MedGen

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. [from GeneReviews]

The phenotypic spectrum of SOX2 disorder includes anophthalmia and/or microphthalmia, brain malformations, developmental delay / intellectual disability, esophageal atresia, hypogonadotropic hypogonadism (manifest as cryptorchidism and micropenis in males, gonadal dysgenesis infrequently in females, and delayed puberty in both sexes), pituitary hypoplasia, postnatal growth delay, hypotonia, seizures, and spastic or dystonic movements. [from GeneReviews]

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is a genetically heterogeneous autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and early death. The phenotype commonly includes cobblestone (type II) lissencephaly, cerebellar malformations, and retinal malformations. More variable features include macrocephaly or microcephaly, hypoplasia of midline brain structures, ventricular dilatation, microphthalmia, cleft lip/palate, and congenital contractures (Dobyns et al., 1989). Those with a more severe phenotype characterized as Walker-Warburg syndrome often die within the first year of life, whereas those characterized as having muscle-eye-brain disease may rarely acquire the ability to walk and to speak a few words. These are part of a group of disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with Brain and Eye Anomalies (Type A) Muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is genetically heterogeneous and can be caused by mutation in other genes involved in DAG1 glycosylation: see MDDGA2 (613150), caused by mutation in the POMT2 gene (607439); MDDGA3 (253280), caused by mutation in the POMGNT1 gene (606822); MDDGA4 (253800), caused by mutation in the FKTN gene (607440); MDDGA5 (613153), caused by mutation in the FKRP gene (606596); MDDGA6 (613154), caused by mutation in the LARGE gene (603590); MDDGA7 (614643), caused by mutation in the ISPD gene (CRPPA; 614631); MDDGA8 (614830) caused by mutation in the GTDC2 gene (POMGNT2; 614828); MDDGA9 (616538), caused by mutation in the DAG1 gene (128239); MDDGA10 (615041), caused by mutation in the TMEM5 gene (RXYLT1; 605862); MDDGA11 (615181), caused by mutation in the B3GALNT2 gene (610194); MDDGA12 (615249), caused by mutation in the SGK196 gene (POMK; 615247); MDDGA13 (615287), caused by mutation in the B3GNT1 gene (B4GAT1; 605517); and MDDGA14 (615350), caused by mutation in the GMPPB gene (615320). [from OMIM]

Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA. [from GeneReviews]

Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean. [from GeneReviews]

Septooptic dysplasia is a clinically heterogeneous disorder loosely defined by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum (Dattani et al., 1998). The diagnosis of this rare congenital anomaly is made when 2 or more features of the classic triad are present. Approximately 30% of patients have complete manifestations, 62% display hypopituitarism, and 60% have an absent septum pellucidum. The disorder is equally prevalent in males and females and is more common in infants born to younger mothers, with a reported incidence of 1 in 10,000 live births (summary by Webb and Dattani, 2010). Also see 516020.0012 for a form of septooptic dysplasia associated with cardiomyopathy and exercise intolerance. [from OMIM]

CASK disorders include a spectrum of phenotypes in both females and males. Two main types of clinical presentation are seen: Microcephaly with pontine and cerebellar hypoplasia (MICPCH), generally associated with pathogenic loss-of-function variants in CASK. X-linked intellectual disability (XLID) with or without nystagmus, generally associated with hypomorphic CASK pathogenic variants. MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of XLID with or without nystagmus and additional clinical features. Males have mild-to-severe intellectual disability, with or without nystagmus and other ocular features. Females typically have normal intelligence with some displaying mild-to-severe intellectual disability with or without ocular features. [from GeneReviews]

Holoprosencephaly-9 refers to a disorder characterized by a wide phenotypic spectrum of brain developmental defects, with or without overt forebrain cleavage abnormalities. It usually includes midline craniofacial anomalies involving the first branchial arch and/or orbits, pituitary hypoplasia with panhypopituitarism, and postaxial polydactyly. The disorder shows incomplete penetrance and variable expressivity (summary by Roessler et al., 2003 and Bertolacini et al., 2012). For general phenotypic information and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100). [from OMIM]

