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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 beta-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.

Original publication




Journal article


J Clin Endocrinol Metab

Publication Date





5386 - 5392


Adolescent, Adult, Bone Density, Case-Control Studies, Cytosine, DNA, Recombinant, Exostoses, Multiple Hereditary, Female, Femur Neck, Guanine, Heterozygote, Humans, Introns, Lumbar Vertebrae, Male, Middle Aged, Mutation, N-Acetylglucosaminyltransferases, Osteoporosis, Pedigree, Radiography, Reverse Transcriptase Polymerase Chain Reaction