Education & Awareness - Learn About Marfan

What is Marfan Syndrome
What causes Marfan Syndrome?
How is the Marfan gene inherited?
The Cause of the Marfan Syndrome
Effects of Marfan Syndrome on the Body

What is Marfan Syndrome?

The Marfan syndrome is a heritable condition that affects the connective tissue. The primary purpose of connective tissue is to hold the body together and provide a framework for growth and development. In the Marfan syndrome, the connective tissue is defective and does not act as it should. Because connective tissue is found throughout the body, the Marfan syndrome can affect many body systems, including the skeleton, eyes, heart and blood vessels, nervous system, skin and lungs.


The Marfan syndrome affects men, women and children, and has been found among people of all races and ethnic backgrounds. It is estimated that at least 1 in 5,000 people in the United States have the disorder. For more detailed information, read an excerpt from the National Marfan Foundation booklet The Marfan Syndrome.

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What causes Marfan Syndrome?

The Marfan syndrome is caused by a defect (mutation) in the gene that determines the structure of fibrillin, a protein that is an important part of connective tissue. A person with the Marfan syndrome is born with the disorder, even though characteristics may not emerge and a diagnosis may not be made until later in life. Although everyone with the Marfan syndrome has a defect in the same gene, usually each family has its own specific mutation. Even with the same mutation, not everyone in a family will have identical medical problems or be equally affected. This is called variable expression, meaning that the defective gene expresses itself in different ways in different people. Scientists do not yet understand why variable expression occurs in people with the Marfan syndrome. For more genetic information read an excerpt from The Marfan Syndrome.

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How is the Marfan gene inherited?

Each child of a person who has the Marfan syndrome has a 50 percent chance of inheriting the disorder. Sometimes a new gene defect (a spontaneous mutation) occurs during the formation of sperm or egg cells resulting in a baby with the Marfan syndrome. However, two unaffected parents have only a 1 in 10,000 chance of having a child with the Marfan syndrome. Approximately 25 percent of cases are due to a spontaneous mutation at the time of conception.

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The Cause of the Marfan Syndrome
(Excerpt from The Marfan Syndrome, by Reed E. Pyeritz, M.D., Ph.D. and Cheryll Gasner, M.N., C./F.N.P. Fifth Edition, July, 1999, Revised September 2001)

Cause must be considered on several levels. The most correct and straightforward answer is that a single altered (mutant) gene causes the condition. But in considering the cause of a condition as complex as the Marfan syndrome, a much broader answer is necessary.

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Connective Tissue

This is the glue and the scaffolding of the body, but also much more. Connective tissue functions in all organs and at all stages of development, from shortly after conception to death, no matter the age. Connective tissue varies from location to location within the body, and throughout the life of a human being. Once thought to be relatively simple in the biochemical sense, connective tissue is now understood to be extremely complex, and is a hot area of research for scientists interested in such diverse topics as embryology, cancer, trauma and pharmacology.

Connective tissue, which includes the substances between cells, consists of fibrous components, such as collagen fibers and elastic fibers, and regions that lack much obvious structure, but which are composed of both huge molecules (among the largest in the body) and small ones that interact in highly specific ways. Disrupt one of the components, and there is a cascade effect that involves other components, and the function of the connective tissue as a whole. When one constituent is defective, many compensatory changes occur in the structure and organization of other components. As a result, it is not possible to look at connective tissue under the microscope or in the test tube and immediately figure out what is abnormal. In a condition like the Marfan syndrome, a host of connective tissue components will be abnormal! Nonetheless, only one was abnormal at conception. The goal-really the Holy Grail for some of us-for decades was to determine what the fundamental problem was with the connective tissue.

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Microfibrils

Over the years from the 1950's, when scientists first seriously began studying connective tissue, until 1991, all of the major constituents were suggested, and even supported, as the cause of the Marfan syndrome. All turned out to be incorrect. No one was able to reconcile the fact that the aorta, which contains most of the connective tissue components, and the lens of the eye, which contains very few, were both affected in the Marfan syndrome. Then, over just a few years, the puzzle finally came together. One of the keys was the description of a component of the extracellular matrix called the microfibril, a structure of remarkably uniform appearance no matter from what tissue it was isolated and no matter what function it was performing. Another key was the discovery of the major protein of the microfibril by Dr. Lynn Sakai and co-workers in 1986. They named thsi protein fibrillin.

Microfibrils are minuscule structures that exist, as the name suggests, as rod-like entities. In some tissues, such as the media of the aorta and the ligaments of the musculoskeletal system, microfibrils form the framework of the elastic fibers. In other tissues, such as the filaments of the eye that hold the lens in place (zonules), microfibrils exist independent of elastic fibers. Perhaps there are other functions as well. But microfibrils exist nearly everywhere in the human body. Testimony to their importance is the finding of microfibril-like structures in very primitive organisms, such as the fruit fly. Two closely related fibrillins, called 1 and 2, exist in human microfibrils and perform slightly different functions.

