Winchester Syndrome

A number sign (#) is used with this entry because of evidence that Winchester syndrome (WNCHRS) is caused by homozygous mutation in the MMP14 gene (600754) on chromosome 14q11. One such family has been reported.

Description

Winchester syndrome presents with severe osteolysis in the hands and feet and generalized osteoporosis and bone thinning, similar to multicentric osteolysis, nodulosis, and arthropathy (MONA; 259600), but subcutaneous nodules are characteristically absent. Various additional features including coarse face, corneal opacities, gum hypertrophy, and EKG changes have been reported (summary by Zankl et al., 2007).

Clinical Features

In 2 daughters of first-cousin Puerto Rican parents, Winchester et al. (1969) described a new 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 was 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.

Winter (1989) provided a review of Winchester syndrome.

Molecular Genetics

Evans et al. (2012) sequenced the MMP2 gene (120360) in 1 of the probands reported by Winchester et al. (1969) and found no mutations. Because of the similarity of the phenotype to that of Mmp14-null mice, they sequenced the MMP14 gene and identified a homozygous missense mutation (T17R; 600754.0001). Functional studies showed that the T17R mutation resulted in decreased amount of the active form of MMP14, although mRNA levels were unchanged.

History

In 2 sisters originally reported by Lambert et al. (1989) as having Winchester syndrome, Rouzier et al. (2006) identified a homozygous mutation in the MMP2 gene (120360.0004), and in an Italian patient diagnosed with Winchester syndrome, Zankl et al. (2005) identified a different homozygous mutation in the MMP2 gene (120360.0003). Based on their finding a mutation in the MMP14 gene in one of the original patients reported by Winchester et al. (1969), Evans et al. (2012) stated that the patients reported by Rouzier et al. (2006) and Zankl et al. (2005) had been misdiagnosed and actually had MONA (259600).

When Winchester syndrome was thought to be allelic to MONA and Torg osteolysis, Zankl et al. (2007) had suggested that they be viewed as a continuous clinical spectrum.