MedGen

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]

Shprintzen-Goldberg syndrome (SGS) is characterized by: delayed motor and cognitive milestones and mild-to-moderate intellectual disability; craniosynostosis of the coronal, sagittal, or lambdoid sutures; distinctive craniofacial features; and musculoskeletal findings including olichostenomelia, arachnodactyly, camptodactyly, pectus excavatum or carinatum, scoliosis, joint hypermobility or contractures, pes planus, foot malposition, and C1-C2 spine malformation. Cardiovascular anomalies may include mitral valve prolapse, secundum atrial septal defect, and aortic root dilatation. Minimal subcutaneous fat, abdominal wall defects, and myopia are also characteristic findings. [from GeneReviews]

Pseudoachondroplasia is characterized by normal length at birth and normal facies. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, the growth rate falls below the standard growth curve by approximately age two years, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive; approximately 50% of individuals with pseudoachondroplasia eventually require hip replacement surgery. [from GeneReviews]

Nemaline myopathy-7 is an autosomal recessive congenital myopathy characterized by very early onset of hypotonia and delayed motor development. Affected individuals have difficulty walking and running due to proximal muscle weakness. The disorder is slowly progressive, and patients may lose independent ambulation. Muscle biopsy shows nemaline rods and may later show minicores, abnormal protein aggregates, and dystrophic changes (summary by Ockeloen et al., 2012). For a discussion of genetic heterogeneity of nemaline myopathy, see 161800. [from OMIM]

CHST3-related skeletal dysplasia is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect and vision are normal. [from GeneReviews]

Ehlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.

The various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were identified more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.

An unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.

Many people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.

Bleeding problems are common in the vascular type of Ehlers-Danlos syndrome and are caused by unpredictable tearing (rupture) of blood vessels and organs. These complications can lead to easy bruising, internal bleeding, a hole in the wall of the intestine (intestinal perforation), or stroke. During pregnancy, women with vascular Ehlers-Danlos syndrome may experience rupture of the uterus. Additional forms of Ehlers-Danlos syndrome that involve rupture of the blood vessels include the kyphoscoliotic, classical, and classical-like types.

Other types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums. [from MedlinePlus Genetics]

CTDP1-related congenital cataracts, facial dysmorphism, and neuropathy (CTDP1-CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils), mildly dysmorphic facial features apparent in late childhood, and a hypo-/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade of life. Secondary foot deformities and scoliosis are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild nonprogressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and most have subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Romani population. [from GeneReviews]

Meier-Gorlin syndrome-4 (MGORS4) is a rare autosomal recessive disorder with the hallmarks of short stature, small external ears, and reduced or absent patellae. Breast hypoplasia is present in females (Guernsey et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of Meier-Gorlin syndrome, see 224690. [from OMIM]

AP-4-associated hereditary spastic paraplegia (HSP), also known as AP-4 deficiency syndrome, is a group of neurodegenerative disorders characterized by a progressive, complex spastic paraplegia with onset typically in infancy or early childhood. Early-onset hypotonia evolves into progressive lower-extremity spasticity. The majority of children become nonambulatory and usually wheelchair bound. Over time spasticity progresses to involve the upper extremities, resulting in a spastic tetraplegia. Associated complications include dysphagia, contractures, foot deformities, dysregulation of bladder and bowel function, and a pseudobulbar affect. About 50% of affected individuals have seizures. Postnatal microcephaly (usually in the -2SD to -3SD range) is common. All have developmental delay. Speech development is significantly impaired and many affected individuals remain nonverbal. Intellectual disability in older children is usually moderate to severe. [from GeneReviews]

The Meier-Gorlin syndrome is a rare disorder characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (summary by Shalev and Hall, 2003). While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal (Bicknell et al., 2011). Genetic Heterogeneity of Meier-Gorlin Syndrome Most forms of Meier-Gorlin syndrome are autosomal recessive disorders, including Meier-Gorlin syndrome-1; Meier-Gorlin syndrome-2 (613800), caused by mutation in the ORC4 gene (603056) on chromosome 2q23; Meier-Gorlin syndrome-3 (613803), caused by mutation in the ORC6 gene (607213) on chromosome 16q11; Meier-Gorlin syndrome-4 (613804), caused by mutation in the CDT1 gene (605525) on chromosome 16q24; Meier-Gorlin syndrome-5 (613805), caused by mutation in the CDC6 gene (602627) on chromosome 17q21; Meier-Gorlin syndrome-7 (617063), caused by mutation in the CDC45L gene (603465) on chromosome 22q11; and Meier-Gorlin syndrome-8 (617564), caused by mutation in the MCM5 gene (602696) on chromosome 22q12. An autosomal dominant form of the disorder, Meier-Gorlin syndrome-6 (616835), is caused by mutation in the GMNN gene (602842) on chromosome 6p22. [from OMIM]

