MedGen

Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010). For a discussion of genetic heterogeneity of malignant melanoma, see 155600. [from OMIM]

The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9]), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures in classic early-onset Glut1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. In some infants, apneic episodes and abnormal episodic eye-head movements similar to opsoclonus may precede the onset of seizures. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress. Symptoms often improve substantially when a ketogenic diet is started. [from GeneReviews]

Kufor-Rakeb syndrome is a rare autosomal recessive form of juvenile-onset atypical Parkinson disease (PARK9) associated with supranuclear gaze palsy, spasticity, and dementia. Some patients have neuroradiologic evidence of iron deposition in the basal ganglia, indicating that the pathogenesis of PARK9 can be considered among the syndromes of neurodegeneration with brain iron accumulation (NBIA; see 234200) (summary by Bruggemann et al., 2010). For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see 168600. Biallelic mutation in the ATP13A2 gene also causes autosomal recessive spastic paraplegia-78 (SPG78; 617225), an adult-onset neurodegenerative disorder with overlapping features. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (summary by Estrada-Cuzcano et al., 2017). [from OMIM]

SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized in the majority of affected newborns by hypotonia, muscle atrophy, feeding difficulties, and lactic acidosis. Affected infants commonly manifest developmental delay / cognitive impairment, growth retardation / failure to thrive, hepatopathy, sensorineural hearing impairment, dystonia, and hypertonia. Notable findings in some affected individuals include hypertrophic cardiomyopathy, epilepsy, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, and/or hypoglycemia. Life span is shortened, with median survival of 20 months. [from GeneReviews]

For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy, see 600669. Juvenile myoclonic epilepsy is a subtype of idiopathic generalized epilepsy; see 254770 for a general phenotypic description and a discussion of genetic heterogeneity of JME. [from OMIM]

POT1 tumor predisposition (POT1-TPD) is characterized by an increased lifetime risk for multiple cutaneous melanomas, chronic lymphocytic leukemia (CLL), angiosarcoma (particularly cardiac angiosarcomas), and gliomas. Additional cancers (e.g., colorectal cancer, thyroid cancer, breast angiosarcomas) have been reported in individuals with POT1-TPD but with very limited evidence. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years. The majority of POT1 associated cancers are diagnosed in adulthood. [from GeneReviews]

Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Classic CCA is characterized by arachnodactyly; flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers; kyphoscoliosis (usually progressive); a marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate); and abnormal "crumpled" ears. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, mild contractures without impairment, and minor ear abnormalities. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Phenotypic expression can vary within and between families. [from GeneReviews]

Rhizomelic chondrodysplasia punctata type 1 (RCDP1), a peroxisome biogenesis disorder (PBD) has a classic (severe) form and a nonclassic (mild) form. Classic (severe) RCDP1 is characterized by proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral bodies, and cataracts that are usually present at birth or appear in the first few months of life. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. Nonclassic (mild) RCDP1 is characterized by congenital or childhood cataracts, CDP or infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, variable rhizomelia, and milder intellectual disability and growth restriction than classic RCDP1. [from GeneReviews]

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. [from GeneReviews]

BBS9 is an autosomal recessive disorder characterized by obesity, polydactyly, renal anomalies, retinopathy, and mental retardation (Abu-Safieh et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900). [from OMIM]

Primary ciliary dyskinesia is an autosomal recessive disorder resulting from loss of normal ciliary function. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus, and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003). For a general description and a discussion of genetic heterogeneity of primary ciliary dyskinesia and Kartagener syndrome, see CILD1 (244400). [from OMIM]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years). [from GeneReviews]

OTOF-related deafness is characterized by two phenotypes: prelingual nonsyndromic auditory neuropathy spectrum disorder (ANSD) and, less frequently, temperature-sensitive auditory neuropathy spectrum disorder (TS-ANSD). OTOF-related ANSD is characterized by congenital or prelingual, typically severe-to-profound bilateral deafness without inner-ear anomalies on MRI or CT examination of the temporal bones. Otoacoustic emissions (OAEs) are present and auditory brain stem response is abnormal at birth. Newborn hearing screening testing of OAEs only will fail to detect this disorder in most individuals. OAEs may decrease or disappear with age in 20%-80% of individuals. TS-ANSD typically presents with normal-to-moderate hearing loss (0-55 dB) at baseline body temperature. An elevation of body temperature (approximately 0.5°C or more) triggers significant bilateral hearing loss ranging from severe to profound, with resolution of hearing loss typically occurring within hours of a return to baseline body temperature. [from GeneReviews]