| #259600 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TORG-WINCHESTER SYNDROME | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TORG SYNDROME WINCHESTER SYNDROME NODULOSIS-ARTHROPATHY-OSTEOLYSIS SYNDROME NAO SYNDROME MULTICENTRIC OSTEOLYSIS, NODULOSIS, AND ARTHROPATHY; MONA AL-AQEEL SEWAIRI SYNDROME OSTEOLYSIS, HEREDITARY MULTICENTRIC | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because Torg-Winchester syndrome is caused by mutation in the gene encoding matrix metalloproteinase-2 (MMP2; 120360). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Torg-Winchester syndrome is an autosomal recessive multicentric osteolysis with predominant involvement of the hands and feet. The disorder was originally defined as 3 separate entities: Torg syndrome, Winchester syndrome, and NAO syndrome. The 2006 revision of the Nosology of Constitutional Disorders of Bone classified Torg and Winchester syndromes as a single entity with NAO syndrome as a variant (Superti-Furga and Unger, 2007). Zankl et al. (2007) defined the continuous clinical spectrum of Torg-Winchester syndrome based on its earlier designations. Torg syndrome is characterized by the presence of multiple, painless, subcutaneous nodules and mild to moderate osteoporosis and osteolysis that is usually limited to the hands and feet. Radiographically, the osteolysis is accompanied by a characteristic widening of the metacarpal and metatarsal bones. Winchester syndrome presents with severe osteolysis in the hands and feet and generalized osteoporosis and bone thinning, similar to NAO, but subcutaneous nodules are characteristically absent. Various additional features including coarse face, corneal opacities, gum hypertrophy, and EKG changes have been reported. NAO syndrome, which has only been described in patients from Saudi Arabia, is generally more severe, with multiple prominent and painful subcutaneous nodules, massive osteolysis in the hands and feet, and generalized osteoporosis. Coarse face and body hirsutism are additional features. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Among the offspring of double second cousins, Torg et al. (1969) described a novel skeletal disorder. In addition to collapse and resorption of the carpal and tarsal bones, there was osteoporosis, cortical thinning, and increased caliber of the tubular and long bones. Clinically, the disorder was characterized by fusiform enlargement of the digits and flexion contractures of the knees, hip, and elbows. The radiologic features mentioned distinguish the disorder from the autosomal dominant form of hereditary osteolysis (166300). Sauvegrain et al. (1981) described what appeared to be the same disorder in 4 members of a family. Eisenstein et al. (1998) described a single case of a 9-year-old girl who initially presented at age 4 years with evidence of arthritis in her hands, feet, and large joints. Although she had a partial response to antiinflammatory medications and had some laboratory results consistent with inflammatory disease, radiographs showed carpal and tarsal osteolysis associated with interphalangeal joint erosions. There was also widening of the shafts of the metacarpals and metatarsals with thinning of the cortices. Based on both the clinical progression of her illness and the radiologic characteristics, the diagnosis of Torg osteolysis was proposed by Eisenstein et al. (1998). In 2 daughters of first-cousin Puerto Rican parents, Winchester et al. (1969) described a syndrome characterized by short stature, severe joint contractures, peripheral corneal opacities, coarsened facies, dissolution of carpal and tarsal bones, and generalized osteoporosis. Changes in and about joints simulated advanced rheumatoid arthritis. Urinary mucopolysaccharide excretion was normal, but cultured skin fibroblasts showed metachromasia and increased uronic acid. Fibroblasts from the parents showed intermediate levels. Brown and Kuwabara (1970) described electron microscopic findings in a corneal biopsy from 1 of the patients reported by Winchester et al. (1969). Together with reported fibroblast studies, the authors concluded that Winchester syndrome is a mucopolysaccharide storage disease. Hollister et al. (1974) studied a Mexican family with 3 affected persons in 2 sibships related as first cousins and each apparently with consanguineous parents. On the basis of electron microscopic studies, they concluded that Winchester syndrome was a nonlysosomal connective tissue disease. Irani et al. (1978) reported a male case, the offspring of first cousins. Dunger et al. (1987) reported 2 unrelated patients with Winchester syndrome. Gum and skin biopsies from 1 patient showed active phagocytosis, an active endoplasmic reticulum, and an abundance of fibrillogranular material consistent with excessive collagen turnover. Both patients had increased urinary oligosaccharide excretion. Lambert et al. (1989) reported 2 affected French sisters, born of consanguineous parents originating from Algeria. Rouzier et al. (2006) provided a detailed clinical history and follow-up of the sisters. At age 3 years, the older sister developed painful contracture of the left fifth finger with a progressive extension to other fingers. Later, she presented with flexion contracture of the wrists, elbows, and shoulders. Lower limbs were also affected in a distal-to-proximal manner, and she was wheelchair-bound by age 10 years. Other features included a shortened trunk, coarse facial features, and thickened skin with hypertrichosis on the anterior sides of the legs and ankles. The younger sister had earlier onset at age 6 months and a more severe course. Reexamination of the sisters at ages 35 and 24 years, respectively, showed short stature, increased weight, flexion contractures of the large joints, kyphosis, and very small hands and feet. The skin was thin, and hypertrichosis in the older sister had disappeared. There