GLYT1 encephalopathy is characterized in neonates by severe hypotonia, respiratory failure requiring mechanical ventilation, and absent neonatal reflexes; encephalopathy, including impaired consciousness and unresponsiveness, may be present. Arthrogryposis or joint laxity can be observed. Generalized hypotonia develops later into axial hypotonia with limb hypertonicity and a startle-like response to vocal and visual stimuli which should not be confused with seizures. To date, three of the six affected children reported from three families died between ages two days and seven months; the oldest reported living child is severely globally impaired at age three years. Because of the limited number of affected individuals reported to date, the phenotype has not yet been completely described. [from GeneReviews]

Odontochondrodysplasia-1 (ODCD1) is characterized by mesomelic shortening of tubular bones, ligamentous laxity, and scoliosis, in association with dentinogenesis imperfecta involving both primary and secondary dentition. Affected individuals show variable severity. Radiologic features include trident pelvis, posteriorly flattened vertebrae, and brachydactyly with cone-shaped epiphyses (Maroteaux et al., 1996). Clinical variability and extraskeletal manifestations have been observed (Wehrle et al., 2019). Genetic Heterogeneity of Odontochondrodysplasia Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2; 619269) is caused by mutation in the TANGO1 gene (MIA3; 613455) on chromosome 1q41. [from OMIM]

The cardinal findings of Neuhauser syndrome, also known as MMR syndrome, are impaired intellectual development or developmental delay, megalocornea, hypotonia, prominent forehead, micrognathia, prominent nasal bridge, and thin upper lip or carp-like mouth (Naritomi et al., 1997). Reviews Gutierrez-Amavizca et al. (2013) reviewed published reports and tabulated the clinical features of 35 patients with Neuhauser syndrome. Primary megalocornea and psychomotor delay were present in all patients. Characteristics observed in more than half of patients included hypotonia, growth retardation, abnormal electroencephalography (EEG) and/or seizures, micro- or macrocephaly, brain malformations such as cerebral atrophy and hypoplastic corpus callosum, craniofacial dysmorphisms, cardiac anomalies, osteoarticular abnormalities, and refractive errors. Additional features found at low frequency included primary hypothyroidism, recurrent infections, feeding difficulties, cerebral hypomyelination, dyslipidemia, sensorineural deafness, laryngomalacia, large fleshy and cup-shaped ears, obesity, and cryptorchidism. The authors stated that the classification suggested by Verloes et al. (1993) did not seem to be applicable, and proposed that the diagnosis of Neuhauser syndrome should be made in the presence of intellectual disability and megalocornea in the absence of elevated intraocular pressure, with at least 1 minor feature from among those observed in more than half of patients. [from OMIM]

Leri pleonosteosis is an autosomal dominant skeletal disorder characterized by flexion contractures of the interphalangeal joints, limited movement of multiple joints, and short, broad metacarpals, metatarsals, and phalanges. Additional features may include chronic joint pain, short stature, bony overgrowths, spinal cord compression, scleroderma-like skin changes, and blepharophimosis. The clinical features overlap with several other musculoskeletal conditions, including Myhre syndrome (MYHRS; 139210) and geleophysic dysplasia (GPHYSD1; 231050) (summary by Banka et al., 2015). [from OMIM]

Neuroocular syndrome-1 (NOC1) 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). Genetic Heterogeneity of Neuroocular Syndrome See also NOC2 (168885), caused by mutation in the DAGLA gene (614015) on chromosome 11q12. [from OMIM]

Congenital disorder of deglycosylation-2 (CDDG2) is an autosomal recessive disorder with variable associated features such as dysmorphic facies, impaired intellectual development, and brain anomalies, including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis (Maia et al., 2022). For a discussion of genetic heterogeneity of congenital disorder of deglycosylation, see CDGG1 (615273). [from OMIM]

Autosomal recessive intellectual developmental disorder-81 (MRT81) is characterized by a variable neurobehavioral and neuromuscular phenotype (summary by Nair et al., 2021). [from OMIM]

An abnormally increased extension of the knee joint, so that the knee can bend backwards. [from HPO]