Aetiology
Caused by mutations in the fibrillin-1 gene in 99% of classical Marfan syndrome patients.[11] In 75% of patients, the gene is passed on from a parent and is autosomal dominant, although the appearance of family members and degree of pathological features may vary. In 25% of patients the mutation occurs spontaneously and may be associated with older paternal age.[4]
The first fibrillin-1 gene mutation was identified in 1990.[12] However, subsequently, over 3000 different mutations have been identified.[13]
Pathophysiology
Mutations in the fibrillin-1 gene result in the production of an abnormal fibrillin protein, leading to abnormalities in the mechanical stability and elastic properties of connective tissue.[14] Up-regulation of C-terminal fragment of filamin-A in dilated aortic media of Marfan syndrome has been found.[15] This is due to cleavage by the protease calpain. Therefore, increased calpain activity may help to explain histological alterations in the dilated aorta.
Research suggests that transforming growth factor-beta is implicated in the failure of normal elastic tissue formation.[16][17]
Early experience from surgical treatment and histological studies has found that patients suffer from a loss of elastic tissue in the aortic wall (medial degeneration). Frequently, particularly in association with aortic dissection, a loss of smooth muscle cells (medial necrosis) is also noted. In addition, a diagnosis of cystic medial necrosis may be made, the so-called cysts being fluid collections of mucin and ground substance. These abnormalities lead to a weakening of the aortic wall with subsequent aortic dilation and potentially aortic dissection, aneurysms, and rupture. They also lead to a reduction of the structural integrity of the skin, ligaments, eye lens zonules, lung airways, and the spinal dura.[16]
Classification
Type according to family history
Familial: 75% of cases; inherited as an autosomal dominant trait.
Sporadic: 25% of cases; the mutation occurs spontaneously and may be associated with older paternal age.[4]
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