Report on the Hypermobility Special Interest Group, British Society for Rheumatology meeting in Glasgow, April 1995.

Abstract

PROFESSOR Grahame welcomed everybody to the third meeting of this special interest group that has run concurrently with the Annual General Meeting. The meeting was opened by Dr Ann Child, who gave a well-illustrated overview of her continued research interests into the microfibril glycoprotein fibrillin. There are now up to 40 fibrillin gene mutations in classical Marfan's syndrome. A recent study of Marfan's syndrome has demonstrated that both hypermobile and female subjects have a better long-term prognosis in respect to cardiovascular involvement than those subjects with stiff contracted joints. Increasing numbers of microfibril-associated proteins and mutations within them are being described each year. This has led to a group of parallel studies searching for fibrillin mutations in individuals who have features associated with Marfan's syndrome. These include the benign joint hypermobility syndrome, ectopia lends, mitral valve prolapse, congenital contractural arachnodactyly (Beal's syndrome) and scoliosis. Mutations have been identified in the fibrillin genes situated on chromosomes 5, 15, 17 in eight families with the benign joint hypermobility syndrome. A study of 90 consecutive patients with mitral valve prolapse revealed Marfanoid features in 75%, skeletal signs in 72%, skin extensibility in 58% and joint hypermobility syndrome in 5%. Up to 80% of Marfan's patients have some degree of lens dislocation and therefore a group of 11 families with dominantly inherited ectopia lentis were studied further. Significant joint hypermobility was seen in four families and mild mitral valve prolapse in four families. An associated mutation in the FBN1 gene has since been described in one of these ectopia lentis families. Defects in a second fibrillin gene, FBN2 (located on chromosome 5), have recently been demonstrated in congenital contractural arachnodactyly. A plea was made for referral of further cases so that this condition could be studied further. Scoliosis is frequently associated with Marfan's syndrome. The inheritance of 40 families with isolated scoliosis would appear to be dominant, but sex influenced, with reduced penetrance in up to one-third of family members. Joint hypermobility is found in one-third of these famines. Defective incorporation of fibrillin into the extracellular matrix was seen in four out of a subset of seven of these cases. Further linkage studies of genes in the fibrillin and elastin families are under way. Each year increased numbers of fibrilassociated proteins are discovered, which could also be candidates for linkage studies into the overlapping inherited connective tissue diseases. In discussion, Dr Paul Wordsworth again stressed the underlying problem of accurately denning the phenotype in this group of patients before linkage studies are performed, and Likened it to osteogenesis imperfecta where mild and severe cases frequently occur within one family. The second presentation, by Dr Lee Hardwick, gave an excellent overview of the principles behind linkage studies and the new methods available for speeding up this process. Three major types of genetic markers have been used over the last 10-15 yr, firstly restriction fragment length polymorphisms (RFLPs), then minisatelh'tes and, more recently, microsatellites. One disadvantage of using the tandom repeats of minisatelhtes is that they are not evenly distributed throughout the genome and are thus not closely associated with individual genes. The microsatellites (dinucleotide repeats) are situated between genes and are evenly distributed throughout the genome. This makes them highly informative and they are therefore the markers of choice. The polymerase chain reaction can be used to amplify dinucleotide repeats and therefore across specific regions of the genome. Fluorescent rather than radioactive tags are now available which enable automatic reading of computergenerated gel images, increasing the speed at which the genome can then be analysed. These new technologies have been used to revisit the collagen genes in Ehlers-Danlos syndrome and possible linkage to the short arms of chromosomes 17, 7 and 2, which contain COL1A1, COL1A2 and COL1A3, respectively. It is now possible to use microsatellite repeats that span the whole genome to determine where the abnormal gene within these famines is segregating. There are plans to study further large families and it is hoped the precise linkage will soon be established.