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Exotropia

MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
Synonyms: Divergent Strabismus; Strabismus, Divergent
SNOMED CT: Exotropia (399054005); Divergent concomitant strabismus (399252000); Divergent strabismus (399054005); External strabismus (399054005); Divergent squint (399054005); XT - Exotropia (399054005)
 
HPO: HP:0000577
Monarch Initiative: MONDO:0001286

Definition

A form of strabismus with one or both eyes deviated outward. [from HPO]

Conditions with this feature

DiGeorge syndrome
MedGen UID:
4297
Concept ID:
C0012236
Disease or Syndrome
Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.
Langer-Giedion syndrome
MedGen UID:
6009
Concept ID:
C0023003
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.
Marfan syndrome
MedGen UID:
44287
Concept ID:
C0024796
Disease or Syndrome
FBN1-related Marfan syndrome (Marfan syndrome), a systemic disorder of connective tissue with a high degree of clinical variability, comprises a broad phenotypic continuum ranging from mild (features of Marfan syndrome in one or a few systems) to severe and rapidly progressive neonatal multiorgan disease. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. Ocular findings include myopia (>50% of affected individuals); ectopia lentis (seen in approximately 60% of affected individuals); and an increased risk for retinal detachment, glaucoma, and early cataracts. Skeletal system manifestations include bone overgrowth and joint laxity; disproportionately long extremities for the size of the trunk (dolichostenomelia); overgrowth of the ribs that can push the sternum in (pectus excavatum) or out (pectus carinatum); and scoliosis that ranges from mild to severe and progressive. The major morbidity and early mortality in Marfan syndrome relate to the cardiovascular system and include dilatation of the aorta at the level of the sinuses of Valsalva (predisposing to aortic tear and rupture), mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. Severe and prolonged regurgitation of the mitral and/or aortic valve can predispose to left ventricular dysfunction and occasionally heart failure. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population.
Angelman syndrome
MedGen UID:
58144
Concept ID:
C0162635
Disease or Syndrome
Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and unique behavior with an apparent happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year.
Craniofrontonasal syndrome
MedGen UID:
65095
Concept ID:
C0220767
Disease or Syndrome
Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism (Twigg et al., 2004; Wieland et al., 2004).
Oromandibular-limb hypogenesis spectrum
MedGen UID:
66357
Concept ID:
C0221060
Disease or Syndrome
The most basic description of Moebius syndrome is a congenital facial palsy with impairment of ocular abduction. The facial nerve (cranial nerve VII) and abducens nerve (CN VI) are most frequently involved, but other cranial nerves may be involved as well. Other variable features include orofacial dysmorphism and limb malformations. Mental retardation has been reported in a subset of patients. Most cases of Moebius syndrome are sporadic, but familial occurrence has been reported (Verzijl et al., 2003). The definition of and diagnostic criteria for Moebius syndrome have been controversial and problematic. The syndrome has most frequently been confused with hereditary congenital facial paresis (HCFP; see 601471), which is restricted to involvement of the facial nerve and no other abnormalities. Verzijl et al. (2003) and Verzijl et al. (2005) concluded that HCFP and Moebius syndrome are distinct disorders, and that Moebius syndrome is a complex developmental disorder of the brainstem. Moebius syndrome was defined at the Moebius Syndrome Foundation Research Conference in 2007 as congenital, nonprogressive facial weakness with limited abduction of one or both eyes. Additional features can include hearing loss and other cranial nerve dysfunction, as well as motor, orofacial, musculoskeletal, neurodevelopmental, and social problems (summary by Webb et al., 2012). Kumar (1990) provided a review of Moebius syndrome, which was critiqued by Lipson et al. (1990). Briegel (2006) provided a review of Moebius sequence with special emphasis on neuropsychiatric findings.
Tyrosinase-positive oculocutaneous albinism
MedGen UID:
82810
Concept ID:
C0268495
Disease or Syndrome
Tyrosinase-positive oculocutaneous albinism (OCA, type II; OCA2) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. Although affected infants may appear at birth to have OCA type I, or complete absence of melanin pigment, most patients with OCA type II acquire small amounts of pigment with age. Individuals with OCA type II have the characteristic visual anomalies associated with albinism, including decreased acuity and nystagmus, which are usually less severe than in OCA type I (Lee et al., 1994; King et al., 2001). OCA type II has a highly variable phenotype. The hair of affected individuals may turn darker with age, and pigmented nevi or freckles may be seen. African and African American individuals may have yellow hair and blue-gray or hazel irides. One phenotypic variant, 'brown OCA,' has been described in African and African American populations and is characterized by light brown hair and skin color and gray to tan irides. The hair and irides may turn darker with time and the skin may tan with sun exposure; the ocular features of albinism are present in all variants (King et al., 2001). In addition, previous reports of so-called 'autosomal recessive ocular albinism,' (see, e.g., Witkop et al., 1978 and O'Donnell et al., 1978) with little or no obvious skin involvement, are now considered most likely to be part of the phenotypic spectrum of OCA1 or OCA2 (Lee et al., 1994; King et al., 2001).
Aniridia 1
MedGen UID:
576337
Concept ID:
C0344542
Congenital Abnormality
PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems.
Wieacker-Wolff syndrome
MedGen UID:
163227
Concept ID:
C0796200
Disease or Syndrome
Wieacker-Wolff syndrome (WRWF) is a severe X-linked recessive neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero (fetal akinesia), which results in arthrogryposis multiplex congenita (AMC) apparent at birth. Affected boys are born with severe contractures, show delayed motor development, facial and bulbar weakness, characteristic dysmorphic facial features, and skeletal abnormalities, such as hip dislocation, scoliosis, and foot deformities. Additional features include global developmental delay with poor or absent speech and impaired intellectual development, feeding difficulties and poor growth, hypotonia, hypogenitalism, and spasticity. Carrier females may be unaffected or have mild features of the disorder (summary by Hirata et al., 2013 and Frints et al., 2019).
