Marfan Syndrome Marfan syndrome is a disorder of connective tissues,manifested principally by changes in the skeleton, eyes,and cardiovascular system. Its prevalence is estimated to be 1 in 5000. Approximately 70% to 85% of cases are familial and transmitted by autosomal dominant inheri- tance. The remainder are sporadic and arise from new mutations. Pathogenesis. Marfan syndrome results from an inherited defect in an extracellular glycoprotein called fibrillin 1. There are two fundamental mechanisms by which loss of fibrillin leads to the clinical manifestations of Marfan syndrome: loss of structural suppo in microfibril rich connective tissue and excessive activation of TGF-b signaling. Each of these is discussed below. * Fibrillin is the major component of microfibrils found in the extracellular matrix . These fibrils provide a scaffolding on which tropoelastin is deposited to form elastic fibers. Although microfibrils are widely distributed in the body, they are paicularly abundant in the aoa, ligaments, and the ciliary zonules that suppo the lens; these tissues are prominently affected in Marfan syndrome. Fibrillin occurs in two homologous forms, fibrillin-1 and fibrillin-2, encoded by two separate genes, FBN1 and FBN2, mapped on chromo- somes 15q21.1 and 5q23.31, respectively. Mutations of FBN1 underlie Marfan syndrome; mutations of the related FBN2 gene are less common, and they give rise to congenital contractural arachnodactyly, an autosomal dominant disorder characterized by skeletal abnormalities. Mutational analysis has revealed more than 600 distinct mutations of the FBN1 gene in individuals with Marfan syndrome. Most of these are missense mutations that give rise to abnormal fibrillin-1. These can inhibit polymerization of fibrillin fibers (dominant negative effect). Alternatively, the reduction of fibrillin content below a ceain threshold weakens the connective tissue (haploinsufficiency). * While many clinical manifestations of Marfan syndrome can be explained by changes in the mechanical propeies of the extracellular matrix resulting from abnormalities of fibrillin, several others such as bone overgrowth and myxoid changes in mitral valves cannot be attributed to changes in tissue elasticity. Recent studies indicate that loss of microfibrils gives rise to abnormal and excessive activation of transforming growth factor-b (TGF-b), since normal microfibrils sequester TGF-b and thus control the bioavailability of this cytokine. Excessive TGF-b signaling has deleterious effects on vascular smooth muscle development and it also increases the activity of metalloproteases, causing loss of extracellular matrix. This schema is suppoed by two sets of observations. First, in a small number of individuals with clinical features of Marfan syndrome (MFS2), there are no mutations in FBN1 but instead gain-of-function mutations in genes that encode TGF-b receptors. Second, in mouse models of Marfan syndrome generated by mutations in Fbn1, administrationof antibodies to TGF-b prevents alterations in the aoa and mitral valves. Clinical Features. Although mitral valve lesions are more frequent, they are clinically less impoant than aoic lesions. Loss of connective tissue suppo in the mitral valve leaflets makes them soft and billowy, creating a so-called floppy valve . Valvular lesions, along with lengthening of the chordae tendineae, frequently give rise to mitral regurgitation. Similar changes may affect the tricuspid and, rarely, the aoic valves. Echocardiography greatly enhances the ability to detect the cardiovascular abnormalities and is therefore extremely valuable in the diagnosis of Marfan syndrome. The great majority of deaths are caused by rupture of aoic dissections, followed in impoance by cardiac failure. Ref Robbins 9/e pg 145