Marfan Syndrome

Definition

Marfan syndrome is an inherited disorder of the connective tissue that causes abnormalities of the patient's eyes, cardiovascular system, and musculoskeletal system. It is named for the French pediatrician, Antoine Marfan (1858–1942), who first described it in 1896. Marfan syndrome is sometimes called arachnodactyly, which means "spider-like fingers" in Greek, since one of the characteristic signs of the disease is disproportionately long fingers and toes. It is estimated that one person in every 3000-5000 has Marfan syndrome, or about 50,000 people in the United States. Marfan syndrome is one of the more common inheritable disorders.

Description

Marfan syndrome affects three major organ systems of the body: the heart and circulatory system, the bones and muscles, and the eyes. The genetic mutation responsible for Marfan was discovered in 1991. It affects the body's production of fibrillin, which is a protein that is an important part of connective tissue. Fibrillin is the primary component of the microfibrils that allow tissues to stretch repeatedly without weakening. Because the patient's fibrillin is abnormal, his or her connective tissues are looser than usual, which weakens or damages the support structures of the entire body.

The most common external signs associated with Marfan syndrome include excessively long arms and legs, with the patient's arm span being greater than his or her height. The fingers and toes may be long and slender, with loose joints that can be bent beyond their normal limits. This unusual flexibility is called hypermobility. The patient's face may also be long and narrow, and he or she may have a noticeable curvature of the spine. It is important to note, however, that Marfan patients vary widely in the external signs of their disorder and in their severity; even two patients from the same family may look quite different. Most of the external features of Marfan syndrome become more pronounced as the patient gets older, so that diagnosis of the disorder is often easier in adults than in children. In many cases, the patient may have few or very minor outward signs of the disorder, and the diagnosis may be missed until the patient develops vision problems or cardiac symptoms.

Marfan syndrome by itself does not affect a person's intelligence or ability to learn. There is, however, some clinical evidence that children with Marfan have a slightly higher rate of hyperactivity and attention-deficit disorder (ADD) than the general population. In addition, a child with undiagnosed nearsightedness related to Marfan may have difficulty seeing the blackboard or reading printed materials, and thus do poorly in school.

Marfan syndrome affects males and females equally, and appears to be distributed equally among all races and ethnic groups. The rate of mutation of the fibrillin gene, however, appears to be related to the age of the patient's father; older fathers are more likely to have new mutations appear in chromosome 15.

Causes and symptoms

Marfan syndrome is caused by a single gene for fibrillin on chromosome 15, which is inherited in most cases from an affected parent. Between 15 and 25% of cases result from spontaneous mutations. Mutations of the fibrillin gene (FBNI) are unique to each family affected by Marfan, which makes rapid genetic diagnosis impossible, given present technology. The syndrome is an autosomal dominant disorder, which means that someone who has it has a 50% chance of passing it on to any offspring.

Another important genetic characteristic of Marfan syndrome is variable expression. This term means that the mutated fibrillin gene can produce a variety of symptoms of very different degrees of severity, even in members of the same family.

Cardiac and circulatory abnormalities

The most important complications of Marfan are those affecting the heart and major blood vessels; some are potentially life-threatening. About 90% of Marfan patients will develop cardiac complications.

• Aortic enlargement. This is the most serious potential complication of Marfan syndrome. Because of the abnormalities of the patient's fibrillin, the walls of the aorta (the large blood vessel that carries blood away from the heart) are weaker than normal and tend to stretch and bulge out of shape. This stretching increases the likelihood of an aortic dissection, which is a tear or separation between the layers of tissue that make up the aorta. An aortic dissection usually causes severe pain in the abdomen, back, or chest, depending on the section of the aorta that is affected. Rupture of the aorta is a medical emergency requiring immediate surgery and medication.
• Aortic regurgitation. A weakened and enlarged aorta may allow some blood to leak back into the heart during each heartbeat; this condition is called aortic regurgitation. Aortic regurgitation occasionally causes shortness of breath during normal activity. In serious cases, it causes the left ventricle of the heart to enlarge and may eventually lead to heart failure.
• Mitral valve prolapse. Between 75 and 85% of Marfan patients have loose or "floppy" mitral valves, which are the valves that separate the chambers of the heart. When these valves do not cover the opening between the chambers completely, the condition is called mitral valve prolapse. Complications of mitral valve prolapse include heart murmurs and arrhythmias. In rare cases, mitral valve prolapse can cause sudden death.
• Infective endocarditis. Infective endocarditis is an infection of the endothelium, the tissue that lines the heart. In patients with Marfan, it is the abnormal mitral valve that is most likely to become infected.
• Other complications. Some patients with Marfan develop cystic disease of the lungs or recurrent spontaneous pneumothorax, which is a condition in which air accumulates in the space around the lungs. Many will also eventually develop emphysema.