The association of a range of ocular anomalies (anophthalmia, microphthalmia and retinal abnormalities) with variable developmental delay and central nervous system malformations. Less than 20 cases have been reported in the literature so far. The clinical picture is highly variable, even between affected members of the same family. Severe developmental delay was noted in some patients, whilst others showed normal cognitive development. Pituitary dysfunction, leading to growth hormone deficiency and short stature, or combined pituitary hormone deficiency, has also been reported. The syndrome is caused by heterozygous mutations in the OTX2 gene (14q22.3). [from SNOMEDCT_US]

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals. [from GeneReviews]

A rare genetic optic nerve disorder characterized by visual impairment or blindness resulting from varying degrees of underdevelopment of the optic nerve or even complete absence of the optic nerve, ganglion cells, and central retinal vessels. It may be unilateral, typically with otherwise normal brain development, or bilateral with accompanying severe and widespread congenital malformations of the central nervous system. [from ORDO]

Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 (215100) is the most frequent form of RCDP (summary by Wanders and Waterham, 2005). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 is classified as a single peroxisome enzyme deficiency (Waterham and Ebberink, 2012). For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100. [from OMIM]

Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern. [from GeneReviews]

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Roscioli et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670). [from OMIM]

Stromme syndrome is an autosomal recessive congenital disorder affecting multiple systems with features of a ciliopathy. Affected individuals typically have some type of intestinal atresia, variable ocular abnormalities, microcephaly, and sometimes involvement of other systems, including renal and cardiac. In some cases, the condition is lethal in early life, whereas other patients show normal survival with or without mild cognitive impairment (summary by Filges et al., 2016). [from OMIM]

The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (Adam et al., 2005). [from OMIM]

Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference =2 SD above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures. Individuals with TBRS have subtle dysmorphic features, including a round face with coarse features, thick horizontal low-set eyebrows, narrow (as measured vertically) palpebral fissures, and prominent upper central incisors. The facial gestalt is most easily recognizable in the teenage years. TBRS may be associated with an increased risk of developing acute myeloid leukemia. There are less clear associations with aortic root dilatation and increased risk of other hematologic and solid tumors. [from GeneReviews]

Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic, and hyperlysinemia is generally considered to be a benign metabolic variant (summary by Tondo et al., 2013; Houten et al., 2013). The AASS gene encodes a bifunctional enzyme: lysine alpha-ketoglutarate reductase and saccharopine dehydrogenase. In hyperlysinemia type I, both enzymatic functions of AASS are defective; in hyperlysinemia type II, also known as saccharopinuria (268700), some of the first enzymatic function is retained (Cox, 1985; Cox et al., 1986). [from OMIM]

SCN8A-related epilepsy with encephalopathy is characterized by developmental delay, seizure onset in the first 18 months of life (mean 4 months), and intractable epilepsy characterized by multiple seizure types (generalized tonic-clonic seizures, infantile spasms, and absence and focal seizures). Epilepsy syndromes can include Lennox-Gastaut syndrome, West syndrome, and epileptic encephalopathies (e.g., Dravet syndrome). Hypotonia and movement disorders including dystonia, ataxia, and choreoathetosis are common. Psychomotor development varies from normal prior to seizure onset (with subsequent slowing or regression after seizure onset) to abnormal from birth. Intellectual disability, present in all, ranges from mild to severe (in ~50% of affected individuals). Autistic features are noted in some. Sudden unexpected death in epilepsy (SUDEP) of unknown cause has been reported in approximately 10% of published cases. To date SCN8A-related epilepsy with encephalopathy has been reported in the literature in about 50 individuals. [from GeneReviews]

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is an autosomal recessive disorder with congenital muscular dystrophy resulting in muscle weakness early in life and brain and eye anomalies. It is usually associated with delayed psychomotor development and shortened life expectancy. The phenotype includes the alternative clinical designations Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (summary by Stevens et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670). [from OMIM]