Marfan Syndrome

Marfan syndrome is a disorder of connective tissue, affecting about 1 in 5,000 people in the United States. The disease is characterized by unusually long limbs, and is believed to have affected Abraham Lincoln.

Causes

Marfan syndrome is caused by mutations in the gene FBN1 that encodes a protein called fibrillin 1. Fibrillin 1 is an important part of connective tissue which holds all the parts of your body together and helps control growth. If you have the defective gene, your body produces fibrillin 1 that does not function as it should. As a result, your connective tissue is not as strong as it should be, and it weakens over time. Fibrillin 1 also plays a role in the growth and development of many of the organs of the body. Defective fibrillin 1 contributes to the tall, thin body type seen in people with Marfan syndrome, as well as other Marfan signs and symptoms.

About 3 out of 4 people with Marfan syndrome inherit the defective gene from a parent. In about 1 out of every 4 people with Marfan syndrome, the gene abnormality occurs due to a chance (spontaneous) mutation of the gene.

Symptoms

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.

Appearance and Body Build

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 Marfan syndrome.
• 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 greater than 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).

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, 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.

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 the aorta grows. In some cases, a dissection does not cause dramatic pain.
• Abnormal heart rhythms called arrhythmias. A person with Marfan syndrome may 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 an overworked 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 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. 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 allows blood 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 an aortic 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.

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, 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.

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 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.

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.

Diagnosis

Although Marfan syndrome is caused by mutations of the fibrillin-1 gene, not all fibrillin-1 mutations are associated with Marfan syndrome. Therefore, genetic testing alone is not enough to diagnose Marfan syndrome. 

Doctors use a set of guidelines called the Ghent criteria to establish the diagnosis of Marfan syndrome. The Ghent criteria specify combinations of family history and symptoms that need to be present in order to diagnose Marfan syndrome. The criteria were updated in 1996 and named for the city in which the expert panel that decided the criteria met. The previous guidelines were called the Berlin criteria.

It is important to note that a person may have some of the features of Marfan syndrome, but not enough to actually be diagnosed with the disorder. In this situation, it is important for the person to be treated for the signs and symptoms he or she does have.

In some cases, Marfan syndrome may not be diagnosed until early adulthood, when the signs and symptoms become more obvious. Infants and children may be diagnosed if the signs and symptoms are obvious or if they are being treated for some other condition. Sometimes Marfan syndrome is identified in children or young adults after a family member has been diagnosed.

Reference:

National Heart, Lung, and Blood Institute, USA.