X-linked intellectual disability-short stature-overweight syndrome
MedGen UID:
901885
Concept ID:
C0796218
Disease or Syndrome
X-linked intellectual developmental disorder-12 (XLID12) is characterized by borderline to severe intellectual disability with variable neurologic features, short stature, and elevated body mass index (BMI) (Kumar et al., 2015).
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.
Ophthalmoplegia, familial total, with iris transillumination
MedGen UID:
371665
Concept ID:
C1833836
Disease or Syndrome
Retinitis pigmentosa 12
MedGen UID:
374019
Concept ID:
C1838647
Disease or Syndrome
Any retinitis pigmentosa in which the cause of the disease is a mutation in the CRB1 gene.
Creatine transporter deficiency
MedGen UID:
337451
Concept ID:
C1845862
Disease or Syndrome
The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs. Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder. AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders. Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported.
Oculofaciocardiodental syndrome
MedGen UID:
337547
Concept ID:
C1846265
Disease or Syndrome
Oculofaciocardiodental (OFCD) syndrome is a condition that affects the development of the eyes (oculo-), facial features (facio-), heart (cardio-) and teeth (dental). This condition occurs only in females.\n\nThe eye abnormalities associated with OFCD syndrome can affect one or both eyes. Many people with this condition are born with eyeballs that are abnormally small (microphthalmia). Other eye problems can include clouding of the lens (cataract) and a higher risk of glaucoma, an eye disease that increases the pressure in the eye. These abnormalities can lead to vision loss or blindness.\n\nPeople with OFCD syndrome often have a long, narrow face with distinctive facial features, including deep-set eyes and a broad nasal tip that is divided by a cleft. Some affected people have an opening in the roof of the mouth called a cleft palate.\n\nHeart defects are another common feature of OFCD syndrome. Babies with this condition may be born with a hole between two chambers of the heart (an atrial or ventricular septal defect) or a leak in one of the valves that controls blood flow through the heart (mitral valve prolapse).\n\nTeeth with very large roots (radiculomegaly) are characteristic of OFCD syndrome. Additional dental abnormalities can include delayed loss of primary (baby) teeth, missing or abnormally small teeth, misaligned teeth, and defective tooth enamel.
Bilateral frontoparietal polymicrogyria
MedGen UID:
376107
Concept ID:
C1847352
Disease or Syndrome
Complex cortical dysplasia with other brain malformations-14A (CDCBM14A) is an autosomal recessive neurologic disorder characterized by global developmental delay with impaired intellectual development, motor delay, poor speech development, and early-onset seizures, often focal or atypical absence. Additional features may include strabismus, nystagmus, exo- or esotropia, axial hypotonia, and spasticity. Brain imaging shows bilateral frontoparietal polymicrogyria, a frontal-predominant cobblestone malformation of the cortex, scalloping of the cortical/white matter junction, enlarged ventricles, and hypoplasia of the pons, brainstem, and cerebellum. The disorder can be classified as a malformation of cortical development (summary by Parrini et al., 2009; Luo et al., 2011; Zulfiqar et al., 2021). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).
Congenital stationary night blindness 2A
MedGen UID:
376299
Concept ID:
C1848172
Disease or Syndrome
X-linked congenital stationary night blindness (CSNB) is characterized by non-progressive retinal findings of reduced visual acuity ranging from 20/30 to 20/200; defective dark adaptation; refractive error, most typically myopia ranging from low (-0.25 diopters [D] to -4.75 D) to high (=-10.00 D) but occasionally hyperopia; nystagmus; strabismus; normal color vision; and normal fundus examination. Characteristic ERG findings can help distinguish between complete X-linked CSNB and incomplete X-linked CSNB.
Hypomyelinating leukodystrophy 3
MedGen UID:
342403
Concept ID:
C1850053
Disease or Syndrome
Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (summary by Feinstein et al., 2010). The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD; 312080), which is caused by mutation in the PLP1 gene (300401). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.
Congenital fibrosis of extraocular muscles type 1
MedGen UID:
376943
Concept ID:
C1851102
Disease or Syndrome
Congenital fibrosis of the extraocular muscles (CFEOM) encompasses several different inherited strabismus syndromes characterized by congenital restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. Classic CFEOM is characterized by bilateral blepharoptosis and ophthalmoplegia with the eyes fixed in an infraducted position about 20 to 30 degrees below the horizontal midline. Involvement of the horizontal extraocular muscles is variable. If all affected members of a family have the classic phenotype with bilateral involvement, the disorder is referred to as 'CFEOM1' (Engle et al., 1997; Heidary et al., 2008). CFEOM2 (602078), an autosomal recessive disorder caused by mutation in the ARIX gene (PHOX2A; 602753) on chromosome 11q13, is characterized by bilateral ptosis with eyes fixed in an exotropic position. The CFEOM3 phenotype shows more variable clinical features: affected individuals may have unilateral eye involvement, may be able raise their eyes above midline, or may not have blepharoptosis. CFEOM3 is diagnosed in a family if even 1 member does not have classic findings of the disorder. CFEOM3 is a genetically heterogeneous disorder; CFEOM3A with or without extraocular involvement (600638) is caused by mutation in the TUBB3 gene (602661) on chromosome 16q24; CFEOM3B is caused by mutation in the KIF21A gene (608283) on chromosome 12q12; and CFEOM3C (609384) maps to chromosome 13q. CFEOM4 (609428), also known as Tukel syndrome, maps to chromosome 21q. CFEOM5 (616219) is caused by mutation in the COL25A1 gene (610004) on chromosome 4q25. See also NOMENCLATURE.
Neuroectodermal melanolysosomal disease
MedGen UID:
348553
Concept ID:
C1860157
Disease or Syndrome