Musculoskeletal abnormalities

Marfan syndrome causes an increase in the length of the patient's bones, with decreased support from the ligaments that hold the bones together. As a result, the patient may develop various deformities of the skeleton or disorders related to the relative looseness of the ligaments.

Disorders of the spine

• Scoliosis. Scoliosis, or curvature of the spine, is a disorder in which the vertebrae that make up the spine twist out of line from side to side into an S-shape or a spiral. It is caused by a combination of the rapid growth of children with Marfan, and the looseness of the ligaments that help the spine to keep its shape.
• Kyphosis is an abnormal outward curvature of the spine at the back, sometimes called hunch back when it occurs in the upper back. Marfan patients may develop kyphosis either in the upper (thoracic) spine or the lower (lumbar) spine.
• Spondylolisthesis. Spondylolisthesis is the medical term for a forward slippage of one vertebra on the one below it. It produces an ache or stiffness in the lower back.
• Dural ectasia. The dura is the tough, fibrous outermost membrane covering the brain and the spinal cord. The weak dura in Marfan patients swells or bulges under the pressure of the spinal fluid. This swelling is called ectasia. In most cases, dural ectasia occurs in the lower spine, producing low back ache, a burning feeling, or numbness or weakness in the legs.

Disorders of the chest and lower body

• Pectus excavatum. Pectus excavatum is a malformation of the chest in which the patient's breastbone, or sternum, is sunken inward. It can cause difficulties in breathing, especially if the heart, spine, and lung have been affected by Marfan. It also usually causes concerns about appearance.
• Pectus carinatum. In other patients with Marfan the sternum is pushed outward and narrowed. Although pectus carinatum does not cause breathing difficulties, it can cause embarassment about appearance. A few patients with Marfan may have a pectus excavatum on one side of their chest and a pectus carinatum on the other.
• Foot disorders. Patients with Marfan are more likely to develop pes planus (flat feet) or so-called "claw" or "hammer" toes than people in the general population. They are also more likely to suffer from chronic pain in their feet.
• Protrusio acetabulae. The acetabulum is the socket of the hip joint. In patient's with Marfan, the acetabulum becomes deeper than normal during growth, for reasons that are not yet understood. Although protrusio acetabulae does not cause problems during childhood and adolescence, it can lead to a painful form of arthritis in adult life.

Disorders of the eyes and face

Although the visual problems that are related to Marfan syndrome are rarely life-threatening, they are important in that they may be the patient's first indication of the disorder. Eye disorders related to the syndrome include the following:

• Myopia (nearsightedness). Most patients with Marfan develop nearsightedness, usually in childhood.
• Ectopia lentis. Ectopia lentis is the medical term for dislocation of the lens of the eye. Between 65 and 75% of Marfan patients have dislocated lenses. This condition is an important indication for diagnosis of the syndrome because there are relatively few other disorders that produce it.
• Glaucoma. This condition is much more prevalent in patients with Marfan syndrome than in the general population.
• Cataracts. Patients with Marfan are more likely to develop cataracts, and to develop them much earlier in life, sometimes as early as 40 years of age.
• Retinal detachment. Patients with Marfan are more vulnerable to this disorder because of the weakness of their connective tissues. Untreated retinal detachment can cause blindness. The danger of retinal detachment is an important reason for patients to avoid contact sports or other activities that could cause a blow on the head or being knocked to the ground.
• Other facial problems. Patients with Marfan sometimes develop dental problems related to crowding of the teeth caused by a high-arched palate and a narrow jaw.

Other disorders

• Striae. Striae are stretch marks in the skin caused by rapid weight gain or growth; they frequently occur in pregnant women, for example. Marfan patients often develop striae over the shoulders, hips, and lower back at an early age because of rapid bone growth. Although the patient may be self-conscious about the striae, they are not a danger to health.
• Obstructive sleep apnea. Obstructive sleep apnea refers to partial obstruction of the airway during sleep, causing irregular breathing and sometimes snoring. In patients with Marfan, obstructive sleep apnea is caused by the unusual flexibility of the tissues lining the patient's airway. This disturbed breathing pattern increases the risk of aortic dissection.

