Marfan syndrome is an autosomal dominant disorder of connective tissue with systemic effects and major manifestations in the cardiovascular, musculoskeletal, and ophthalmic systems and the integument. Diagnostic criteria, based mainly on clinical findings, are reasonably successful in differentiating Marfan syndrome (MIM 154700) from related disorders, such as congenital contractural arachnodactyly, mitral valve prolapse in association with aortic, skeletal, and skin manifestations (MASS) phenotype, mitral valve prolapse syndrome, familial aortic aneurysm, and familial forms of ectopia lentis.
The basic genetic defect in Marfan syndrome involves mutations in the extracellular matrix glycoprotein fibrillin-1, encoded by FBN1 at 15q21.1. Mutations in a highly homologous gene, genes for fibrillin-2 (FBN2) , at 5q23-q31, cause congenital contractural arachnodactyly (MIM 121050).
The cardinal clinical manifestations of Marfan syndrome include tall stature with dolichostenomelia and arachnodactyly; deformity of the spine and anterior chest; joint hypermobility or contracture; dilatation and dissection of the ascending aorta; mitral valve prolapse; myopia; ectopia lentis; pneumothorax; hernias; and dural ectasia. The prevalence of Marfan syndrome is uncertain, but is at least 2 to 3 in 10,000 individuals without regard to ethnicity. One-quarter to one-third of all cases represent new mutations; germinal mosaicism, while reported, is rare. The Marfan syndrome phenotype exhibits high penetrance but highly variable expression. If untreated, the condition leads to premature death, generally from cardiovascular complications. Aggressive management can result in nearly normal life expectancy. Management must be multidisciplinary to cover all aspects of medical care, surgical intervention, and genetic counseling.
Among the Marfan-related conditions is congenital contractural arachnodactyly, which exhibits dolichostenomelia, progressive scoliosis, congenital joint contractures, and deformity of the helix of the ear. Some people with CCA have mitral valve prolapse but aortic dilatation or ectopia lentis should prompt consideration of Marfan syndrome. In most inherited forms of ectopia lentis, findings are limited to the eye. Some families with autosomal dominant ectopia lentis have mild skeletal and cardiovascular features suggestive of the Marfan syndrome, but do not meet diagnostic criteria; some of these families have mutations in FBN1 . Similarly, families lacking ectopia lentis and severe skeletal features, but having mitral valve prolapse, or aortic root dilatation, or both, have been shown, in a few cases, to link to or have mutations in FBN1. However, some families with autosomal dominant aortic aneurysm or dissection, and many sporadic patients with aortic aneurysm do not appear to have a mutation in FBN1.
Fibrillin is a major component of the 10-nM microfibrils of extracellular matrices. The primary structure of fibrillin exhibits a multidomain organization characterized by several cysteine-rich motifs reminiscent of the epidermal growth factor module. Extracellularly, fibrillin monomers aggregate into a supramolecular structure that has a “beads on a string“ appearance on transmission electron microscopy. Characterization of a variety of fibrillin mutations has emphasized the importance of the structural integrity of individual cysteine-rich repeats, as well as the requirement that the fibrillin monomer must have a certain absolute length for normal microfibril assembly.
In addition to being linked to the Marfan syndrome, FBN1 has been genetically linked to dominantly inherited ectopia lentis, MASS phenotype and familial aortic aneurysm, suggesting that mutations in functionally distinct domains of this gene product may cause seemingly distinct clinical phenotypes. On the other hand, linkage between congenital contractural arachnodactyly and FBN2 suggests that fibrillin proteins have distinct functions in different tissues.