Elejalde neuroectodermal melanolysosomal syndrome is a rare autosomal recessive disorder characterized by silvery-gray hair and severe dysfunction of the central nervous system, present from infancy or early childhood and consisting of severe hypotonia, seizures, and impaired intellectual development. Skin may be hypopigmented with bronzing after sun exposure. Microscopy of hair reveals large granules of melanin unevenly distributed in the hair shaft. Abnormal melanocytes and melanosomes and abnormal inclusion bodies in fibroblasts may be present (Elejalde et al., 1979; Duran-McKinster et al., 1999). It has been proposed that, in at least some cases, Elejalde neuroectodermal melanolysosomal syndrome and Griscelli syndrome type 1 (GS1; 214450) represent the same entity; see below. GS1 is caused by mutation in the MYO5A gene (160777).
Deficiency of 2-methylbutyryl-CoA dehydrogenase
MedGen UID:
355324
Concept ID:
C1864912
Disease or Syndrome
2-Methylbutyryl-CoA dehydrogenase deficiency is an autosomal recessive metabolic disorder of impaired isoleucine degradation. It is most often ascertained via newborn screening and is usually clinically asymptomatic, although some patients have been reported to have delayed development and neurologic signs. Therefore, the clinical relevance of the deficiency is unclear (Sass et al., 2008).
Fibrosis of extraocular muscles, congenital, with synergistic divergence
MedGen UID:
351285
Concept ID:
C1865040
Disease or Syndrome
RHYNS syndrome
MedGen UID:
356371
Concept ID:
C1865794
Disease or Syndrome
RHYNS syndrome is characterized by gaze palsy, retinitis pigmentosa, sensorineural hearing loss, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (Di Rocco et al., 1997).
Fibrosis of extraocular muscles, congenital, 2
MedGen UID:
356119
Concept ID:
C1865915
Disease or Syndrome
Congenital fibrosis of extraocular muscles-2 (CFEOM2) is an autosomal recessive disorder in which affected individuals are born with bilateral ptosis and restrictive ophthalmoplegia with the globes fixed in extreme abduction (exotropia) (Wang et al., 1998, Nakano et al., 2001). For a general phenotypic description and a discussion of genetic heterogeneity of various forms of CFEOM, see CFEOM1 (135700).
External auditory canal atresia-vertical talus-hypertelorism syndrome
MedGen UID:
361813
Concept ID:
C1876181
Disease or Syndrome
A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by the triad: congenital, bilateral, symmetrical, subtotal, external auditory canal atresia, bilateral vertical talus and increased interocular distance.
Severe achondroplasia-developmental delay-acanthosis nigricans syndrome
MedGen UID:
393098
Concept ID:
C2674173
Congenital Abnormality
SADDAN dysplasia (severe achondroplasia with developmental delay and acanthosis nigricans) is a very rare skeletal dysplasia characterized by the constellation of these features. Radiology reveals 'ram's horn' shaped clavicles and reverse bowing of lower limbs. Approximately half of patients die before the fourth week of life secondary to respiratory failure (summary by Zankl et al., 2008).
Loeys-Dietz syndrome 2
MedGen UID:
382398
Concept ID:
C2674574
Disease or Syndrome
Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.
Faciocardiomelic syndrome
MedGen UID:
436265
Concept ID:
C2674798
Disease or Syndrome
Chromosome 6pter-p24 deletion syndrome
MedGen UID:
393396
Concept ID:
C2675486
Disease or Syndrome
Distal monosomy 6p is responsible for a distinct chromosome deletion syndrome with a recognizable clinical picture including intellectual deficit, ocular abnormalities, hearing loss, and facial dysmorphism.
Intellectual disability, autosomal dominant 4
MedGen UID:
393397
Concept ID:
C2675487
Mental or Behavioral Dysfunction
Any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the KIRREL3 gene.
Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement
MedGen UID:
412638
Concept ID:
C2748801
Disease or Syndrome
Congenital fibrosis of the extraocular muscles (CFEOM) encompasses several different inherited strabismus syndromes characterized by congenital restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. If all affected members of a family have classic CFEOM with bilateral involvement and inability to raise the eyes above midline, the phenotype is classified as CFEOM1 (135700). CFEOM2 (602078) shows autosomal recessive inheritance. CFEOM3 is characterized by autosomal dominant inheritance of a more variable phenotype than classic CFEOM1. Individuals with CFEOM3 may not have bilateral involvement, may be able to raise the eyes above midline, or may not have blepharoptosis (reviews by Yamada et al., 2004 and Heidary et al., 2008). Yamada et al. (2003) concluded that CFEOM3 is a relatively rare form of CFEOM. Genetic Heterogeneity of CFEOM3 The CFEOM3 phenotype is genetically heterogeneous; see also CFEOM3B (135700), caused by mutation in the KIF21A gene on chromosome 12q12, and CFEOM3C (609384), which maps to chromosome 13q.
Chromosome 5p13 duplication syndrome
MedGen UID:
416385
Concept ID:
C2750805
Disease or Syndrome
A rare partial autosomal trisomy/tetrasomy characterized by global developmental delay, intellectual disability, autistic behavior, muscular hypotonia, macrocephaly and facial dysmorphism (frontal bossing, short palpebral fissures, low set, dysplastic ears, short or shallow philtrum, high arched or narrow palate, micrognathia). Other associated clinical features include sleep disturbances, seizures, aplasia/hypoplasia of the corpus callosum, skeletal abnormalities (large hands and feet, long fingers and toes, talipes).
DPAGT1-congenital disorder of glycosylation
MedGen UID:
419694
Concept ID:
C2931004
Disease or Syndrome
Like all CDGs, which are caused by a shortage of precursor monosaccharide phosphate or deficiencies in the glycosyltransferases required for lipid-linked oligosaccharide precursor (LLO) synthesis, CDG Ij is caused by a defect in the formation of DPAGT1, the first dolichyl-linked intermediate of the protein N-glycosylation pathway. For a general discussion of CDGs, see CDG1A (212065).
Aneurysm-osteoarthritis syndrome
MedGen UID:
462437
Concept ID:
C3151087
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.
Oculocutaneous albinism type 7
MedGen UID:
815116
Concept ID:
C3808786
Disease or Syndrome
Oculocutaneous albinism type VII (OCA7) is an autosomal recessive hypopigmentation disorder with predominant eye involvement including nystagmus, iris transillumination, and crossed asymmetry of the cortical visual response (Gronskov et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of oculocutaneous albinism, see OCA1 (203100).
Polymicrogyria, bilateral perisylvian, autosomal recessive
MedGen UID:
816735
Concept ID:
C3810405
Disease or Syndrome