Diagnosis

Presently, there is no objective diagnostic test for Marfan syndrome, in part because the disorder does not produce any measurable biochemical changes in the patient's blood or body fluids, or cellular changes that could be detected from a tissue sample. Although researchers in molecular biology are currently investigating the FBNI gene through a process called mutational analysis, it is presently not useful as a diagnostic test because there is evidence that there can be mutations in the fibrillin gene that do not produce Marfan. Similarly, there is no reliable prenatal test, although some physicians have used ultrasound to try to determine the length of fetal limbs in at-risk pregnancies.

The diagnosis is made by taking a family history and a thorough examination of the patient's eyes, heart, and bone structure. The examination should include an echocardiogram taken by a cardiologist, a slit-lamp eye examination by an ophthalmologist, and a work-up of the patient's spinal column by an orthopedic specialist. In terms of the cardiac examination, a standard electrocardiogram (EKG) is not sufficient for diagnosis; only the echocardiogram can detect possible enlargement of the aorta. The importance of the slit-lamp examination is that it allows the doctor to detect a dislocated lens, which is a significant indication of the syndrome.

The symptoms of Marfan syndrome in some patients resemble the symptoms of homocystinuria, which is an inherited disorder marked by extremely high levels of homocystine in the patient's blood and urine. This possibility can be excluded by a urine test.

In other cases, the diagnosis remains uncertain because of the mildness of the patient's symptoms, the absence of a family history of the syndrome, and other variables. These borderline conditions are sometimes referred to as marfanoid syndromes.

Treatment

The treatment and management of Marfan is tailored to the specific symptoms of each patient. Some patients find that the syndrome has little impact on their overall lifestyle; others have found their lives centered on the disorder.

Cardiovascular system

After a person has been diagnosed with Marfan, he or she should be monitored with an echocardiogram every six months until it is clear that the aorta is not growing larger. After that, the patient should have an echocardiogram once a year. If the echocardiogram does not allow the physician to visualize all portions of the aorta, CT (computed tomography) or MRI (magnetic resonance imaging ) may be used. In cases involving a possible aortic dissection, the patient may be given a TEE (transesophageal echocardiogram).

Medications. A Marfan patient may be given drugs called beta-blockers to slow down the rate of aortic enlargement and decrease the risk of dissection by lowering the blood pressure and decreasing the forcefulness of the heartbeat. The most commonly used beta-blockers in Marfan patients are propranolol (Inderal) and atenolol (Tenormin). Patients who are allergic to beta-blockers may be given a calcium blocker such as verapamil.

Because Marfan patients are at increased risk for infective endocarditis, they must take a prophylactic dose of an antibiotic before having dental work or minor surgery, as these procedures may allow bacteria to enter the bloodstream. Penicillin and amoxicillin are the antibiotics most often used.

Surgical treatment. Surgery may be necessary if the width of the patient's aorta increases rapidly or reaches a critical size (about 2 inches). As of 2000, the most common surgical treatment involves replacing the patient's aortic valve and several inches of the aorta itself with a composite graft, which is a prosthetic heart valve sewn into one end of a Dacron tube. This surgery has been performed widely since about 1985; most patients who have had a composite graft have not needed additional surgery.

Patients who have had a valve replaced must take an anticoagulant medication, usually warfarin (Coumadin), in order to minimize the possibility of a clot forming on the prosthetic valve.

Musculoskeletal system

Children diagnosed with Marfan should be checked for scoliosis by their pediatricians at each annual physical examination. The doctor simply asks the child to bend forward while the back is examined for changes in the curvature. In addition, the child's spine should be x rayed in order to measure the extent of scoliosis or kyphosis. The curve is measured in degrees by the angle between the vertebrae as seen on the x ray. Curves of 20° or less are not likely to become worse. Curves between 20 and 40 degrees are likely to increase in children or adolescents. Curves of 40 degrees or more are highly likely to worsen, even in an adult, because the spine is so badly imbalanced that the force of gravity will increase the curvature.

