Weedon et al. (2008) listed GDF5 as the nearby candidate gene implicated by this SNP, based on the knockout mouse phenotype, associated monogenic human syndromes caused by mutations, and its role in bone formation.
Auditory neuropathy may accompany peripheral neuropathy in a variety of dominant syndromes such as Charcot-Marie-Tooth disease (Satya-Murti et al., 1979) and has been observed in Friedreich ataxia (Satya-Murti et al., 1980).
Mapping The prevalences of coronary heart disease (CHD), type II diabetes (NIDDM; 125853), and the metabolic syndrome (605552) in Mauritius are among the highest in the world.
Differential diagnosis Differential diagnosis includes generalized lymphatic anomaly (the major distinguishing characteristic is the progressive osteolysis seen in GSD), acroosteolysis dominant type, multicentric carpo-tarsal osteolysis with or without nephropathy, autosomal recessive carpotarsal osteolysis, hereditary sensory and autonomic neuropathy type 2, Farber lipogranulomatosis, Torg-Winchester syndrome, and idiopathic phalangeal acro-osteolysis (see these terms).
Gorham's disease is a rare bone disorder characterized by bone loss (osteolysis), often associated abnormal blood vessel growth (angiomatous proliferation). Bone loss can occur in just one bone, or spread to soft tissue and adjacent bones. Symtoms may include pain, swelling, and increased risk of fracture. It may affect any part of the skeleton, but most commonly involves the skull, collarbone (clavicle), pelvis, ribs, spine, and/or jaw. Depending on the bones affected, various complications may occur. The cause of Gorham's disease is currently unknown. Most cases occur sporadically . Treatment is based on the signs and symptoms in each affected person, and most commonly involves surgery and/or radiation therapy.
Reid et al. (1989) described a family in which 12 persons in 4 generations had diffuse cystic angiomatosis of bone. The affected individuals were asymptomatic. Roentgenographically, the lesions occurred throughout the length of long bones and were osteolytic, with a thin sclerotic rim. The cortex of the bone was rarely involved and showed no periosteal reaction. Growth plate closure and remodeling were unaffected. With age, increasing sclerosis occurred, resulting in complete obliteration of the cyst with irregular reactive trabeculations. Five of the affected individuals were female. There were several examples of male-to-male transmission.
These individuals are said to have moyamoya syndrome. Frequency Moyamoya disease was first identified in Japan, where it is most prevalent, affecting about 5 in 100,000 individuals.
Description Dermochondrocorneal dystrophy, or Francois syndrome, is a rare disorder characterized by the development of skin nodules, acquired deformities of the extremities, and a corneal dystrophy.
Dermochondrocorneal dystrophy is characterised by osteochondrodystrophy of the hands and feet, corneal dystrophy and the presence of skin nodules clustered around the metacarpophalangeal and interphalangeal joints, around the nose and ears and on the posterior surface of the elbow. Gingival lesions may also be present. It has been described in less than 20 patients. Transmission is autosomal recessive.
Mapping On the basis of 13 clinically heterogeneous SMA families, Brzustowicz et al. (1990) concluded that 'chronic' childhood-onset SMA (including intermediate SMA, or SMA type II, and Kugelberg-Welander syndrome, or SMA type III) is genetically homogeneous, mapping to chromosomal region 5q11.2-q13.3.
Spinal muscular atrophy type 2 (SMA2) is a genetic neuromuscular disorder that affects the nerve cells that control voluntary muscles (motor neurons). Without treatment, progressive muscle weakness develops in babies with SMA2 between ages 6 and 12 months. Babies with SMA2 can sit without support, however, they cannot stand or walk independently. Feeding and breathing problems also develop. SMA2 is caused by changes (pathogenic variants also called mutations) in the SMN1 gene and is inherited in an autosomal recessive manner. Diagnosis of SMA2 is suspected by symptoms and confirmed by genetic testing.
Most patients report a prodromal 'flu-like' illness preceding the overt vasculitic syndrome. Pauci-immune GN can occur as a renal-limited disease or as a component of systemic vasculitis.
In the neonatal period also herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, and staphylococcal scalded skin syndrome (see these terms) may need to be considered.
