Marfan's syndrome.

1978 www.thelancet.com Vol 366 December 3, 2005 Marfan’s syndrome is a multisystem connective tissue disorder of autosomal dominant inheritance. Approximately one in every 5000 individuals is affected, though this figure is probably an underestimate. The condition shows no predilection for any particular race or geographical background. It exhibits complete penetrance but variable expression and age dependency. About a quarter of affected individuals have no family history of the disease—ie, they are new mutations. Marfan’s syndrome demonstrates pleiotropy with diverse manifestations in different organ systems. Clinical diagnosis depends on a combination of major and minor signs defined in the revised 1996 Ghent criteria. The hallmark features are noted in the cardiovascular, ocular, and skeletal systems (table). The diagnosis of Marfan’s syndrome can be challenging because of phenotypic variability even between affected individuals of the same family, low specificity of many of the clinical signs, and multiple Marfan-like microfibrillar disorders with overlapping features. The gene for Marfan’s syndrome was localised to chromosome 15q21 in 1990 and cloned in 1991. FBN1 is a huge gene, spanning 110 kb of genomic DNA and comprising 65 exons. It encodes the microfibrillar protein fibrillin 1. Mutational analysis is difficult and impractical at times, in part because of the size of the gene, the heterogeneity of mutations discovered, and the lack of mutational hot spots. Moreover, there are currently no molecular techniques that offer a highly sensitive mutation detection rate of FBN1. Fibrillin 1 is a major component of extracellular microfibrils. It consists of cysteine-rich repeats interspersed by latent transforming growth factor binding protein-like and epidermal growth factor-like motifs. The microfibrils are thought to confer important biomechanical properties in connecting, anchoring, and maintaining tissues and organs. Many mutations associated with fibrillin 1 appear to confer a dominant negative mechanism of pathogenesis, but some associated with fibrillin-1 haploinsufficiency have also been described. These mutations can lead to defects in the synthesis, secretion, modification, folding, stabilisation, incorporation, and assembly of the FBN1 protein. Severe neonatal Marfan’s syndrome is associated with a cluster of mutations in the middle portion of FBN1, but there are no other established correlations between genotype and phenotype. Currently, our understanding of fibrillin biochemistry and microfibrillar assembly is limited. Experiments in mice could provide insight into fibrillin pathogenesis and microfibrillar organisation, leading to a better understanding of the pleiotropic manifestations of Marfan’s syndrome and perhaps development of a cure. Lancet 2005; 366: 1978–81