Scoliosis between 20 and 40 degrees in children is usually treated with a back brace. The child must wear this appliance about 23 hours a day until growth is complete. If the spinal curvature increases to 40 or 50 degrees, the patient may require surgery in order to prevent lung problems, back pain, and further deformity. Surgical treatment of scoliosis involves straightening the spine with metal rods and fusing the vertebrae in the straightened position.

Spondylolisthesis is treated with a brace in mild cases. If the slippage is more than 30 degree, the slipped vertebra may require surgical realignment.

Dural ectasia can be distinguished from other causes of back pain on an MRI. Mild cases are usually not treated. Medication or spinal shunting to remove some of the spinal fluid are used to treat severe cases.

Pectus excavatum and pectus carinatum can be treated by surgery. In pectus excavatum, the deformed breastbone and ribs are raised and straightened by a metal bar. After four to six months, the bar is removed in an outpatient procedure.

Protrusio acetabulae may require surgery in adult life to provide the patient with an artificial hip joint, if the arthritic pains are severe.

Pain in the feet or limbs is usually treated with a mild analgesic such as acetaminophen. Patients with Marfan should consider wearing shoes with low heels, special cushions, or orthotic inserts. Foot surgery is rarely necessary.

Visual and dental concerns

Patients with Marfan should have a thorough eye examination, including a slit-lamp examination, to test for dislocation of the lens as well as nearsightedness. Dislocation can be treated by a combination of special glasses and daily use of one percent atropine sulfate ophthalmic drops, or by surgery.

Because patients with Marfan are at increased risk of glaucoma, they should have the fluid pressure inside the eye measured every year as part of an eye examination. Glaucoma can be treated with medications or with surgery.

Cataracts are treated with increasing success by implant surgery. It is important, however, to seek treatment at medical centers with eye surgeons familiar with the possible complications of cataract surgery in patients with Marfan syndrome.

All persons with Marfan should be taught to recognize the signs of retinal detachment (sudden blurring of vision in one eye becoming progressively worse without pain or redness) and to seek professional help immediately.

Children with Marfan should be evaluated by their dentist at each checkup for crowding of the teeth and possible misalignment, and referred to an orthodontist if necessary.

Athletic activities and occupational choice. People with Marfan should avoid sports or occupations that require heavy weight lifting, rough physical contact, or rapid changes in atmospheric pressure (e.g., scuba diving). Weight lifting increases blood pressure, which in turn may enlarge the aorta. Rough physical contact may cause retinal detachment. Sudden changes in air pressure may produce pneumothorax. Regular noncompetitive physical exercise, however, is beneficial for Marfan patients. Good choices include brisk walking, shooting baskets, and slow-paced tennis.

Social and lifestyle issues

Smoking. Smoking is particularly harmful for Marfan patients because it increases their risk of emphysema.

Pregnancy. Until very recently, women with Marfan were advised not to become pregnant because of the risk of aortic enlargement or dissection. The development of beta-blockers and echocardiograms, however, allows doctors now to monitor patients throughout pregnancy. It is recommended that patients have an echocardiogram during each of the three trimesters of pregnancy. Normal, vaginal delivery is not necessarily more stressful than a Caesarian section, but patients in prolonged labor may be given a Caesarian to reduce strain on the heart. A pregnant woman with Marfan should also receive genetic counseling regarding the 50% risk of having a child with the syndrome.

Appearance and Social Concerns. Children and adolescents with Marfan may benefit from supportive counseling regarding appearance, particularly if their symptoms are severe and causing them to withdraw from social activities. In addition, families may wish to seek counseling regarding the effects of the syndrome on relationships within the family. Many people respond with guilt, fear, or blame when a genetic disorder is diagnosed in the family, or they may overprotect the affected member. Support groups are often good sources of information about Marfan; they can offer helpful suggestions about living with it as well as emotional support.

Prognosis

The prognosis for patient's with Marfan has improved markedly in recent years. As of 1995, the life expectancy of people with the syndrome has increased to 72 years, up from 48 years in 1972. This dramatic improvement is attributed to new surgical techniques, improved diagnosis, and new techniques of medical treatment.

The most important single factor in improving the patient's prognosis is early diagnosis. The earlier that a patient can benefit from the new techniques and lifestyle modifications, the more likely he or she is to have a longer life expectancy.

Resources

BOOKS

Beers, Mark H., and Robert Berkow, editors. Pediatrics. Whitehouse Station, NJ: Merck Research Laboratories, 1999.