Complex cortical dysplasia with other brain malformations-14B (CDCBM14B) is an autosomal recessive disorder characterized by strikingly restricted polymicrogyria limited to the cortex surrounding the Sylvian fissure. Affected individuals have variable intellectual and language difficulty and seizures, but no motor disability (Bae et al., 2014). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).
Hermansky-Pudlak syndrome 8
MedGen UID:
854728
Concept ID:
C3888026
Disease or Syndrome
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.
Coloboma, ocular, autosomal recessive
MedGen UID:
860411
Concept ID:
C4011974
Disease or Syndrome
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 1 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). For a discussion of genetic heterogeneity of ocular coloboma, see 120200.
Short stature with microcephaly and distinctive facies
MedGen UID:
862776
Concept ID:
C4014339
Disease or Syndrome
Short stature with microcephaly and distinctive facies (SSMCF) is characterized by pre- or postnatal growth retardation, frontal bossing, high forehead, sparse hair and eyebrows, and telecanthus. Patients also show skin dyspigmentation, with hyper- and/or hypopigmented areas (Leduc et al., 2016).
Mitochondrial complex III deficiency nuclear type 8
MedGen UID:
862877
Concept ID:
C4014440
Disease or Syndrome
Mitochondrial complex III deficiency, nuclear type 8, is an autosomal recessive disorder characterized by progressive neurodegeneration with onset in childhood. Affected individuals may have normal or delayed early development, and often have episodic acute neurologic decompensation and regression associated with febrile illnesses. The developmental regression results in variable intellectual disability and motor deficits, such as hypotonia, axial hypertonia, and spasticity; some patients may lose the ability to walk independently. Laboratory studies show increased serum lactate and isolated deficiency of mitochondrial complex III in skeletal muscle and fibroblasts. Brain imaging shows a characteristic pattern of multifocal small cystic lesions in the periventricular and deep cerebral white matter (summary by Dallabona et al., 2016). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1
MedGen UID:
864165
Concept ID:
C4015728
Disease or Syndrome
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-1 (IMNEPD1) is an autosomal recessive multisystemic disorder with variable expressivity. The core features usually include global developmental delay with impaired intellectual development and speech delay, ataxia, sensorineural hearing loss, and pancreatic insufficiency. Additional features may include peripheral neuropathy, postnatal microcephaly, dysmorphic facial features, and cerebellar atrophy. However, some patients may not display all features (summary by Picker-Minh et al., 2016, Sharkia et al., 2017). Genetic Heterogeneity of Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease See also IMNEPD2 (619418), caused by mutation in the YARS1 gene (603623) on chromosome 1p35.
Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome
MedGen UID:
906646
Concept ID:
C4225222
Disease or Syndrome
Takenouchi-Kosaki syndrome is a highly heterogeneous autosomal dominant complex congenital developmental disorder affecting multiple organ systems. The core phenotype includes delayed psychomotor development with variable intellectual disability, dysmorphic facial features, and cardiac, genitourinary, and hematologic or lymphatic defects, including thrombocytopenia and lymphedema. Additional features may include abnormalities on brain imaging, skeletal anomalies, and recurrent infections. Some patients have a milder disease course reminiscent of Noonan syndrome (see, e.g., NS1, 163950) (summary by Martinelli et al., 2018).
Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome
MedGen UID:
895943
Concept ID:
C4225229
Disease or Syndrome
Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome is a rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, axial hypotonia, palate abnormalities (including cleft palate and/or high and narrow palate), dysmorphic facial features (including prominent forehead, hypertelorism, downslanting palpebral fissures, wide nasal bridge, thin lips and widely spaced teeth), and short stature. Additional manifestations may include digital anomalies (such as brachydactyly, clinodactyly, and hypoplastic toenails), a single palmar crease, lower limb hypertonia, joint hypermobility, as well as ocular and urogenital anomalies.
Neuropathy, hereditary motor and sensory, type 6B
MedGen UID:
895482
Concept ID:
C4225302
Disease or Syndrome
Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals may also have cerebellar or pontocerebellar atrophy on brain imaging, and they may show abnormal movements such as ataxia, dysmetria, and myoclonus (summary by Abrams et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (601152).
Hypomyelinating leukodystrophy 10
MedGen UID:
904191
Concept ID:
C4225332
Disease or Syndrome
Hypomyelinating leukodystrophy-10 is an autosomal recessive neurologic disorder characterized by postnatal progressive microcephaly, severely delayed psychomotor development, and hypomyelination on brain imaging (summary by Nakayama et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.
Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome
MedGen UID:
897984
Concept ID:
C4225351
Disease or Syndrome
White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), hypotonia, autism spectrum disorder, and other behavioral problems. Additional features commonly reported include seizures, refractive errors and strabismus, hearing loss, sleep disturbance (particularly sleep apnea), feeding and gastrointestinal problems, mild genital abnormalities in males, and urinary tract involvement in both males and females.
Myofibrillar myopathy 8
MedGen UID:
934612
Concept ID:
C4310645
Disease or Syndrome
Myofibrillar myopathy-8 (MFM8) is an autosomal recessive myopathy characterized by slowly progressive proximal muscle weakness and atrophy affecting the upper and lower limbs, resulting in increased falls, gait problems, difficulty running or climbing stairs, and upper limb weakness or scapular winging. Some patients develop distal muscle weakness and atrophy. The phenotype may also be consistent with a clinical diagnosis of limb-girdle muscular dystrophy (LGMD). Age at symptom onset ranges from infancy to adulthood. Ambulation is generally preserved and cardiac involvement is rare, but respiratory compromise with decreased forced vital capacity often occurs. Muscle biopsy shows a mix of myopathic features, including myofibrillar inclusions and sarcomeric disorganization; some patients have been reported to have dystrophic changes on muscle biopsy (O'Grady et al., 2016; Daimaguler et al., 2021). There is significant phenotypic variation, even in patients with the same mutation, which must be taken into account when counseling affecting individuals (Woods et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).
