Context: Hereditary multiple exostosis (HME) is an autosomal dominant disorder characterized by the development of benign cartilage-capped tumors at the juxta-epiphyseal regions of long bones. HME is usually caused by mutations of EXT1 or EXT2.

Objective: The objective of this study was to investigate a three-generation Austrian kindred with HME for EXT1 and EXT2 mutations and for abnormalities of bone mineral density (BMD).

Methods: DNA sequence and mRNA analyses were used to identify the mutation and its associated consequences. Serum biochemical and radiological investigations assessed bone metabolism and BMD.

Results: HME-affected members had a lower femoral neck BMD compared with nonaffected members (z-scores, −2.98 vs. −1.30; P = 0.011), and in those less than 30 yr of age, the lumbar spine BMD was also low (z-scores, −2.68 vs. −1.42; P = 0.005). However, they had normal mobility and normal serum concentrations of calcium, phosphate, alkaline phosphatase activity, creatinine, PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin, and β-crosslaps. DNA sequence analysis of EXT1 revealed a heterozygous g→c transversion that altered the invariant ag dinucleotide of the intron 8 acceptor splice site. RT-PCR analysis using lymphoblastoid RNA showed that the mutation resulted in skipping of exon 9 with a premature termination at codon 599. DNA sequence abnormalities of the osteoprotegerin gene, which is in close proximity to the EXT1 gene, were not detected.

Conclusions: A novel heterozygous acceptor splice site mutation of EXT1 results in HME that is associated with a low peak bone mass, indicating a possible additional role for EXT1 in bone biology and in regulating BMD.