Pyeritz, Reed E., and Cheryll Gasner. The Marfan Syndrome. New York: National Marfan Syndrome, 1999.

KEY TERMS

Arachnodactyly— A condition characterized by abnormally long and slender fingers and toes.

Ectopia lentis— Dislocation of the lens of the eye. It is one of the most important single indicators in diagnosing Marfan syndrome.

Fibrillin— A protein that is an important part of the structure of the body's connective tissue. In Marfan's syndrome, the gene responsible for fibrillin has mutated, causing the body to produce a defective protein.

Hypermobility— Unusual flexibility of the joints, allowing them to be bent or moved beyond their normal range of motion.

Kyphosis— An abnormal outward curvature of the spine, with a hump at the upper back.

Pectus carinatum— An abnormality of the chest in which the sternum (breastbone) is pushed outward. It is sometimes called "pigeon breast."

Pectus excavatum— An abnormality of the chest in which the sternum (breastbone) sinks inward; sometimes called "funnel chest."

Scoliosis— An abnormal, side-to-side curvature of the spine.

Marfan syndrome

Definition

Marfan syndrome is an inherited disorder of the connective tissue that causes abnormalities of a child's eyes, cardiovascular system, and musculoskeletal system. It is named for the French pediatrician, Antoine Marfan (1858-1942), who first described it in 1896.

Description

Marfan syndrome affects three major organ systems of the body: the heart and circulatory system, the bones and muscles, and the eyes. The genetic mutation responsible for Marfan was discovered in 1991. It affects the body's production of fibrillin, which is a protein that is an important part of connective tissue. Fibrillin is the primary component of the microfibrils that allow tissues to stretch repeatedly without weakening. Because the child's fibrillin is abnormal, his or her connective tissues are looser than usual, which weakens or damages the support structures of the entire body.

The most common external signs associated with Marfan syndrome include excessively long arms and legs, with the child's arm span being greater than his or her height. The fingers and toes may be long and slender, with loose joints that can be bent beyond their normal limits. This unusual flexibility is called hypermobility. The child's face may also be long and narrow, and he or she may have a noticeable curvature of the spine. It is important to note, however, that children with Marfan vary widely in the external signs of their disorder and in their severity; even two children from the same family may look quite different. Most of the external features of Marfan syndrome become more pronounced as the child gets older, so that diagnosis of the disorder is often easier in adults than in children. In many cases, the child may have few or very minor outward signs of the disorder, and the diagnosis may be missed until the child develops vision problems or cardiac symptoms.

Marfan syndrome by itself does not affect a child's intelligence or ability to learn. There is, however, some clinical evidence that children with Marfan have a slightly higher rate of hyperactivity and attention-deficit disorder (ADD) than the general population. In addition, a child with undiagnosed nearsightedness related to Marfan may have difficulty seeing the blackboard or reading printed materials, and thus do poorly in school.

Marfan syndrome affects males and females equally, and appears to be distributed equally among all races and ethnic groups. The rate of mutation of the fibrillin gene, however, appears to be related to the age of the child's father; older fathers are more likely to have new mutations appear in chromosome 15.

Marfan syndrome is sometimes called arachnodactyly, which means "spider-like fingers" in Greek, since one of the characteristic signs of the disease is disproportionately long fingers and toes.

Demographics

It is estimated that one person in every 3000-5000 has Marfan syndrome, or about 50,000 people in the United States. Marfan syndrome is one of the more common inheritable disorders.

Causes and symptoms

Marfan syndrome is caused by a single gene for fibrillin on chromosome 15, which is inherited in most cases from an affected parent. Between 15 and 25 percent of cases result from spontaneous mutations. Mutations of the fibrillin gene (FBNI) are unique to each family affected by Marfan, which makes rapid genetic diagnosis impossible, given present technology. The syndrome is an autosomal dominant disorder, which means that someone who has it has a 50 percent chance of passing it on to any offspring.

Another important genetic characteristic of Marfan syndrome is variable expression. This term means that the mutated fibrillin gene can produce a variety of symptoms of very different degrees of severity, even in members of the same family.