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The Fibrillin Gene

The cause of the Marfan syndrome is alteration of the gene (called FBN1) that encodes the protein fibrillin-1. This gene resides on chromosom 15 and was discovered to be the cause of the Marfan syndrome in 1991 by a variety of scientific approaches.

Fibrillin-1 is one of the larger proteins that humans make. Accordingly, the gene FBN-1 is quite large and is composed of many different pieces (or exons) spanning a long region of chromosome 15. Fibrillin-2 is encoded by a separate gene on chromosome 5 (FBN2); mutations in this gene do not cause the Marfan syndrome, but rather a related condition called congenital contractural arachnodactyly.

Thus far, several hundred mutations in FBN1 on chromosome 15 have been found in people with the Marfan syndrome. Not surprisingly, everyone in the same family who has the Marfan syndrome has the same mutation. But, each unrelated patient or family studied to date (with just a few exceptions, in which the same mutation has occurred by chance in different families), has had a different mutation. Finding mutations is currently very laborious and time-consuming, so that it is far from a routine medical test. Rather, discovering a mutation remains the work of a relatively few research laboratories scattered around the world.

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Effects of Marfan Syndrome on the Body

The signs and symptoms of Marfan syndrome vary from one person to another, even within the same family. Some people have mild signs and symptoms, while others may have severe problems and discomfort. Signs and symptoms occur in many parts of the body, including:

  • The bones and ligaments
  • The heart and blood vessels
  • The eyes
  • The lungs
  • The skin

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Appearance and Body Build

Some of the major signs of Marfan syndrome are the common physical features seen in people with the condition. People with Marfan syndrome often have:

  • A tall, slender body build. They may be very tall or taller than other family members who do not have the condition. However, it should be noted that short, heavy people also can have Marfansyndrome.
  • Long arms, legs, fingers, and toes. A person's arm span (the distance from the fingertips of one hand to the fingertips of the other with the arms stretched out from the sides) may be greaterthan his or her height.
  • A long and narrow face.
  • A highly arched roof of the mouth with crowded teeth.
  • A receding lower jaw, causing an overbite.
  • A protruding or sunken chest.
  • A curved spine.
  • Flat feet that are rotated inward (some people, however, have exaggerated arches).

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Bones, Cartilage, and Ligaments

The bones of the limbs, hands, and feet often grow too long in people with Marfan syndrome. This typically leads to a tall, thin body with disproportionately long arms, fingers, legs, and toes. People with Marfan syndrome have loose, relaxed ligaments and are usually loose jointed.

Chest abnormalities may occur due to an overgrowth of the ribs. There are two types of chest abnormalities:

  • Pigeon breast, also called pectus carinatum. The chest protrudes outward like a bird's chest. This can affect heart and lung function.
  • Funnel chest, also called pectus excavatum. The chest is sunken or indented, reducing the space between the breastbone and the backbone. As a result, the heart and lungs are displaced. Heart and lung function may be affected, leading to breathing and endurance problems.

Curvature of the spine may occur. It usually develops during childhood, often gets worse during the teenage growth spurt, and may require surgical treatment. The three main types of abnormal spine curvature are:

  • Scoliosis - a side-to-side curvature
  • Lordosis - an inward curvature of the spine in the lower back, just above the buttocks
  • Kyphosis - an outward curvature of the spine in the upper back (hunchback)

Curvature of the spine can cause back pain, posture problems, and deformity. Scoliosis can sometimes reduce lung function.

Another problem that can occur is dural ectasia (ek-TA-ze-a), which is the stretching of the membrane surrounding the brain and spinal cord. Dural ectasia can wear down the bones of the spine over time. Symptoms may include:

  • Pain in the lowest part of the back
  • Pain in the abdomen
  • Pain, numbness, or weakness of the legs

Dural ectasia is a hallmark of Marfan syndrome that is very rare in the general population.

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Heart and Blood Vessels

People who have Marfan syndrome often have problems with the heart and blood vessels. The valves of the heart may not work properly and may permit some blood flow to be reversed, causing the heart to do extra work. The aorta-the large artery that carries blood away from the heart to the body-may stretch and enlarge. These problems can cause signs and symptoms, such as:

  • A heart murmur. This can be the result of valves not functioning properly or other heart problems.
  • Sudden chest pain. This can be a symptom of aortic dissection, a life-threatening complication that can occur due to weakened aorta walls. The pain may occur in the front or in the back, usually in the midline of the body. The location of the pain may change as the tear in theaorta grows. In some cases, a dissection does not cause dramatic pain.
  • Abnormal heart rhythms called arrhythmias (a-RITH-me-as). A person with Marfan syndromemay develop an arrhythmia as a result of problems with the heart valves or due to cardiomyopathy or congestive heart failure.
  • Shortness of breath and fatigue (tiredness). These can be symptoms of heart failure due to anoverworked heart.

Two of the heart and blood vessel complications that can occur in people with Marfan syndrome are mitral valve prolapse (MVP) and enlargement of the aorta.

Mitral Valve Prolapse

MVP is a problem with the heart's mitral valve. The mitral valve controls the flow of blood through two of the chambers in the heart, the left atrium and the left ventricle. The flaps of the valve are designed to allow blood to flow in one direction-from the left atrium into the left ventricle-and to prevent blood from flowing the other way.