Recessive dystrophic epidermolysis bullosa inversa (RDEB-I) is rare subtype of dystrophic epidermolysis bullosa (DEB, see this term) characterized by blisters and erosions which are primarily confined to intertriginous skin sites, the base of the neck, the uppermost back, and the lumbosacral area. Epidemiology Less than 100 cases have been reported to date. Clinical description The disease manifests at birth or shortly thereafter with generalized blistering and superficial erosions that heal with atrophic scarring and milia formation. After the first years of life, blistering tends to localize to folds, particularly axillae, inframammary folds and the groin, as well as to the base of the neck, the uppermost back, and the lumbosacral and perianal area. Nail dystrophy is typical but of variable severity. Lesions of the oral cavity are always present and can lead to microglossia (loss of lingual papillae and fusion of the tongue to the mouth floor) and ankyloglossia (obliteration of the oral vestibules and progressive restriction of oral aperture). Esophageal involvement is often severe and is associated with a risk of esophageal stricture (10% and 90% by ages 5 and 30, respectively) that can impair intake of nutrients.
One patient had skin missing from the left thumb and both feet at birth, showing phenotypic overlap with Bart syndrome (132000). Obligate heterozygous parents were clinically unaffected.
Severe generalized recessive dystrophic epidermolysis bullosa is the most severe types of dystrophic epidermolysis bullosa. The signs and symptoms of this condition involve widespread blistering that can lead to vision loss, disfigurement, and other serious medical problems. As the blisters heal, they result in severe scarring. Scarring in the mouth and esophagus can make it difficult to eat food, leading to poor nutrition and slow growth. Additionally, individuals with this condition have a very high risk of developing a form of skin cancer called squamous cell carcinoma, which tends to be unusually aggressive and is often life-threatening. Severe generalized recessive dystrophic epidermolysis bullosa is caused by mutations in the COL7A1 gene and is inherited in an autosomal recessive pattern.
Initially, PFIC2 was reported under the name Byler syndrome. Epidemiology Estimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000.
Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare condition that affects the liver. People with this condition generally develop signs and symptoms during infancy, which may include severe itching, jaundice, failure to thrive , portal hypertension (high blood pressure in the vein that provides blood to the liver) and hepatosplenomegaly (enlarged liver and spleen). PFIC2 generally progresses to liver failure in the first few years of life. Affected people also have an increased risk of developing hepatocellular carcinoma (a form of liver cancer). PFIC2 is caused by change (mutations) in the ABCB11 gene and is inherited in an autosomal recessive manner.
A number sign (#) is used with this entry because benign recurrent intrahepatic cholestasis-2 (BRIC2) is caused by mutation in the ABCB11 gene (603201), also known as the bile salt export pump (BSEP), on chromosome 2q31. For a discussion of genetic heterogeneity of BRIC, see 243300. Description Benign recurrent intrahepatic cholestasis is characterized by intermittent episodes of cholestasis without progression to liver failure. The cholestatic attacks vary in severity and duration and patients are asymptomatic between episodes, both clinically and biochemically (van Mil et al., 2004). Clinical Features Van Mil et al. (2004) reported clinical features of 11 patients from 8 families with BRIC2 confirmed by genetic analysis. Inheritance followed an autosomal recessive pattern. Age at onset ranged from 2 months to 24 years.
In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007).
Mothers may develop massive anasarca, hypertension, and proteinuria (described as mirror syndrome). Death of the fetus is due to pulmonary hypoplasia and heart failure.
Differential diagnosis Differential diagnosis of PMF includes other closely related myeloid neoplasms, such as chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, myelodysplastic syndromes, chronic myelomonocytic leukemia, acute panmyelosis with myelofibrosis and acute megakaryoblastic leukemia.
A number sign (#) is used with this entry because of evidence that many cases of myelofibrosis are associated with a somatic mutation in the JAK2 gene (147796) on chromosome 9p, somatic mutation in the MPL gene (159530) on 1p34, or somatic mutation in the CALR gene (109091) on chromosome 19p13. Somatic mutations in the TET2 gene (612839), the ASXL1 gene (612990), the SH2B3 gene (605093), the SF3B1 gene (605590), and the NFE2 gene (601490) have also been found in cases of myelofibrosis. Clinical Features Sieff and Malleson (1980) described a brother and sister who developed fulminant fatal myeloproliferative disease at 7 and 8 weeks of age. The bone marrow showed reduced hemopoiesis with generalized fibrosis. Although clinically resembling familial hemophagocytic reticulosis, the disorder did not show the characteristic hemophagocytosis as a prominent feature.
