A Genotype-Phenotype Study of Multiple Hereditary Exostoses in Forty-Three Patients.

Multiple hereditary exostoses (MHE) is a rare autosomal dominant skeletal disorder with a variety of clinical manifestations. We aimed to evaluate the general clinical phenotypic severity of MHE using our own scoring system and analyzed the risk factors associated with severe clinical phenotypes. In this study, 43 patients from 30 families were analyzed. The mutations were identified by direct sequencing of polymerase chain reaction-amplified genomic DNA or by multiplex ligation-dependent probe amplification. According to a new scoring system devised by the authors, the severity of the phenotype was assessed as mild, moderate, or severe based on the deformity of each segment, number of exostoses, leg length discrepancy, and functional limitations. Of 43 patients from 30 families, 39 patients (90.7%) and 24 families (80%) presented with EXT1 or EXT2 mutations. Patients with EXT1 mutations had a significantly worse phenotype than that of patients with EXT2 mutations or without any detectable mutation. The mean clinical score of patients with an EXT1 mutation (5.76; range, 2.0-8.0; SD = 1.60) was higher than that of patients with an EXT2 mutation (4.06; range, 2.0-7.0; SD = 1.47) or of those without any detectable mutation (4.63; range, 3.0-6.0; SD = 1.44; = 0.005). According to our classification system, more patients with EXT1 mutations had 'severe disease' than those with EXT2 mutations. Deformity scores were also higher in patients with EXT1 mutations ( = 0.018). In the multivariate analysis, the deformity score was found to be associated with the 'severe' class ( = 0.031). In conclusion, 90.7% of patients with MHE showed EXT mutations. Our scoring system showed reliable results. We suggest that the extent of deformity is an important factor in determining the phenotype of MHE and close monitoring for the development of severe disease is recommended in patients with high deformity scores.