual loss was progressive, with stabilization in adolescence.
Waardenburg syndrome type 2B
MedGen UID:
373973
Concept ID:
C1838447
Disease or Syndrome
Waardenburg syndrome type II (WS2) is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and the absence of 'dystopia canthorum,' the lateral displacement of the inner canthus of each eye, which is seen in some other forms of WS (Hughes et al., 1994). WS type 2B (WS2B) maps to chromosome 1p. Waardenburg syndrome type 2 is genetically heterogeneous (see WS2A; 193510). For a description of other clinical variants of Waardenburg syndrome, see WS1 (193500), WS3 (148820), and WS4 (277580).

Recent clinical studies

Etiology

Hopper RA, Kapadia H, Morton T
Plast Reconstr Surg 2013 Jul;132(1):129-40. doi: 10.1097/PRS.0b013e318290fa8a. PMID: 23508053
Popat H, Zhurov AI, Richmond S, Marshall D, Rosin PL
J Oral Rehabil 2013 May;40(5):348-57. Epub 2013 Feb 8 doi: 10.1111/joor.12037. [Epub ahead of print] PMID: 23397893
Song JJ, Park JH, Jang JH, Lee JH, Oh SH, Chang SO, Kim CS
Acta Otolaryngol 2012 Jul;132(7):788-94. Epub 2012 Jun 5 doi: 10.3109/00016489.2012.656765. [Epub ahead of print] PMID: 22668344
Hammond P, Suttie M
Hum Mutat 2012 May;33(5):817-25. Epub 2012 Mar 20 doi: 10.1002/humu.22054. [Epub ahead of print] PMID: 22434506Free PMC Article
Palermo R, Rivolta D, Wilson CE, Jeffery L
Neuropsychologia 2011 Dec;49(14):3801-12. Epub 2011 Oct 1 doi: 10.1016/j.neuropsychologia.2011.09.039. [Epub ahead of print] PMID: 21986295

Diagnosis

Kubova Z, Kuba M, Kremlacek J, Langrova J, Szanyi J, Vit F, Chutna M
Doc Ophthalmol 2014 Apr;128(2):121-9. Epub 2014 Feb 23 doi: 10.1007/s10633-014-9429-y. [Epub ahead of print] PMID: 24563372
Jankowski R, Kuntzler S, Boulanger N, Morel O, Tisserant J, Benterkia N, Vignaud JM
Surg Radiol Anat 2014 Jul;36(5):429-37. Epub 2013 Oct 27 doi: 10.1007/s00276-013-1222-1. [Epub ahead of print] PMID: 24162268
Turner AM
J Paediatr Child Health 2014 Oct;50(10):E14-20. Epub 2011 Jul 19 doi: 10.1111/j.1440-1754.2010.01970.x. [Epub ahead of print] PMID: 21771153
Popat H, Zhurov AI, Richmond S, Marshall D, Rosin PL
J Oral Rehabil 2013 May;40(5):348-57. Epub 2013 Feb 8 doi: 10.1111/joor.12037. [Epub ahead of print] PMID: 23397893
Hammond P, Suttie M
Hum Mutat 2012 May;33(5):817-25. Epub 2012 Mar 20 doi: 10.1002/humu.22054. [Epub ahead of print] PMID: 22434506Free PMC Article

Therapy

Ferrario VF, Sforza C, Dellavia C, Galassi A, Brancaccio D
Angle Orthod 2005 May;75(3):320-5. doi: 10.1043/0003-3219(2005)75[320:AVITFS]2.0.CO;2. PMID: 15898367
Nargozian C, Ririe DG, Bennun RD, Mulliken JB
Paediatr Anaesth 1999;9(5):393-8. PMID: 10447900
Sarhan OA, al-Balkhi KM
J Oral Rehabil 1993 Mar;20(2):233-9. PMID: 8468633
Regan D, Kothe AC, Sharpe JA
Brain 1991 Jun;114 ( Pt 3):1129-55. PMID: 2065244

Prognosis

Ohno-Matsui K
Ophthalmology 2014 Sep;121(9):1798-809. Epub 2014 May 9 doi: 10.1016/j.ophtha.2014.03.035. [Epub ahead of print] PMID: 24813630
Caruso N, Herberth B, Bartoli M, Puppo F, Dumonceaux J, Zimmermann A, Denadai S, Lebossé M, Roche S, Geng L, Magdinier F, Attarian S, Bernard R, Maina F, Levy N, Helmbacher F
PLoS Genet 2013 Jun;9(6):e1003550. Epub 2013 Jun 13 doi: 10.1371/journal.pgen.1003550. PMID: 23785297Free PMC Article
Hopper RA, Kapadia H, Morton T
Plast Reconstr Surg 2013 Jul;132(1):129-40. doi: 10.1097/PRS.0b013e318290fa8a. PMID: 23508053
Popat H, Zhurov AI, Richmond S, Marshall D, Rosin PL
J Oral Rehabil 2013 May;40(5):348-57. Epub 2013 Feb 8 doi: 10.1111/joor.12037. [Epub ahead of print] PMID: 23397893
Song JJ, Park JH, Jang JH, Lee JH, Oh SH, Chang SO, Kim CS
Acta Otolaryngol 2012 Jul;132(7):788-94. Epub 2012 Jun 5 doi: 10.3109/00016489.2012.656765. [Epub ahead of print] PMID: 22668344

Clinical prediction guides

Ohno-Matsui K
Ophthalmology 2014 Sep;121(9):1798-809. Epub 2014 May 9 doi: 10.1016/j.ophtha.2014.03.035. [Epub ahead of print] PMID: 24813630
Li XH, Jing J, Yang DS, Wang H, Wang QX, Song SS, Fan F
Chin Med J (Engl) 2013 Nov;126(22):4306-11. PMID: 24238519
Caruso N, Herberth B, Bartoli M, Puppo F, Dumonceaux J, Zimmermann A, Denadai S, Lebossé M, Roche S, Geng L, Magdinier F, Attarian S, Bernard R, Maina F, Levy N, Helmbacher F
PLoS Genet 2013 Jun;9(6):e1003550. Epub 2013 Jun 13 doi: 10.1371/journal.pgen.1003550. PMID: 23785297Free PMC Article
Rochelson B, Vohra N, Krantz D, Macri VJ
Ultrasound Obstet Gynecol 2006 Feb;27(2):167-72. doi: 10.1002/uog.2629. PMID: 16404711
Ferrario VF, Sforza C, Dellavia C, Galassi A, Brancaccio D
Angle Orthod 2005 May;75(3):320-5. doi: 10.1043/0003-3219(2005)75[320:AVITFS]2.0.CO;2. PMID: 15898367

Recent systematic reviews

Tonni G, Panteghini M, Rossi A, Baldi M, Magnani C, Ferrari B, Lituania M
Arch Gynecol Obstet 2011 Apr;283(4):909-16. Epub 2010 Sep 2 doi: 10.1007/s00404-010-1643-6. [Epub ahead of print] PMID: 20811900

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