Metachondromatosis

A number sign (#) is used with this entry because of evidence that metachondromatosis (METCDS) is caused by heterozygous mutation in the PTPN11 gene (176876) on chromosome 12q24.

Description

Metachondromatosis is characterized by exostoses (osteochondromas), commonly of the hands and feet, and enchondromas of long bone metaphyses and iliac crests (summary by Sobreira et al., 2010).

Clinical Features

Maroteaux (1971) described 2 families with skeletal radiologic features of both multiple exostoses (133700) and Ollier disease (166000). He called the disorder metachondromatosis and suggested autosomal dominant inheritance on the basis of 1 family with 5 affected persons.

Lachman et al. (1974) reported a case. Kennedy (1983) presented the case of a 9.5-year-old boy in whom 'bumps' on the hands, feet and knees had been noted at age 5. In the next few years, some of these enlarged, new ones appeared, and others regressed. Peculiar striations were noted radiologically in the metaphyses of the long bones and iliac crests. The mother had a similar although milder history; x-ray showed a single exostosis in the wrist. The maternal grandfather had had lesions of the hands, feet, and knees, but none was evident at the time of radiologic study. Two cousins were said to have similar lesions. Differentiation from multiple exostoses of the classic type (133700) is important because of the usual regression with little or minimal residual deformity. Involvement of the hands and feet is the rule in metachondromatosis but is said by Kennedy (1983) to be unusual in classic multiple exostoses. Furthermore, in metachondromatosis, the exostoses point toward the epiphysis.

Dorst (1983) observed metachondromatosis in a brother and sister of Korean extraction. The radiologic findings combined those of multiple exostoses, multiple enchondromatosis (Ollier disease), and dysplasia epiphysealis hemimelica (127800). No other affected relatives were known but the parents were not available for study.

In the family studied by Vanek (1982), the mother of 2 of the affected persons had a history of exostoses as a child, which regressed as she grew older. X-ray studies showed no peripheral exostoses but the proximal end of one humerus was wide and a first metatarsal was abnormally thin. A brother was said also to have had nodular growths near joints as a child.

Bassett and Cowell (1985) studied 4 members of a kindred that had at least 8 cases in all. They pointed out that the enchondromatous lesions involve the iliac crest and metaphyseal region of the long bones of the lower extremities as in Ollier disease. The exostoses of metachondromatosis, unlike those of hereditary multiple exostosis, point toward the nearby joint and do not cause shortening or bowing of the long bone, joint deformity, or subluxation. They affect particularly the digits and may resolve spontaneously.

Inheritance

Metachondromatosis is an autosomal dominant disorder with incomplete penetrance (Bowen et al., 2011).

Mapping

Sobreira et al. (2010) performed a genomewide scan in a 5-generation family segregating autosomal dominant metachondromatosis and identified 6 regions showing suggestive evidence for linkage, including chromosome 7p14.1 (maximum lod score, 2.5), 8q24.1, and 12q23 (lod score of 1.8 for both), and 2p25, 5q12.1, and 9q31.1-q33.1 (lod scores between 1.0 and 1.5).

Bowen et al. (2011) performed linkage analysis with high-density SNP arrays in a family with metachondromatosis and identified an 8.6-Mb interval on chromosome 12 that attained a maximum lod score of 2.7.

Molecular Genetics

Sobreira et al. (2010) performed whole-genome sequencing in 1 affected individual from a 5-generation family with metachondromatosis and identified a heterozygous 11-bp deletion in the PTPN11 gene (176876.0025); analysis of family members confirmed that the deletion segregated with the disease. Sequencing of the PTPN11 gene in another 3-generation family with autosomal dominant metachondromatosis revealed a heterozygous nonsense mutation (176876.0026) in affected individuals. Neither mutation was detected in 469 controls.

Bowen et al. (2011) used a targeted array to capture exons and promoter sequences from an 8.6-Mb linked interval in 16 participants from 11 metachondromatosis families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. They identified heterozygous putative loss-of-function mutations in the PTPN11 gene in 4 of the 11 families (176876.0028-176876.0031). Sanger sequence analysis of PTPN11 coding regions in the 7 remaining families and in 6 additional metachondromatosis families identified novel heterozygous mutations in 4 families (176876.0032-176876.0035). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an metachondromatosis patient with a 15-kb deletion spanning exon 7 of PTPN11 (176876.0036). In total, of 17 metachondromatosis families, Bowen et al. (2011) identified mutations in 11 (5 frameshift, 2 nonsense, 3 splice site, and 1 large deletion). Each family had a different mutation, and the mutations were scattered across the gene. Microdissected metachondromatosis lesions from 2 patients with PTPN11 mutations demonstrated loss of heterozygosity for the wildtype allele. Bowen et al. (2011) suggested that metachondromatosis may be genetically heterogeneous because 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations.