MedGen

Homocystinuria caused by cystathionine ß-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). All four ? or only one ? of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant. Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6-non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis. [from GeneReviews]

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. [from GeneReviews]

FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population. [from GeneReviews]

Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease. [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]

Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Variable phenotypic expression of Stickler syndrome occurs both within and among families; interfamilial variability is in part explained by locus and allelic heterogeneity. [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]

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]

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]

Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation. [from GeneReviews]

Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones. [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]

Coffin-Lowry syndrome (CLS) is usually characterized by severe-to-profound intellectual disability in males; less severely impaired individuals have been reported. Neuropsychiatric concerns can include behavioral problems, loss of strength, progressive spasticity or paraplegia, sleep apnea, or stroke. Stimulus-induced drop attacks (SIDAs) in which unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness are present in approximately 20% of affected individuals. Typically SIDAs begin between mid-childhood and the teens. Characteristic facial features may be more apparent with age. Upper-extremity differences may be subtle and include short, soft, fleshy hands with tapered fingers as well as fleshy forearms. Progressive kyphoscoliosis is one of the most difficult aspects of long-term care. Affected females tend to have intellectual disability in the mild-to-moderate range and may also have the typical facial, hand, and skeletal findings noted in males. [from GeneReviews]

Classic Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft and doughy to the touch, and hyperextensible, extending easily and snapping back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Mitral valve prolapse can occur infrequently, but tends to be of little clinical consequence. Aortic root dilatation has been reported, appears to be more common in young individuals, and rarely progresses. [from GeneReviews]

Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN2A), and MEN2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN2A and MEN2B involve an increased risk for pheochromocytoma; MEN2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN2B, early adulthood in MEN2A, and middle age in FMTC. [from GeneReviews]

Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML. [from GeneReviews]

Mowat-Wilson syndrome (MWS) is characterized by distinctive facial features (widely spaced eyes, broad eyebrows with a medial flare, low-hanging columella, prominent or pointed chin, open-mouth expression, and uplifted earlobes with a central depression), congenital heart defects with predilection for abnormalities of the pulmonary arteries and/or valves, Hirschsprung disease or chronic constipation, genitourinary anomalies (particularly hypospadias in males), and hypogenesis or agenesis of the corpus callosum. Most affected individuals have moderate-to-severe intellectual disability. Speech is typically limited to a few words or is absent, with relative preservation of receptive language skills. Growth restriction with microcephaly and seizure disorder are also common. Most affected people have a happy demeanor and a wide-based gait that can sometimes be confused with Angelman syndrome. [from GeneReviews]

Aarskog-Scott syndrome is a genetic disorder that affects the development of many parts of the body, most commonly the head and face, the hands and feet, and the genitals and urinary system (genitourinary tract). This condition mainly affects males, although females may have mild features of the syndrome.

People with Aarskog-Scott syndrome often have distinctive facial features, such as widely spaced eyes (hypertelorism), a small nose, a long area between the nose and mouth (philtrum), and a widow's peak hairline. They frequently have mild to moderate short stature during childhood, but their growth usually catches up with that of their peers during puberty. Hand abnormalities are common in this syndrome and include short fingers (brachydactyly), curved pinky fingers (fifth finger clinodactyly), webbing of the skin between some fingers (cutaneous syndactyly), and a single crease across the palm. Affected individuals can also have wide, flat feet with broad, rounded toes. Other abnormalities in people with Aarskog-Scott syndrome include heart defects and a split in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate).

Most males with Aarskog-Scott syndrome have a shawl scrotum, in which the scrotum surrounds the penis instead of hanging below. Less often, they have undescended testes (cryptorchidism) or a soft out-pouching around the belly-button (umbilical hernia) or in the lower abdomen (inguinal hernia).

The intellectual development of people with Aarskog-Scott syndrome varies widely. Most individuals with Aarskog-Scott syndrome have normal intelligence; however, some may have mild learning and behavior problems, and in rare cases, severe intellectual disability has been reported. [from MedlinePlus Genetics]

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]

The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata. [from GeneReviews]