Cardiac and circulatory abnormalities

The most important complications of Marfan are those affecting the heart and major blood vessels; some are potentially life-threatening. About 90 percent of children with Marfan will develop cardiac complications, including:

• Aortic enlargement. This is the most serious potential complication of Marfan syndrome. Because of the abnormalities of the child's fibrillin, the walls of the aorta (the large blood vessel that carries blood away from the heart) are weaker than normal and tend to stretch and bulge out of shape. This stretching increases the likelihood of an aortic dissection, which is a tear or separation between the layers of tissue that make up the aorta. An aortic dissection usually causes severe pain in the abdomen, back, or chest, depending on the section of the aorta that is affected. Rupture of the aorta is a medical emergency requiring immediate surgery and medication.
• Aortic regurgitation. A weakened and enlarged aorta may allow some blood to leak back into the heart during each heartbeat; this condition is called aortic regurgitation. Aortic regurgitation occasionally causes shortness of breath during normal activity. In serious cases, it causes the left ventricle of the heart to enlarge and may eventually lead to heart failure.
• Mitral valve prolapse. Between 75 and 85% of children with Marfan have loose or "floppy" mitral valves, which are the valves that separate the chambers of the heart. When these valves do not cover the opening between the chambers completely, the condition is called mitral valve prolapse. Complications of mitral valve prolapse include heart murmurs and arrhythmias. In rare cases, mitral valve prolapse can cause sudden death.
• Infective endocarditis. Infective endocarditis is an infection of the endothelium, the tissue that lines the heart. In children with Marfan, it is the abnormal mitral valve that is most likely to become infected.
• Other complications. Some children with Marfan develop cystic disease of the lungs or recurrent spontaneous pneumothorax, which is a condition in which air accumulates in the space around the lungs. Many will also eventually develop emphysema.

Musculoskeletal abnormalities

Marfan syndrome causes an increase in the length of the child's bones, with decreased support from the ligaments that hold the bones together. As a result, the child may develop various deformities of the skeleton or disorders related to the relative looseness of the ligaments.

Disorders of the spine

Children with Marfan syndrome also can experience spinal disorders, including:

• Scoliosis . Scoliosis, or curvature of the spine, is a disorder in which the vertebrae that make up the spine twist out of line from side to side into an S-shape or a spiral. It is caused by a combination of the rapid growth of children with Marfan, and the looseness of the ligaments that help the spine to keep its shape.
• Kyphosis. Kyphosis is an abnormal outward curvature of the spine at the back, sometimes called hunch back when it occurs in the upper back. Children with Marfan may develop kyphosis either in the upper (thoracic) spine or the lower (lumbar) spine.
• Spondylolisthesis. Spondylolisthesis is the medical term for a forward slippage of one vertebra on the one below it. It produces an ache or stiffness in the lower back.
• Dural ectasia. The dura is the tough, fibrous outermost membrane covering the brain and the spinal cord. The weak dura in a child with Marfan swells or bulges under the pressure of the spinal fluid. This swelling is called ectasia. In most cases, dural ectasia occurs in the lower spine, producing low back ache, a burning feeling, or numbness or weakness in the legs.

Disorders of the chest and lower body

Disorders of the chest and lower body of children with Marfan include:

• Pectus excavatum. Pectus excavatum is a malformation of the chest in which the child's breastbone, or sternum, is sunken inward. It can cause difficulties in breathing, especially if the heart, spine, and lung have been affected by Marfan. It also usually causes concerns about appearance.
• Pectus carinatum. In other children with Marfan, the sternum is pushed outward and narrowed. Although pectus carinatum does not cause breathing difficulties, it can cause embarassment about appearance. A few children with Marfan may have a pectus excavatum on one side of their chest and a pectus carinatum on the other.
• Foot disorders. Children with Marfan are more likely to develop pes planus (flat feet) or so-called "claw" or "hammer" toes than people in the general population. They are also more likely to suffer from chronic pain in their feet.
• Protrusio acetabulae. The acetabulum is the socket of the hip joint. In a child with Marfan, the acetabulum becomes deeper than normal during growth, for reasons that are not yet understood. Although protrusio acetabulae does not cause problems during childhood and adolescence , it can lead to a painful form of arthritis in adult life.

