Hereditary multiple exostoses is an autosomal dominant disorder characterized by multiple exostoses most commonly arising from the juxtaepiphyseal region of the long bones.
Francannet et al. (2001) identified mutations in 36 of the 38 families linked to EXT1 or EXT2. No mutations were found in 2 EXT1-linked families. Nine of the mutations occurred in the EXT2 gene. A severe phenotype ('S') ... Francannet et al. (2001) identified mutations in 36 of the 38 families linked to EXT1 or EXT2. No mutations were found in 2 EXT1-linked families. Nine of the mutations occurred in the EXT2 gene. A severe phenotype ('S') was shown to be significantly associated with EXT1 mutations, whereas a moderate phenotype ('M') was associated with EXT2 mutations. One subgroup of the S phenotype, IS (10 to 25 exostoses, no vertebral exostoses, height below the 10th centile), was associated with mutations in EXT1 or EXT2. Mutations associated with another S subgroup, IVS (very short stature), were located in exon 1 of EXT1. Chondrosarcomas were found only in patients with EXT1 mutations. In 7 patients with EXT1 mutations and 16 patients with EXT2 mutations, Alvarez et al. (2006) analyzed the anatomic burden of disease by clinical and radiographic examination and evaluation of 76 phenotypic parameters. Patients with EXT1 mutation were found to have more exostoses, more limb malalignment with shorter limb segments and height, and more pelvic and flatbone involvement. Heinritz et al. (2009) identified 9 different mutations in the EXT2 gene in 11 of 23 German patients with multiple exostoses. Eleven other patients had mutations in the EXT1 gene; 1 patient had no detectable mutations. Among the EXT2 mutations, there were 3 recurrent mutations, Q172X (608210.0002), D227N (608210.0004), and Q258X (608210.0006), and 6 novel mutations (see, e.g., 608210.0007). Multiple splice site defects were identified. Although clinical details were limited, those with EXT1 mutations tended to have a more severe phenotype.
In a family with multiple exostoses, Stickens et al. (1996) identified a 4-bp deletion in the EXT2 gene (608210.0001), resulting in a premature stop codon and truncated gene product. Stickens et al. (1996) speculated that a second mutation ... In a family with multiple exostoses, Stickens et al. (1996) identified a 4-bp deletion in the EXT2 gene (608210.0001), resulting in a premature stop codon and truncated gene product. Stickens et al. (1996) speculated that a second mutation event was necessary for the development of exostoses, thus accounting for the asymmetry of exostoses observed in the long bones. In 2 families with multiple exostoses, Wuyts et al. (1996) identified 2 different mutations in the EXT2 gene: a nonsense mutation (608210.0002) and a splice site mutation (608210.0003). In 5 of 17 (29%) families with hereditary multiple exostoses, Philippe et al. (1997) identified 4 mutations in the EXT2 gene, including a missense mutation (608210.0004) and 3 alterations that resulted in premature stop codons. Seven (41%) of the families had mutations in the EXT1 gene. Of 26 EXT families originating from 9 countries, Wuyts et al. (1998) found that 10 families had an EXT1 mutation and 10 had an EXT2 mutation. Twelve of these mutations had not previously been described. From a review of these and previously reported mutations, Wuyts et al. (1998) concluded that mutations in either the EXT1 or the EXT2 gene are responsible for most cases of multiple exostoses. Most of the mutations in these 2 genes cause premature termination of the EXT proteins, whereas missense mutations are rare. The authors concluded that the development of exostoses is mainly due to loss of function of EXT genes, consistent with the hypothesis that the EXT genes have a tumor suppressor function. Wuyts and Van Hul (2000) stated that 49 different EXT1 and 25 different EXT2 mutations had been identified in patients with multiple exostoses, and that mutations in these 2 genes were responsible for over 70% of the EXT cases.