Cerebral palsy, spastic quadriplegic, 3
MedGen UID:
934734
Concept ID:
C4310767
Disease or Syndrome
Any spastic quadriplegia in which the cause of the disease is a mutation in the ADD3 gene.
Intellectual disability, autosomal dominant 42
MedGen UID:
934741
Concept ID:
C4310774
Mental or Behavioral Dysfunction
GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis.
Intellectual disability, X-linked, syndromic, Bain type
MedGen UID:
934781
Concept ID:
C4310814
Disease or Syndrome
Most individuals with HNRNPH2-related neurodevelopmental disorder (HNRNPH2-NDD) have symptoms early in life, before age 12 months. The major features of HNRNPH2-NDD are developmental delay / intellectual disability, motor and language delays, behavioral and psychiatric disorders, and growth and musculoskeletal abnormalities. Minor features include dysmorphic facies, gastrointestinal disturbances, epilepsy, and visual defects. Although HNRNPH2-NDD is an X-linked condition, there is not enough information on affected females versus affected males to make any generalizations about phenotypic differences between the two sexes.
Combined oxidative phosphorylation deficiency 32
MedGen UID:
1617600
Concept ID:
C4540029
Disease or Syndrome
Combined oxidative phosphorylation deficiency-32 is an autosomal recessive neurodegenerative disorder characterized by onset of delayed psychomotor development and developmental regression in infancy. Affected individuals have multiple variable symptoms, including poor or absent speech, inability to walk, and abnormal movements. Brain imaging shows T2-weighted abnormalities in the basal ganglia and brainstem consistent with Leigh syndrome (256000). Patient cells showed decreased activities of mitochondrial respiratory chain complexes, I, III, and IV, as well as impaired mitochondrial translation (summary by Lake et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
MedGen UID:
1619876
Concept ID:
C4540192
Disease or Syndrome
NEMMLAS is an autosomal recessive multisystemic disorder characterized by delayed psychomotor development, intellectual disability, and abnormal motor function, including hypotonia, dystonia, ataxia, and spasticity. Patient tissues may show deficiencies in one or more of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes, but this is not a constant finding (summary by Wortmann et al., 2017).
Tyrosinase-negative oculocutaneous albinism
MedGen UID:
1643910
Concept ID:
C4551504
Disease or Syndrome
Oculocutaneous albinism is a group of conditions that affect coloring (pigmentation) of the skin, hair, and eyes. Affected individuals typically have very fair skin and white or light-colored hair. Long-term sun exposure greatly increases the risk of skin damage and skin cancers, including an aggressive form of skin cancer called melanoma, in people with this condition. Oculocutaneous albinism also reduces pigmentation of the colored part of the eye (the iris) and the light-sensitive tissue at the back of the eye (the retina). People with this condition usually have vision problems such as reduced sharpness; rapid, involuntary eye movements (nystagmus); and increased sensitivity to light (photophobia).\n\nResearchers have identified multiple types of oculocutaneous albinism, which are distinguished by their specific skin, hair, and eye color changes and by their genetic cause. Oculocutaneous albinism type 1 is characterized by white hair, very pale skin, and light-colored irises. Type 2 is typically less severe than type 1; the skin is usually a creamy white color and hair may be light yellow, blond, or light brown. Type 3 includes a form of albinism called rufous oculocutaneous albinism, which usually affects dark-skinned people. Affected individuals have reddish-brown skin, ginger or red hair, and hazel or brown irises. Type 3 is often associated with milder vision abnormalities than the other forms of oculocutaneous albinism. Type 4 has signs and symptoms similar to those seen with type 2.\n\nSeveral additional types of this disorder have been proposed, each affecting one or a few families.
Loeys-Dietz syndrome 1
MedGen UID:
1646567
Concept ID:
C4551955
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.
Brain small vessel disease 1 with or without ocular anomalies
MedGen UID:
1647320
Concept ID:
C4551998
Disease or Syndrome
The spectrum of COL4A1-related disorders includes: small-vessel brain disease of varying severity including porencephaly, variably associated with eye defects (retinal arterial tortuosity, Axenfeld-Rieger anomaly, cataract) and systemic findings (kidney involvement, muscle cramps, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, and hemolytic anemia). On imaging studies, small-vessel brain disease is manifest as diffuse periventricular leukoencephalopathy, lacunar infarcts, microhemorrhage, dilated perivascular spaces, and deep intracerebral hemorrhages. Clinically, small-vessel brain disease manifests as infantile hemiparesis, seizures, single or recurrent hemorrhagic stroke, ischemic stroke, and isolated migraine with aura. Porencephaly (fluid-filled cavities in the brain detected by CT or MRI) is typically manifest as infantile hemiparesis, seizures, and intellectual disability; however, on occasion it can be an incidental finding. HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome usually associates asymptomatic small-vessel brain disease, cerebral large vessel involvement (i.e., aneurysms), and systemic findings involving the kidney, muscle, and small vessels of the eye. Two additional phenotypes include isolated retinal artery tortuosity and nonsyndromic autosomal dominant congenital cataract.
Ophthalmoplegia, external, with rib and vertebral anomalies
MedGen UID:
1648445
Concept ID:
C4748418
Disease or Syndrome
External ophthalmoplegia with rib and vertebral anomalies (EORVA) is characterized by congenital nonprogressive external ophthalmoplegia and ptosis, with torticollis and scoliosis developing during childhood. In addition, patients exhibit hypoplastic or missing ribs with fusion anomalies (Di Gioia et al., 2018).
Intellectual disability-hypotonic facies syndrome, X-linked, 1
MedGen UID:
1676827
Concept ID:
C4759781
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.
Cataract 48
MedGen UID:
1684457
Concept ID:
C5193082
Disease or Syndrome
Cataract-48 (CTRCT48) is characterized by infantile or early-childhood cataracts and visual impairment (Ansar et al., 2018).
Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities
MedGen UID:
1672905
Concept ID:
C5193124
Disease or Syndrome
Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities (HIDEA) is an autosomal recessive neurodevelopmental syndrome characterized by global developmental delay, poor or absent speech, hypotonia, variable ocular movement and visual abnormalities, and respiratory difficulties, including hypoventilation, and sleep apnea. Patients may have significant breathing problems during respiratory infections that may lead to early death (summary by Rahikkala et al., 2019).
Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities
MedGen UID:
1682403
Concept ID:
C5193134
Disease or Syndrome
Stolerman neurodevelopmental syndrome (NEDSST) is a highly variable disorder characterized by developmental delay, often with motor and speech delay, mildly impaired intellectual development (in most patients), learning difficulties, and behavioral abnormalities, including autism spectrum disorder. Psychosis is observed in a small percentage of individuals over the age of 12 years. Most individuals have nonspecific and mild dysmorphic facial features without a common gestalt. A subset of patients may have involvement of other organ systems, including gastrointestinal with poor early feeding or gastroesophageal reflux, distal skeletal anomalies, and congenital heart defects. Most mutations occur de novo, but rare autosomal dominant inheritance with incomplete penetrance has been observed (Stolerman et al., 2019; Rots et al., 2023).
Shukla-Vernon syndrome
MedGen UID:
1674076
Concept ID:
C5193146
Disease or Syndrome
Shukla-Vernon syndrome (SHUVER) is an X-linked recessive neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development, and behavioral abnormalities, including autism spectrum disorder and ADHD. Dysmorphic features are common and may include tall forehead, downslanting palpebral fissures, and tapering fingers. Some patients may have seizures and/or cerebellar atrophy on brain imaging. Carrier mothers may have mild manifestations, including learning disabilities (summary by Shukla et al., 2019).
Retinitis pigmentosa 88
MedGen UID:
1720448
Concept ID:
C5394208
Disease or Syndrome
Retinitis pigmentosa-88 (RP88) is characterized by night blindness and constriction of peripheral visual fields, with mildly reduced visual acuity. Examination shows typical findings of RP, including attenuated retinal vessels, pale optic discs, and pigment deposits in the peripheral retinal pigment epithelium (Zobor et al., 2018; Hu et al., 2019; Albarry et al., 2019). For a discussion of genetic heterogeneity of RP, see 268000.
Neurodevelopmental disorder with hypotonia, microcephaly, and seizures
MedGen UID:
1710110
Concept ID:
C5394312
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, microcephaly, and seizures (NEDHYMS) is an autosomal recessive disorder characterized by global developmental delay with axial hypotonia, inability to sit or walk, and severely impaired intellectual development with absent language. Most patients develop early-onset intractable seizures that prevent normal development. Additional features include feeding difficulties with poor overall growth and microcephaly. Some patients may have spastic quadriplegia, poor eye contact due to cortical blindness, variable dysmorphic features, and nonspecific abnormalities on brain imaging (summary by Tan et al., 2020).
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
MedGen UID:
1748867
Concept ID:
C5399977
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 2 (MC4DN2) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms at birth or in the first weeks or months of life. Affected individuals have severe hypotonia, often associated with feeding difficulties and respiratory insufficiency necessitating tube feeding and mechanical ventilation. The vast majority of patients develop hypertrophic cardiomyopathy in the first days or weeks of life, which usually leads to death in infancy or early childhood. Patients also show neurologic abnormalities, including developmental delay, nystagmus, fasciculations, dystonia, EEG changes, and brain imaging abnormalities compatible with a diagnosis of Leigh syndrome (see 256000). There may also be evidence of systemic involvement with hepatomegaly and myopathy, although neurogenic muscle atrophy is more common and may resemble spinal muscular atrophy type I (SMA1; 253300). Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels in various tissues, including heart and skeletal muscle. Most patients die in infancy of cardiorespiratory failure (summary by Papadopoulou et al., 1999). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia
MedGen UID:
1776912
Concept ID:
C5436585
Disease or Syndrome
Neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (NEDDISH) is an autosomal recessive disorder characterized by global developmental delay and mildly to severely impaired intellectual development with poor speech and language acquisition. Some patients may have early normal development with onset of the disorder in the first years of life. More variable neurologic abnormalities include hypotonia, seizures, apnea, mild signs of autonomic or peripheral neuropathy, and autism. Aside from dysmorphic facial features and occasional findings such as scoliosis or undescended testes, other organ systems are not involved (summary by Schneeberger et al., 2020).
Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy
MedGen UID:
1755716
Concept ID:
C5436747
Disease or Syndrome
Neurodevelopmental disorder with microcephaly, seizures, and brain atrophy (NEDMISB) is an autosomal recessive disorder characterized by severe global developmental delay, developmental regression with loss of milestones, severe microcephaly, and brain abnormalities, primarily cerebral atrophy and hypoplasia of the corpus callosum. Affected individuals develop seizures in the first year of life; eventually they are unable to sit, feed, or communicate, and may be unresponsive to stimuli. Other features include muscle weakness, spasticity with hyperreflexia, irritability, and contractures (Coulter et al., 2020).
Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis
MedGen UID:
1780157
Concept ID:
C5543257
Disease or Syndrome
SHILCA is characterized by early-onset retinal degeneration in association with sensorineural hearing loss, short stature, vertebral anomalies, and epiphyseal dysplasia, as well as motor and intellectual delay. Delayed myelination, leukoencephalopathy, and hypoplasia of the corpus callosum and cerebellum have been observed on brain MRI (Bedoni et al., 2020).
Buratti-Harel syndrome
MedGen UID:
1788293
Concept ID:
C5543351
Disease or Syndrome
Buratti-Harel syndrome (BURHAS) is a neurodevelopmental disorder characterized by infantile hypotonia, global developmental delay, mild motor and speech delay, and mild to moderately impaired intellectual development. Some patients are able to attend special schools and show learning difficulties, whereas others are more severely affected. Patients have prominent dysmorphic facial features, including hypertelorism, downslanting palpebral fissures, strabismus, and small low-set ears. Additional features may include laryngomalacia with feeding difficulties and distal skeletal anomalies (summary by Buratti et al., 2021).
Neuroocular syndrome
MedGen UID:
1790414
Concept ID:
C5551362
Disease or Syndrome
Neuroocular syndrome (NOC) encompasses a broad spectrum of overlapping anomalies, with developmental delay or impaired intellectual development as a consistent finding. Eye abnormalities show marked variability in the type and severity of defects, and include anophthalmia, microphthalmia, and coloboma. Other common systemic features include congenital heart and kidney defects, hypotonia, failure to thrive, and microcephaly (summary by Chowdhury et al., 2021).
Luo-Schoch-Yamamoto syndrome
MedGen UID:
1794156
Concept ID:
C5561946
Disease or Syndrome
Luo-Schoch-Yamamoto syndrome (LUSYAM) is a neurodevelopmental disorder characterized by global developmental delay and impaired intellectual development apparent from infancy. Affected individuals have delayed walking, early-onset seizures, hypotonia, dysmorphic facial features, and white matter abnormalities on brain imaging (Luo et al., 2021).
Neurodevelopmental disorder with hypotonia and dysmorphic facies
MedGen UID:
1794184
Concept ID:
C5561974
Disease or Syndrome
Neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF) is characterized by global developmental delay and hypotonia apparent from birth. Affected individuals have variably impaired intellectual development, often with speech delay and delayed walking. Seizures are generally not observed, although some patients may have single seizures or late-onset epilepsy. Most patients have prominent dysmorphic facial features. Additional features may include congenital cardiac defects (without arrhythmia), nonspecific renal anomalies, joint contractures or joint hyperextensibility, dry skin, and cryptorchidism. There is significant phenotypic variability in both the neurologic and extraneurologic manifestations (summary by Tan et al., 2022).
Combined oxidative phosphorylation deficiency 55
MedGen UID:
1806598
Concept ID:
C5676915
Disease or Syndrome
Combined oxidative phosphorylation deficiency-55 (COXPD55) is characterized by global developmental delay, hypotonia, short stature, and impaired intellectual development with speech disabilities in childhood. Indolent progressive external ophthalmoplegia phenotype has been described in 1 patient (summary by Olahova et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Neurodevelopmental disorder with poor growth and skeletal anomalies
MedGen UID:
1804653
Concept ID:
C5676990
Disease or Syndrome
Neurodevelopmental disorder with poor growth and skeletal anomalies (NEDGS) is an autosomal recessive disorder characterized by global developmental delay and impaired intellectual development apparent from infancy. Affected individuals have hypotonia, delayed walking, poor or absent speech, and variable skeletal anomalies. More variable features include seizures, nonspecific dysmorphic facial features, oculomotor apraxia, and nonspecific brain imaging abnormalities (Iqbal et al., 2021).
Developmental and epileptic encephalopathy 106
MedGen UID:
1823985
Concept ID:
C5774212
Disease or Syndrome
Developmental and epileptic encephalopathy-106 (DEE106) is an autosomal recessive disorder characterized by the onset of various types of frequent, often refractory, seizures within the first year of life. Affected individuals demonstrate profound global developmental delay with limited ability to move and severely impaired intellectual development with absent speech. Nonspecific brain abnormalities may be observed on MRI (Ni et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Developmental delay, language impairment, and ocular abnormalities
MedGen UID:
1824035
Concept ID:
C5774262
Disease or Syndrome
Developmental delay, language impairment, and ocular abnormalities (DEVLO) is characterized by delayed acquisition of skills particularly affecting speech and language development, although many patients show mild motor delay. Most affected individuals also have a small head circumference (down to -3 SD) and may have mild dysmorphic features. Variable ocular anomalies include strabismus, cataracts, and cortical visual impairment. Older patients require special schooling and often demonstrate behavioral abnormalities (Laboy Cintron et al., 2022).
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities
MedGen UID:
1824058
Concept ID:
C5774285
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities (NEDHFS) is an autosomal recessive disorder characterized by severe global developmental delay with impaired intellectual development and poor or absent speech. Affected individuals have dysmorphic facies, including large abnormally shaped ears and strabismus, hypotonia, and dry skin with keratosis pilaris. Some patients develop seizures. Metabolic studies are unremarkable (Morava et al., 2021).
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures
MedGen UID:
1840880
Concept ID:
C5830244
Disease or Syndrome
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures (NEDFSS), is characterized by these features and global developmental delay with delayed or absent walking, moderate to severely impaired intellectual development, and poor or absent speech acquisition. Affected individuals may also have behavioral abnormalities. About half of patients develop various types of seizures that are usually well-controlled with medication. Rare patients are noted to have heat intolerance or insensitivity to pain (Lines et al., 2022).
Intellectual developmental disorder, autosomal recessive 78
MedGen UID:
1840905
Concept ID:
C5830269
Mental or Behavioral Dysfunction
Autosomal recessive intellectual developmental disorder-78 (MRT78) is a neurodevelopmental disorder characterized by impaired intellectual development that is usually mild, but shows variable severity. Affected individuals have microcephaly and mild short stature. Additional features may include ocular abnormalities and mild skeletal defects (Haag et al., 2021).

