Perspective:

The following are 10 points to remember about the translational science of Marfan syndrome.

1. Recent discoveries regarding the genetic basis for Marfan syndrome have dramatically altered our understanding of this disease. It was formerly thought to be a structural disease, the result of a mutation in the gene for fibrillin, a structural component of blood vessel walls. We now have an evolving understanding of the functional biological abnormalities resulting from this mutation, and leading to disease expression. This evolving functional understanding centers on the pivotal role of transforming growth factor (TGF)-beta in the pathogenesis of Marfan syndrome disease expression.

2. The underlying genetic mutation thought to be responsible for Marfan syndrome, is mutations in the fibrillin-1 (FBN1), which result in an alteration in TGF-beta binding by fibrillin. A clinically similar disease, known either as Loeys-Dietz syndrome or as another form of Marfan syndrome, can result from mutations in the TGF-beta receptor genes (TGFBR2 or TGFBR1). All of these mutations lead to alterations affecting TGF-beta metabolism, and a seemingly wide range of phenotypic clinical manifestations.

3. Many different disease-associated mutations of both the FBN1 and TGFBR1/TGFBR2 genes have been identified. This makes genetic screening difficult, as the genes need to be sequenced in their entirety to ascertain normality. It is also clear that private mutations occur, so not all patients with Marfan syndrome will have affected family members.

4. This new biological understanding of Marfan syndrome, accompanied by refined clinical observations, has led to a new clinical classification system. This system is known as the revised Ghent classification, and is based on either a combination of family history and clinical manifestations of disease (first and foremost aortic dilation, as well as FBN1 gene mutation and ectopia lentis), or an anthropomorphic score based on extra aortic anthropometric clinical manifestations.

5. Fibrillin gene mutations may result in disease through a resulting deficiency of normal fibrillin molecules (haplo-insufficiency) due to defective synthesis or excessive destruction of the mutant fibrillin; or through dysfunction of abnormal mutant fibrillin molecules overwhelming some normal fibrillin molecules (negative dominance). It is also possible that some mutations result in insufficiency, while others result in negative dominance. (This is one possible etiology of phenotypic variation.)

6. A final common pathway for thoraco-abdominal aneurysms of all genetic causes may involve the cytokine pathway as well.

7. Clinically, aortic dilation is the hallmark of Marfan syndrome. As such, it is considered a key diagnostic criterion and, therefore, needs to be measured accurately. The aortic dilation seen in both FBN1 and TGFBR mutations is similar, predominating at the sinuses of Valsalva, and also resulting in a loss of compliance in the entire aorta.

8. Prognostic or phenotypic Marfan syndrome can vary significantly, even for a specific, given gene mutation, as evidenced by intrafamilial variability.

9. One of the next great research challenges for improving our understanding of Marfan syndrome is to better understand the genetic modifiers. Modification may lead to, or account for, phenotypic variation. A better understanding of modification may lead to improved prognostication, as well as identify opportunities for therapeutic intervention.

10. Animal models suggest that the angiotensin receptor blocker losartan, by blunting the overstimulation of TGF-beta seen in Marfan syndrome, decreases the phenotypic manifestations of disease in Marfan (FBN1 mutated) mice. Clinical trials are ongoing to determine if this dramatic effect seen in mice leads to an alteration in the natural history of Marfan syndrome in humans. Published series have documented a change in the progression of disease in small numbers of children with Marfan syndrome, in small, uncontrolled reports.