Incomplete penetrance and expressivity skewing in hereditary multiple exostoses

Hereditary multiple exostosis (EXT) is an autosomal dominant skeletal disorder characterized by the formation of cartilage-capped prominences developing from the juxta-epiphyseal regions of the long bones and causing orthopedic deformities and occasionally sarcomatous degeneration. Reviewing a large cohort of 175 EXT patients referred to us over the last 40 years (1955-1995), we found 109 familial forms (62%) and 66 isolated cases (38%). The disease is consistently diagnosed before the age of 12 years and the risk of malignancy, although increased, is quite modest in our series (0.57%). The observation of seven unaffected individuals (six females, one male) with a family history and affected offspring supports the incomplete penetrance of the disease. Moreover, the observation of an unequal sex-ratio with a preponderance of males among probands in this series (103:72, p<0.02) and in all series reported to date (198:133, p<0.001) gives support to the variable penetrance of EXT genes among sexes. Whether this incomplete penetrance is associated with one of the disease genes recently identified in EXT is currently under investigation.