In MVP, the mitral valve does not work correctly. The valve flaps are large and floppy. They may overlap or not close completely. One or both flaps may flutter or swing back into the atrium.

The abnormal mitral valve can allow blood to flow backward through the valve in the wrong direction. This is called mitral regurgitation. When this happens, the heart has to work harder to make up for the backward flow of blood. Over time, the heart can become overworked, leading to heart failure.

figure_marfan

Figure A shows the normal mitral valve separating the left atrium from the left ventricle. Figure B shows the heart with mitral valve prolapse. Figure C shows the detail of mitral valve prolapse. Figure D shows a mitral valve that allows blood to flow backward into the left atrium.

MVP occurs in about 3 out of every 4 people with Marfan syndrome. It also occurs in people who do not have Marfan syndrome. In many people with MVP, little or no blood leaks back through the valve, there are no symptoms, and no treatment is needed. In some people, blood does leak back through the valve, and these people may have symptoms and require treatment.

Enlargement of the Aorta (Aortic Dilation)

The aorta is the large artery that carries oxygen-rich blood away from your heart out to the rest of the body. When weak connective tissue causes the walls of the aorta to weaken, the aorta widens and stretches. Most often, the enlargement begins where the aorta connects with the left ventricle of the heart, just above the aortic valve. This part of the aorta is called the aortic root.

Enlargement of the aorta can lead to several serious complications:

  • Aortic root dilation. The aorta can widen and bulge where it attaches to the heart. This happens due to continued weakening of the wall of the aorta. Aortic root dilation may not cause any symptoms until it becomes quite large. If symptoms occur, they may include pain in the chest, upper back, neck, and jaw; coughing and hoarseness; and trouble swallowing. As part of this dilation, one section may enlarge and bulge out. This is called an aortic aneurysm (AN-u-rism). The aneurysm can rupture, causing massive internal bleeding, which is a life- threatening medical emergency.
  • Aortic regurgitation. The aortic valve sits between the left ventricle and the aorta and allows blood to flow one way, from the ventricle to the aorta. In Marfan syndrome, as the aorta widens,the aortic valve also is stretched, and the valve flaps cannot close properly. This allowsblood to leak the wrong way, from the aorta back into the left ventricle (regurgitation). As a result, the heart has to work harder to pump blood out to the body. The heart can become overworked, leading to heart failure. People with aortic regurgitation may have shortness of breath and exercise intolerance.
  • Aortic dissection. This is a tear that occurs in the weakened layers of the inner wall of the aorta. The tear allows blood to get under the inner layer of the wall. As a result, the aorta tears further. An aortic dissection is a life-threatening emergency. Signs and symptoms of anaortic dissection include abrupt onset of chest pain, which may range from mild to severe.There may be pain in the back or the abdomen, or both. The person may sweat, vomit, faint, and have a weak pulse.

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Eyes and Vision

Nearsightedness (myopia) is the most common eye problem in people with Marfan syndrome. It can range from mild to severe. People with Marfan syndrome often have astigmatism (a-STIG-ma-tizm), which causes visual distortion and blurred vision.

Dislocation of the lens of the eye (ectopia lentis) is another common complication of Marfan syndrome. It is considered a hallmark of Marfan syndrome because it occurs in very few other conditions. It may affect one or both eyes, and the lens may be higher or lower than normal or shifted off to the side. Vision in the affected eye(s) may be severely affected.

Other, less common eye problems in Marfan syndrome include detached retina, cataracts, and glaucoma. A detached retina occurs when there are holes or tears in the inner lining of the eye. A cataract is a clouding of the lens. Glaucoma occurs as a result of high pressure in the eye. People with Marfan syndrome tend to get cataracts and glaucoma at a younger age than people who do not have Marfan syndrome.

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Lungs

In Marfan syndrome, the air sacs in the lungs may be larger than normal. This can cause breathing problems. People with Marfan syndrome are at an increased risk of developing emphysema or chronic obstructive pulmonary disease (COPD), a serious lung disease.

Sudden collapse of the lung, called spontaneous pneumothorax (noo-mo-THOR-aks) can occur in people with Marfan syndrome. About 1 in every 20 people with Marfan syndrome develops this problem. Collapsed lung can happen after only a slight blow to the chest, or even while at rest without a known cause. Collapsed lung usually causes sudden shortness of breath and requires immediate medical attention.

Sleep apnea is a problem that is often associated in the general population with being overweight or obese. But thin people with Marfan syndrome can also suffer from it. This may be due to looseness of the connective tissue in the airways.

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Skin

Stretch marks on the skin occur in about 2 out of every 3 people with Marfan syndrome. The stretch marks are usually on the lower back, buttocks, shoulders, breasts, thighs, and abdomen. They differ from stretch marks in the general population because, in people with Marfan syndrome, they occur without excessive weight gain or loss. The marks usually appear around the time of puberty, but may occur in childhood. They do not require treatment.

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Source: National Marfan Foundation