Professional guidelines

PubMed

Demer JL
JAMA Ophthalmol 2024 Mar 1;142(3):247-248. doi: 10.1001/jamaophthalmol.2023.6783. PMID: 38358748
Bort-Martí AR, Rowe FJ, Ruiz Sifre L, Ng SM, Bort-Martí S, Ruiz Garcia V
Cochrane Database Syst Rev 2023 Mar 14;3(3):CD006499. doi: 10.1002/14651858.CD006499.pub5. PMID: 36916692Free PMC Article
Lemos J, Eggenberger E
Curr Opin Ophthalmol 2013 Nov;24(6):558-65. doi: 10.1097/ICU.0000000000000003. PMID: 24100374

Recent clinical studies

Etiology

Jeong S, Han SY, Moon S, Lee D, Kim SY, Kim M, Park J, Kim MM, Jae Kim W
J AAPOS 2024 Apr;28(2):103862. Epub 2024 Mar 6 doi: 10.1016/j.jaapos.2024.103862. PMID: 38458599
Varrone E, Lenhart P, Peragallo J, Hutchinson A, Weil N
J AAPOS 2023 Jun;27(3):147.e1-147.e5. Epub 2023 May 13 doi: 10.1016/j.jaapos.2023.04.005. PMID: 37182651
Kim M, Kim HK, Kim WJ
BMC Ophthalmol 2023 Mar 28;23(1):125. doi: 10.1186/s12886-023-02873-w. PMID: 36978009Free PMC Article
Dohlman JC, Hunter DG, Heidary G
Semin Ophthalmol 2023 Jan;38(1):52-56. Epub 2022 Nov 29 doi: 10.1080/08820538.2022.2152701. PMID: 36447371
Hatt SR, Gnanaraj L
Cochrane Database Syst Rev 2013 May 31;2013(5):CD003737. doi: 10.1002/14651858.CD003737.pub3. PMID: 23728647Free PMC Article

Diagnosis

Hernández Martínez P, Rodríguez Del Valle JM
Arch Soc Esp Oftalmol 2017 Dec;92(12):585-593. Epub 2017 Jul 23 doi: 10.1016/j.oftal.2017.06.007. PMID: 28743414
Clarke MP
J Pediatr Ophthalmol Strabismus 2007 May-Jun;44(3):153-7; quiz 178-9. doi: 10.3928/0191-3913-20070301-07. PMID: 17542436
Hutchinson AK
Ophthalmol Clin North Am 2001 Sep;14(3):399-406. doi: 10.1016/s0896-1549(05)70237-6. PMID: 11705139
Biglan AW, Davis JS, Cheng KP, Pettapiece MC
J Pediatr Ophthalmol Strabismus 1996 Mar-Apr;33(2):79-84. doi: 10.3928/0191-3913-19960301-04. PMID: 8965243
Kran BS, Duckman R
J Am Optom Assoc 1987 Nov;58(11):921-30. PMID: 3320163

Therapy

Pang Y, Gnanaraj L, Gayleard J, Han G, Hatt SR
Cochrane Database Syst Rev 2021 Sep 13;9(9):CD003737. doi: 10.1002/14651858.CD003737.pub4. PMID: 34516656Free PMC Article
Chen AM, Erzurum SA, Chandler DL, Hercinovic A, Melia BM, Bhatt AR, Suh DW, Vricella M, Erickson JW, Miller AM, Marsh JD, Bodack MI, Martinson SR, Titelbaum JR, Gray ME, Holtorf HL, Kong L, Kraker RT, Rahmani B, Shah BK, Holmes JM, Cotter SA; Pediatric Eye Disease Investigator Group
JAMA Ophthalmol 2021 Apr 1;139(4):464-476. doi: 10.1001/jamaophthalmol.2021.0082. PMID: 33662112Free PMC Article
Scheiman M, Kulp MT, Cotter SA, Lawrenson JG, Wang L, Li T
Cochrane Database Syst Rev 2020 Dec 2;12(12):CD006768. doi: 10.1002/14651858.CD006768.pub3. PMID: 33263359Free PMC Article
Nuijts RMMA, Saelens IEY, Bauer NJC
J Cataract Refract Surg 2018 Sep;44(9):1163. doi: 10.1016/j.jcrs.2018.07.039. PMID: 30165945
Schworm HD, Rudolph G
Curr Opin Ophthalmol 2000 Oct;11(5):310-7. doi: 10.1097/00055735-200010000-00004. PMID: 11148695

Prognosis

Jeong S, Han SY, Moon S, Lee D, Kim SY, Kim M, Park J, Kim MM, Jae Kim W
J AAPOS 2024 Apr;28(2):103862. Epub 2024 Mar 6 doi: 10.1016/j.jaapos.2024.103862. PMID: 38458599
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Varrone E, Lenhart P, Peragallo J, Hutchinson A, Weil N
J AAPOS 2023 Jun;27(3):147.e1-147.e5. Epub 2023 May 13 doi: 10.1016/j.jaapos.2023.04.005. PMID: 37182651
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Gökgöz Özişik G, Gokgoz G, Caglar C, Cakmak HB
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Chen AM, Erzurum SA, Chandler DL, Hercinovic A, Melia BM, Bhatt AR, Suh DW, Vricella M, Erickson JW, Miller AM, Marsh JD, Bodack MI, Martinson SR, Titelbaum JR, Gray ME, Holtorf HL, Kong L, Kraker RT, Rahmani B, Shah BK, Holmes JM, Cotter SA; Pediatric Eye Disease Investigator Group
JAMA Ophthalmol 2021 Apr 1;139(4):464-476. doi: 10.1001/jamaophthalmol.2021.0082. PMID: 33662112Free PMC Article
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J AAPOS 2018 Feb;22(1):2.e1-2.e5. Epub 2017 Dec 30 doi: 10.1016/j.jaapos.2017.10.009. PMID: 29292047

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Scheiman M, Kulp MT, Cotter SA, Lawrenson JG, Wang L, Li T
Cochrane Database Syst Rev 2020 Dec 2;12(12):CD006768. doi: 10.1002/14651858.CD006768.pub3. PMID: 33263359Free PMC Article
Tang SM, Chan RY, Bin Lin S, Rong SS, Lau HH, Lau WW, Yip WW, Chen LJ, Ko ST, Yam JC
Sci Rep 2016 Oct 12;6:35177. doi: 10.1038/srep35177. PMID: 27731389Free PMC Article
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Cochrane Database Syst Rev 2013 May 31;2013(5):CD003737. doi: 10.1002/14651858.CD003737.pub3. PMID: 23728647Free PMC Article

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