Hereditary Multiple Exostoses: A Current Understanding of Clinical and Genetic Advances

Osteochondroma is the most common bone tumor seen in children [6,22,59]. This cartilage-capped exostosis is found primarily at the juxta-epiphyseal region of the most rapidly growing ends of long bones [59,78]. The true prevalence is not known since many patients with asymptomatic lesions are never diagnosed. A unique subset of patients, however, suffers from hereditary multiple exostosis (HME), an autosomal-dominant disorder manifested by multiple osteochondromas and frequently associated with characteristic progressive skeletal deformities. Recent advances in understanding the molecular and genetic basis of this condition not only offer hope for patients and families with HME, but also offer clues to the underlying basis for the formation of the human musculoskeletal system. Historically, John Hunter was perhaps the first to comment on the condition now known as HME. In 1786, he described a patient with multiple exostoses in his Lectures on the principles of surgery [37]. In 1814, Boyer published the first description of a family with HME, and this was followed by Guy’s description of a second family in 1825 [9,32]. Most of the clinical aspects of the disease had been described by the late 1800’s. HME was introduced into the American literature in 1915 by Ehrenfried. In 1943, Jaffe made a significant contribution by further elucidating the pathology of HME and helping to differentiate the disorder from Ollier’s disease [24,38]. As with HME, patients with Ollier’s disease have multiple, benign cartilaginous lesions of bone, but the lesions of Ollier’s disease are enchondromas, located within the tubular bones. The name “multiple exostoses” was given to the condition by Virchow in 1876 [92]. A number of synonyms have been used for this disorder including osteochondromatosis, multiple hereditary osteochondromata, multiple congenital osteochondromata, diaphyseal aclasis, chondral osteogenic dysplasia of direction, chondral osteoma, deforming chondrosysplasia, dyschondroplasia, exostosing disease, exostotic dysplasia, hereditary deforming chondrodysplasia, multiple osteomatoses, and osteogenic disease [24,35,59]. A related entity known as dysplasia epiphysealis hemimelica, or Trevor’s disease, is a rare disorder in which osteochondromas arise from an epiphysis [88]. HME is most frequently described in Caucasions and affects 0.9 to 2 individuals per 100,000; higher prevalences of the condition have been identified in isolated communities such as the Chamorros of Guam or the Ojibway Indian community of Pauingassi in Manitoba, Canada [6,35,42, 56,69,85,94]. These populations have a prevalence of 100 and 1310 per 100,000, respectively [6,42]. Although previously thought to have a male predominance [13,38,78], HME now appears to affect both sexes similarly [69,97].