Bilateral hereditary micro-epiphyseal dysplasia : clinical and genetic analysis of a Dutch family

Abstract

This thesis is based upon a study of a Dutch family with a unique skeletal dysplasia first described by Elsbach in 1959. Because of the presence of microepiphyses, he called this disorder bilateral hereditary micro-epiphyseal dysplasia (BHMED) and distinguished it from more common multiple epiphyseal dysplasia (MED). Clinical features were early onset of bilateral symmetric synchronic complaints of pain in hip and knee, and radiographically small epiphyses of the hip joint. Although Elsbach regarded this disorder as different from common multiple epiphyseal dysplasia, others suggested that it was only a variant of common MED. Recent advances in molecular genetics allow for solving this etiological question of lumping versus splitting of entities by molecular genetic identification of the basic gene defects. Furthermore, the original family requested genetic counselling and wanted be informed about the genetic risks to the offspring and to obtain more information about the nature of the disease, which would clearly benefit from resolving the genetic defect underlying the skeletal disorder in their family. The aim of the study was to obtain answers to four main questions: 1.Is BHMED indeed a separate clinical entity among the MEDs? 2.What are the diagnostic radiographic features of BHMED? 3.What is the molecular genetic basis of BHMED? 4.What is the diagnostic value of metacarpophalangeal pattern (MCPP) profile analysis? The study included the original family including 40 years follow-up period, as well as new family members born since the first report by Elsbach. The clinical and radiological findings confirmed Elsbach’s conclusion that the disease in this family, designated by him as BHMED, indeed represents a separate entity that can be differentiated from common MED. Short stature was not only observed in affected patients, but also though to a lesser degree in their healthy siblings and the unaffected parents, which was explained by height-related partner choice consistently over several generations. Through linkage analysis, three candidate gene loci, EDM1-3, were excluded. A whole genome scan showed linkage to a region on chromosome 2 harbouring a functional candidate gene, matrilin-3. Mutation analysis of matrilin-3 revealed a previously unreported pathogenic missense mutation in the Von Willebrand domain of this gene (G382C base pair substitution leading to an A128P amino acid substitution). The mutation segregated completely with the affection status defined by both clinical and radiographic diagnostic criteria. The metacarpophalangeal pattern (MCPP) profile observed in BHMED was found to be different from that of one of the currently known common MED variants (EDM2) and was consistent with the clinical diagnosis, the radiological observations and the segregation of the matrilin-3 mutation. BHMED affected patients were frequently affected by secondary aspecific osteoarthritis. In view of the current findings, the authors suggest that subtler sequence variants of this gene or its promotor may predispose to more common osteoarthritis, and that this deserves further studies in large population-based samples. This investigation proved that BHMED is indeed a separate variant within the MED group that is more heterogeneous than thought before. Furthermore, the identification of the gene defect helped the genetic counselling of family members, especially in support of the clinical and radiological diagnosis