MedGen

Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies. [from GeneReviews]

Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – are most often present in those children ascertained without a major complication. [from GeneReviews]

While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults. [from GeneReviews]

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palatal abnormalities); and commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma. [from GeneReviews]

Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic craniofacial features are downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect. Additional features include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryptorchidism, feeding problems, recurrent infections, and severe constipation. [from GeneReviews]

Nail-patella syndrome (NPS) (previously referred to as Fong's disease), encompasses the classic clinical tetrad of changes in the nails, knees, and elbows, and the presence of iliac horns. Nail changes are the most constant feature of NPS. Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored; separated into two halves by a longitudinal cleft or ridge of skin; and thin or (less often) thickened. The patellae may be small, irregularly shaped, or absent. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. Renal involvement, first manifest as proteinuria with or without hematuria, occurs in 30%-50% of affected individuals; end-stage renal disease occurs up to 15% of affected individuals. Primary open-angle glaucoma and ocular hypertension occur at increased frequency and at a younger age than in the general population. [from GeneReviews]

Campomelic dysplasia (CD) is a skeletal dysplasia characterized by distinctive facies, Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and clubfeet. Other findings include laryngotracheomalacia with respiratory compromise and ambiguous genitalia or normal female external genitalia in most individuals with a 46,XY karyotype. Many affected infants die in the neonatal period; additional findings identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive scoliosis, and hearing impairment. [from GeneReviews]

GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß. [from GeneReviews]

Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth. [from GeneReviews]

Wolf-Hirschhorn syndrome is a congenital malformation syndrome characterized by pre- and postnatal growth deficiency, developmental disability of variable degree, characteristic craniofacial features ('Greek warrior helmet' appearance of the nose, high forehead, prominent glabella, hypertelorism, high-arched eyebrows, protruding eyes, epicanthal folds, short philtrum, distinct mouth with downturned corners, and micrognathia), and a seizure disorder (Battaglia et al., 2008). [from OMIM]

GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, and autonomic disturbances generally do not occur. [from GeneReviews]

Diastrophic dysplasia (DTD) is characterized by limb shortening, normal-sized head, hitchhiker thumbs, spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and contractures of the large joints with deformities and early-onset osteoarthritis. Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. On occasion, the disease can be lethal at birth, but most affected individuals survive the neonatal period and develop physical limitations with normal intelligence. [from GeneReviews]

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. [from GeneReviews]

Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur. [from GeneReviews]

The clinical manifestations of glycogen storage disease type IV (GSD IV) discussed in this entry span a continuum of different subtypes with variable ages of onset, severity, and clinical features. Clinical findings vary extensively both within and between families. The fatal perinatal neuromuscular subtype presents in utero with fetal akinesia deformation sequence, including decreased fetal movements, polyhydramnios, and fetal hydrops. Death usually occurs in the neonatal period. The congenital neuromuscular subtype presents in the newborn period with profound hypotonia, respiratory distress, and dilated cardiomyopathy. Death usually occurs in early infancy. Infants with the classic (progressive) hepatic subtype may appear normal at birth, but rapidly develop failure to thrive; hepatomegaly, liver dysfunction, and progressive liver cirrhosis; hypotonia; and cardiomyopathy. Without liver transplantation, death from liver failure usually occurs by age five years. Children with the non-progressive hepatic subtype tend to present with hepatomegaly, liver dysfunction, myopathy, and hypotonia; however, they are likely to survive without progression of the liver disease and may not show cardiac, skeletal muscle, or neurologic involvement. The childhood neuromuscular subtype is rare and the course is variable, ranging from onset in the second decade with a mild disease course to a more severe, progressive course resulting in death in the third decade. [from GeneReviews]

Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (summary by Ruiz-Perez et al., 2000). The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (604831) or in the EVC2 gene (607261) (Ruiz-Perez et al., 2003, Galdzicka et al., 2002). [from OMIM]

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. [from GeneReviews]

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord. [from GeneReviews]

L1 syndrome involves a phenotypic spectrum ranging from severe to mild and includes three clinical phenotypes: X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS). MASA (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) syndrome including X-linked complicated hereditary spastic paraplegia type 1. X-linked complicated corpus callosum agenesis. Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay; intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). It is important to note that all phenotypes can be observed in affected individuals within the same family. [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]