Primary myelofibrosis is a condition characterized by the buildup of scar tissue (fibrosis) in the spongy tissue tissue inside the bone (bone marrow), the tissue that contains the stem cells that will produce blood cells. Because of the fibrosis, the bone marrow is unable to make enough normal blood cells. In myelofibrosis, the bone marrow is replaced by fibrous (scar) tissue. When the bone marrow is scarred, it cannot make enough blood cells. This leads to anemia, weakness, fatigue, and often, swelling of the liver and spleen. The disorder occurs when blood stem cells develop somatic mutations in the JAK2 , MPL , CALR , and TET2 genes.
Differential diagnosis Differential diagnoses include Hurler syndrome; GM1 gangliosidosis type 1; the infantile form of galactosialidosis; sialidosis type 2; free sialic acid storage disease, infantile form; hypocalcemic rickets; and ML III.
Mucolipidosis II alpha/beta (also known as I-cell disease) is a progressively debilitating disorder that affects many parts of the body. Most affected individuals do not survive past early childhood. At birth, children with mucolipidosis II alpha/beta are small and have weak muscle tone (hypotonia) and a weak cry. Affected individuals grow slowly after birth and usually stop growing during the second year of life. Development is delayed, particularly the development of speech and motor skills such as sitting and standing. Children with mucolipidosis II alpha/beta typically have several bone abnormalities, many of which are present at birth.
A number sign (#) is used with this entry because of evidence that mucolipidosis II alpha/beta, also known as I-cell disease, is caused by homozygous or compound heterozygous mutation in the GNPTAB gene (607840). Mucolipidosis III alpha/beta (252600), or pseudo-Hurler polydystrophy, is also caused by mutation in the GNPTAB gene. A mucolipidosis variant called mucolipidosis III gamma (252605) is caused by mutations in the GNPTG gene (607838). Nomenclature Cathey et al. (2008) reported an updated nomenclature classification system for mucolipidosis II and III. ML II was renamed ML II alpha/beta; ML IIIA was renamed ML III alpha/beta; and ML IIIC was renamed ML III gamma.
Mucolipidosis II (ML II), also known as I cell disease, is a rare and progressive metabolic disorder that involves our body’s ability to break down certain fats ( mucolipids) . Symptoms typically present in infancy or early childhood and include weak muscle tone (hypotonia), developmental delay, limited mobility, clubfeet , thickened skin, and short hands and fingers. ML II can also cause heart valve abnormalities and repeated respiratory infections. This reduces the individual’s ability to breathe effectively and typically results in death by early adolescence. ML II is caused by mutation in the GNPTAB gene, and is inherited in an autosomal recessive manner.
In the neonatal period, aplasia cutis congenita, herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, linear IgA bullous dermatosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, bullous impetigo, and staphylococcal scalded skin syndrome (see these terms) may need to be considered.
Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a disorder that affects several parts of the eyes, including the clear gel that fills the eye (the vitreous), the light-sensitive tissue that lines the back of the eye (the retina ), and the network of blood vessels within the retina (the choroid). The eye abnormalities in ADVIRC can lead to varying degrees of vision impairment, from mild reduction to complete loss, although some people with the condition have normal vision. The signs and symptoms of ADVIRC vary, even among members of the same family. Many affected individuals have microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved. The area behind the cornea can also be abnormally small, which is described as a shallow anterior chamber.
DA1 is the second most frequent type of DA, after DA2B (Sheldon-Hall syndrome). However, the overlap between the two conditions favors a similar frequency of the two forms.
Distal arthrogryposis type 1 is a disorder characterized by joint deformities (contractures) that restrict movement in the hands and feet. The term "arthrogryposis" comes from the Greek words for joint (arthro-) and crooked or hooked (gryposis). The characteristic features of this condition include permanently bent fingers and toes (camptodactyly ), overlapping fingers , and a hand deformity in which all of the fingers are angled outward toward the fifth finger (ulnar deviation ). Clubfoot , which is an inward- and upward-turning foot, is also commonly seen with distal arthrogryposis type 1. The specific hand and foot abnormalities vary among affected individuals.