FBN2 mutation associated with manifestations of Marfan syndrome and congenital contractural arachnodactyly

ongenital contractural arachnodactyly (CCA; OMIM #121050) and Marfan syndrome (MFS; OMIM #154700]) are autosomal dominant disorders of connective tissue that are often difficult to differentiate clinically because of phenotypic similarities.Both syndromes have skeletal complications including arachnodactyly, dolichostenomelia, pectus deformities, and kyphoscoliosis.[1][2][3][4][5] Congenital contractures involving multiple joints and a crumpled appearance of the helix of the ear are more common in CCA than MFS.Ectopia lentis is a complication present in approximately half of patients with MFS.The most common cardiovascular complication in patients with MFS is progressive dilatation of the ascending aorta, initially involving the sinuses of Valsalva.6 Although patients affected with CCA were initially felt not to have aortic involvement, three children under 6 years of age with CCA have had dilated aortic roots, further blurring the clinical distinction between the two syndromes.5 The overlap in the clinical features has a molecular basis; CCA and MFS result from mutations in two homologous genes, FBN2 and FBN1, respectively.5 7-9 These genes encode the large, cysteine rich, extracellular matrix (ECM) glycoproteins, fibrillin-2 and fibrillin-1, which are major components of microfibrils.Although the mutations in FBN1 causing MFS can occur over the length of the gene, FBN2 mutations causing CCA cluster in a central region of the gene bracketed by exons 22 and 36.10 11 Most mutations in both FBN1 and FBN2 are missense mutations that disrupt one of the numerous domains of the proteins with homology to epidermal growth factor.Exon splicing errors occur in both genes but are more common in FBN2 than FBN1. 5 We describe a family from Mexico with three members affected with CCA, in whom a genomic FBN2 mutation causing missplicing of exon 32 was identified.Serial echocardiograms of the affected children demonstrated aortic dilatation at the level of the sinuses of Valsalva that persisted over 5 years as the children grew.In contrast, the affected mother had a normal echocardiogram.These results indicate that the aortic dilatation can persist over time, and emphasises the need for aortic imaging of patients with CCA.The affected children met the diagnostic criteria for MFS, further blurring the clinical distinction between the syndromes.12