Zankl et al. (2007) defined what they considered to be a continuous clinical spectrum involving Torg syndrome, Winchester syndrome (277950), and NAO syndrome. Torg syndrome is characterized by the presence of multiple, painless, subcutaneous nodules and mild to ... Zankl et al. (2007) defined what they considered to be a continuous clinical spectrum involving Torg syndrome, Winchester syndrome (277950), and NAO syndrome. 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.
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 ... 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). 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. 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.
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 diagnosed with ... 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 diagnosed with Winchester syndrome, Zankl et al. (2005) identified a homozygous mutation in the MMP2 gene (120360.0003), and in 2 sisters of Algerian origin reported by Lambert et al. (1989) as having Winchester syndrome, Rouzier et al. (2006) identified a homozygous in-frame deletion in the MMP2 gene (120360.0004). Evans et al. (2012) found no mutation in the MMP2 gene in one of the original patients with Winchester syndrome (Winchester et al., 1969) and instead identified a homozygous mutation in the MMP14 gene (600754.0001). Evans et al. (2012) stated that the patients reported by Zankl et al. (2005) and Rouzier et al. (2006) had MONA, not Winchester syndrome. 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.