Marfan Syndrome

NewsRx Bundle A quick and inexpensive way to view the most recent articles for a one-time project. Custom Reports on Marfan Syndrome Tired of prepackaged reports that just don't meet your needs? Target your needs!

What is Marfan syndrome?

Marfan syndrome is a disorder of the connective tissue. Connective tissue provides strength and flexibility to structures throughout the body such as bones, ligaments, muscles, walls of blood vessels, and heart valves.

Marfan syndrome affects most organs and tissues, especially the skeleton, lungs, eyes, heart, and the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). The signs and symptoms of Marfan syndrome vary widely in severity, timing of onset, and rate of progression. Affected individuals often are tall and lean, have elongated fingers and toes (arachnodactyly), and have an arm span that exceeds body height. Other common features include unusually flexible joints, a long and narrow face, a highly arched roof of the mouth and crowded teeth, an abnormal curvature of the spine (scoliosis), and either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum). About half of people with Marfan syndrome have a dislocated lens (ectopia lentis) in one or both eyes, and most have some degree of nearsightedness (myopia). Clouding of the lens (cataract) may occur in mid adulthood, and increased pressure within the eye (glaucoma) occurs more frequently than in people without Marfan syndrome.

Most people with Marfan syndrome have abnormalities of the heart and the aorta. Leaks in valves that control blood flow through the heart can cause shortness of breath, fatigue, and an irregular heartbeat felt as skipped or extra beats (palpitations). If leakage occurs, it usually affects the mitral valve, which is a valve between two chambers of the heart, or the aortic valve that regulates blood flow from the heart into the aorta. The first few inches of the aorta can weaken and stretch, which may lead to a bulge in the blood vessel wall (an aneurysm). The increased size of the aorta may cause the aortic valve to leak, which can lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life threatening.

Marfan syndrome is sometimes classified as type I or type II, although this classification system is not universally accepted. When used, type I or classic Marfan syndrome refers to the most common form of this disorder, characterized by the features described above. Type II Marfan syndrome is less common. It is similar to classic Marfan syndrome except eye problems (such as ectopia lentis) are absent, and the genetic cause is different.

How common is Marfan syndrome?

Worldwide, Marfan syndrome affects at least 1 in 5,000 people.

What genes are related to Marfan syndrome?

Mutations in the FBN1 and TGFBR2 genes cause Marfan syndrome.

Mutations in the FBN1 gene cause classic Marfan syndrome. The FBN1 gene provides instructions for making a protein called fibrillin-1. Fibrillin-1 binds to itself and other proteins and molecules to form threadlike filaments called microfibrils. Microfibrils become part of the fibers that provide strength and flexibility to connective tissue. Additionally, microfibrils trap molecules called growth factors and release them at the appropriate time to control the growth and repair of tissues and organs throughout the body. A mutation in the FBN1 gene can reduce the amount and/or quality of fibrillin-1 that is available to form microfibrils. As a result, growth factors are released inappropriately, causing the characteristic features of Marfan syndrome.

Some researchers believe that a small percentage of Marfan syndrome cases are caused by mutations in the TGFBR2 gene. These cases are called Marfan syndrome type II. Other researchers believe that TGFBR2 mutations cause a disorder that may have some Marfan-like features but is not Marfan syndrome. The TGFBR2 gene provides instructions for making a protein that transmits signals from the cell surface to the nucleus. Through this signaling process, the environment outside the cell affects activities inside the cell such as division and growth. Mutations in the TGFBR2 gene alter the signaling activity of the protein, which disturbs the growth and development of connective tissue.

How do people inherit Marfan syndrome?

This condition is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder.

At least 25 percent of classic Marfan syndrome cases result from a new mutation in the FBN1 gene. These cases occur in people with no history of the disorder in their family.

Source: National Institutes of Health

Researchers at University Hospital have published new data on Marfan syndrome genetics

"The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling)," wrote L. Faivre and colleagues, University Hospital.

The researchers concluded: "Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages."

Faivre and colleagues published their study in The American Journal of Human Genetics (Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. The American Journal of Human Genetics, 2007;81(3):454-66).

For additional information, contact L. Faivre, Centre Hospitalier Universitaire, Centre de Genetique, Dijon, France.

The publisher of the The American Journal of Human Genetics can be contacted at: University Chicago Press, 1427 E 60th St., Chicago, IL 60637-2954, USA.

Keywords: France, Dijon, Marfan Syndrome Genetics, Cardiology, Genetics, Marfan Syndrome.

This article was prepared by Cardiovascular Week editors from staff and other reports. Copyright 2007, Cardiovascular Week via NewsRx.com.