Marfan Syndrome

Marfan syndrome is genetic disease that involves defects in the connective tissues of the body with the cardinal collection of abnormalities affecting the skeletal, ocular, and cardiovascular systems. It is inherited as an autosomal dominant disorder, meaning that inheriting only one defective gene from either the paternal or maternal side will lead to the disorder. Although the majority of mutations are inherited from one of the parents, approximately 25% of affected individuals develop Marfan syndrome as a result of a new mutation. The prevalence is 1/20,000 and the disorder is inherited with variable expression. This means that each individual may have a different combination of the possible clinical features that characterize the disorder.

There are a variety of skeletal deformities associated with the syndrome including disproportionately long limbs and digits, myopia (extreme near-sightedness), a chest deformity, joint laxity, and vertebral column deformities such as scoliosis. Dislocation of the lens of the eye represents a hallmark clinical feature. The most serious and potentially life-threatening complication of Marfan syndrome relates to abnormalities in the heart and blood vessels. The mitral valve (the gateway out of the heart for all the blood entering the body's circulation) frequently billows backwards when the heart contracts. The wall of the aorta (the major artery leaving the heart) is prone to stretching and becomes increasingly weak, leading to bulging and susceptibility to rupture called an aortic aneurysm. Such a rupture leads to severe hemorrhaging (internal bleeding) and if untreated, death.

Former American President Abraham Lincoln (1809–1865) was thought to have Marfan syndrome in that he manifested several key clinical features. However, it wasn't until after he died, in 1896, when French Pediatrician Antoine Marfan first described a specific cluster of skeletal abnormalities in a five and a half year-old girl. In the 1950s, a large number of patients and their families were assessed and the clinical features of the syndrome were characterized. At the time the relationship between the abnormality of the aorta and the dislocated lens of the eye eluded physicians. It later became clear that both the ligaments of the lens and the lining of the aorta had a similar defect elucidated only after the candidate gene was discovered and it's functional significance studied.

Marfan syndrome is caused by mutations in the fibrillin-1 gene located on chromosome 15. Fibrillin is a protein that plays a role in the characteristically elastic properties of connective tissue. The biochemical abnormality that leads to Marfan syndrome is not well understood. Biochemical defects are thought to involve the synthesis, secretion and incorporation of fibrillin into connective tissue.

There are no genetic tests available to help diagnose Marfan syndrome. A clinical geneticist might be more inclined to diagnose a patient with Marfan syndrome if there are other first-degree relatives that have a Marfan-like habitus. Without such an observation, skeletal involvement and at least two other systems affected by at least one major manifestation (for example, dislocated lens of the eye and the aortic abnormality) is required for a definitive diagnosis. It is also common that the wingspan, or the distance from one outstretched hand to another, is larger than the height. Early diagnosis is important so that the cardiovascular system can be carefully evaluated to prevent aortic rupture. Currently, there is no treatment for Marfan syndrome that can reverse the overall connective tissue defects. Each manifestation of the syndrome is addressed individually (eg., braces and physical therapy for the spinal curvature, occasional lens removal for the lens dislocations). Some medications seem to be somewhat useful in slowing the stretching of the aorta, although surgical replacement of part of the aorta or the defective mitral valve is sometimes necessary.