Clinical variability and genetic heterogeneity in multiple epiphyseal dysplasia. M.D. Briggs¹, W. Newman¹, I.D. Young², G.R. Mortier³. 1) Wellcome Trust Centre for Cell Matrix Research, School of Biological Sciences, Univ. of Manchester; 2) Clinical Genetics Service, City Hospital, Nottingham, England; 3) Dept. Medical Genetics, Univ. Hospital of Gent, Gent, Belgium.

   Multiple epiphyseal dysplasia (MED) is characterised by early-onset degenerative joint disease and in severe cases short stature. The mild 'Ribbing' and severe 'Fairbank' forms have been used to define the phenotypic spectrum within this autosomal dominant disease. MED can result from mutations in the genes encoding cartilage oligomeric matrix protein (COMP) and type IX collagen (COL9A2 and COL9A3). We are performing genetic linkage and mutational analysis in families with various MED phenotypes and comparing molecular findings to clinical and radiographic presentation. In a family with severe MED we identified a COMP mutation (D473N) that has also been shown to cause pseudoachondroplasia. In 2 families with mild MED, different mutations have been identified in the exon 3 splice-donor site of COL9A2, one of which results in the degradation of mRNA from the mutant allele. In another family in which COL9A2 is implicated, affected individuals are of normal stature, but osteochondritis dissecans has contributed significantly to early onset degenerative joint disease. Electron microscopy of cartilage from an affected family member shows normal extracellular matrix and chondrocyte morphology. Finally, we have ascertained a four generation family with MED in which preliminary genetic analysis has excluded linkage to the COMP or type IX collagen genes. Affected individuals have a normal birth length and an adult height around the third percentile (150-165 cm). Most have complained during childhood of knee and hip pain after exercise and some underwent hip replacements or knee surgery because of early-onset osteoarthritis. Current studies are focused on identifying the disease gene in this family and the genetic defect of MED in 5 other families. Our data suggest that mutations in at least five genes are likely to result in phenotypes within the MED disease spectrum, which helps to explain the clinical variability within this osteochondrodysplasia. (This work is funded by the Arthritis Research Campaign).