were no cataracts and intellectual development was normal. Radiographic examination showed obvious progression of osteopenia with generalized cortical thinning, progressive osteolysis of the carpal and tarsal bones, resorptive deformities of the phalanges, and destruction of the interphalangeal and metacarpophalangeal joints. Other radiographic features included slender metatarsal diaphyses, ankylosed knee joints, incurved diaphyses of the femur and fibula, misshapen pelvis, marked excavation of the acetabulum, erosions of the articular surfaces of the hip joint, and biconcave aspect of the vertebral bodies and scoliosis. Winter (1989) provided a review of Winchester syndrome. Zankl et al. (2005) reported an affected child born of consanguineous parents from southern Italy. After a healthy first year of life, the child's height and weight fell below the third percentile. During the second year of life, she developed degenerative changes in the fingers which extended rapidly to other joints, confining her to a wheelchair at age 3 years. During childhood, she developed type I diabetes mellitus (see 222100) and hypothyroidism. Despite her disabilities, she showed normal mental development and attended a regular school. Clinical examination at age 21 years showed a woman of very short stature, low weight (16 kg), and marked brachydactyly of the hands and feet. She had mild coarse facial features, generalized hypertrichosis, and a serpiginous, erythematous skin lesion on the neck. Subcutaneous nodules were not present. Radiologic evaluation showed severe generalized osteoporosis and osteolytic changes, particularly in the hands and feet. Zankl et al. (2005) considered the absence of subcutaneous nodules to be consistent with Winchester syndrome. The authors noted that the endocrine abnormalities had not previously been reported in association with Winchester syndrome and may be fortuitous, especially as there was a family history for thyroid disease. Al-Mayouf et al. (2000) studied 10 patients (6 females and 4 males) from 6 unrelated families in Saudi Arabia with an autosomal recessive disorder characterized by simultaneous presentation of nodulosis, arthropathy, and osteolysis. All 10 patients had nodulosis and distal arthropathy. Eight of them presented with deformed hands and 4 with painful hands. The parents were first cousins in all cases, and 3 families had more than 1 affected child. Osteopenia and undertubulation of bones, distally more than proximally, and upper limbs affected more often than lower limbs, were found in all patients. Osteolysis was seen in carpal and tarsal bones. Other common findings were sclerotic cranial sutures, brachycephaly, and broad medial ends of the clavicles. Al-Aqeel et al. (2000) also studied a consanguineous Saudi Arabian family in which 2 affected sibs with facial anomalies and short stature displayed a distal arthropathy of the metacarpal, metatarsal, and interphalangeal joints starting in the first few months of life. The arthropathy eventually progressed to the proximal joints, resulting in crippling ankylosis and severe generalized osteopenia in both sibs. Facial changes included proptosis, a narrow nasal bridge, bulbous nose, and micrognathia. In addition, they had large, painful fibrocollagenous palmar and plantar pads and mild body hirsutism. Affected individuals were of normal intelligence and had normal renal function. Although Al-Aqeel et al. (2000) suggested that this form of multicentric osteolysis with autosomal recessive inheritance closely resembled the Torg osteolysis syndrome, a unique facial appearance, fibrocollagenous pads, and body hirsutism were not noted in the original description of Torg osteolysis syndrome. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Martignetti et al. (2001) mapped the NAO syndrome disease locus to chromosome 16q12-q21 by using members of families studied by Al-Aqeel et al. (2000) and Al-Mayouf et al. (2000) for a genomewide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spanned the gene encoding matrix metalloproteinase-2 (MMP2; 120360), also known as gelatinase A and collagenase type IV. They found no MMP2 enzymatic activity in serum or fibroblasts of affected family members. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In the families with NAO syndrome studied by Al-Aqeel et al. (2000) and Al-Mayouf et al. (2000), Martignetti et al. (2001) identified different family-specific homoallelic MMP2 mutations (120360.0001 and 120360.0002). In an Italian patient with Winchester syndrome, Zankl et al. (2005) identified a homozygous mutation in the MMP2 gene (120360.0003). In 2 sisters of Algerian origin with Winchester syndrome, originally reported by Lambert et al. (1989), Rouzier et al. (2006) identified a homozygous in-frame deletion in the MMP2 gene (120360.0004). In the patient with Torg syndrome reported by Eisenstein et al. (1998), Zankl et al. (2007) identified compound heterozygosity for mutations in the MMP2 gene (120360.0001 and 120360.0005). Gelatin zymography indicated complete loss of MMP activity in this patient. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mosig et al. (2007) generated Mmp2 -/- mice and observed attenuated features of human multicentric osteolysis with arthritis, including progressive loss of bone mineral density, articular cartilage destruction, and abnormal long bone and craniofacial development. These changes were associated with marked and developmentally restricted decreases in osteoblast and osteoclast numbers in vivo. Mmp2 -/- mice had approximately 50% fewer osteoblasts and osteoclasts than control littermates at 4 days of life, but these differences were nearly resolved by 4 weeks of age. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Al-Aqeel (2005); Hollister et al. (1973) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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