Disorders of the eyes and face

Although the visual problems that are related to Marfan syndrome are rarely life-threatening, they are important in that they may be the child's first indication of the disorder. Eye disorders related to the syndrome include the following:

• Myopia (nearsightedness). Most children with Marfan develop nearsightedness, usually in childhood.
• Ectopia lentis. Ectopia lentis is the medical term for dislocation of the lens of the eye. Between 65 and 75 percent of children with Marfan have dislocated lenses. This condition is an important indication for diagnosis of the syndrome because there are relatively few other disorders that produce it.
• Glaucoma. This condition is much more prevalent in children with Marfan syndrome than in the general population.
• Cataracts. Children with Marfan are more likely to develop cataracts, and to develop them much earlier in life, sometimes as early as 40 years of age.
• Retinal detachment. Children with Marfan are more vulnerable to this disorder because of the weakness of their connective tissues. Untreated retinal detachment can cause blindness. The danger of retinal detachment is an important reason for children to avoid contact sports or other activities that could cause a blow on the head or being knocked to the ground.
• Other facial problems. Children with Marfan sometimes develop dental problems related to crowding of the teeth caused by a high-arched palate and a narrow jaw.

Other disorders

Other disorders associated with Marfan syndrome include:

• Striae. Striae are stretch marks in the skin caused by rapid weight gain or growth; they frequently occur in pregnant women, for example. Children with Marfan often develop striae over the shoulders, hips, and lower back at an early age because of rapid bone growth. Although the child may be self-conscious about the striae, they are not a danger to health.
• Obstructive sleep apnea. Obstructive sleep apnea refers to partial obstruction of the airway during sleep, causing irregular breathing and sometimes snoring. In children with Marfan, obstructive sleep apnea is caused by the unusual flexibility of the tissues lining the child's airway. This disturbed breathing pattern increases the risk of aortic dissection.

When to call the doctor

Prospective parents with a family history of Marfan syndrome should check with their doctor concerning genetic counseling. Also a doctor should be called if a child has symptoms suggestive of Marfan syndrome.

Diagnosis

Presently, there is no objective diagnostic test for Marfan syndrome, in part because the disorder does not produce any measurable biochemical changes in the child's blood or body fluids, or cellular changes that can be detected from a tissue sample. Although researchers in molecular biology are currently investigating the FBNI gene through a process called mutational analysis, it is presently not useful as a diagnostic test because there is evidence that there can be mutations in the fibrillin gene that do not produce Marfan. Similarly, there is no reliable prenatal test, although some physicians have used ultrasound to try to determine the length of fetal limbs in at-risk pregnancies.

The diagnosis is made by taking a family history and a thorough examination of the child's eyes, heart, and bone structure. The examination should include an echocardiogram taken by a cardiologist, a slit-lamp eye examination by an ophthalmologist, and a work-up of the child's spinal column by an orthopedic specialist. In terms of the cardiac examination, a standard electrocardiogram (EKG) is not sufficient for diagnosis; only the echocardiogram can detect possible enlargement of the aorta. The importance of the slit-lamp examination is that it allows the doctor to detect a dislocated lens, which is a significant indication of the syndrome.

The symptoms of Marfan syndrome in some children resemble the symptoms of homocystinuria, which is an inherited disorder marked by extremely high levels of homocystine in the child's blood and urine. This possibility can be excluded by a urine test.

In other cases, the diagnosis remains uncertain because of the mildness of the child's symptoms, the absence of a family history of the syndrome, and other variables. These borderline conditions are sometimes referred to as marfanoid syndromes.

Treatment

The treatment and management of Marfan is tailored to the specific symptoms of each child. Some children find that the syndrome has little impact on their overall lifestyle; others have found their lives centered on the disorder.

Cardiovascular system

After a child has been diagnosed with Marfan, he or she should be monitored with an echocardiogram every six months until it is clear that the aorta is not growing larger. After that, he or she should have an echocardiogram once a year. If the echocardiogram does not allow the physician to visualize all portions of the aorta, CT (computed tomography ) or MRI (magnetic resonance imaging ) may be used. In cases involving a possible aortic dissection, the child may be given a TEE (transesophageal echocardiogram).

Medications. A child with Marfan may be given drugs called beta-blockers to slow down the rate of aortic enlargement and decrease the risk of dissection by lowering the blood pressure and decreasing the forcefulness of the heartbeat. The most commonly used beta-blockers in chidren with Marfan are propranolol (Inderal) and atenolol (Tenormin). Children who are allergic to beta-blockers may be given a calcium blocker such as verapamil.

Because children with Marfan are at increased risk for infective endocarditis, they must take a prophylactic dose of an antibiotic before having dental work or minor surgery, as these procedures may allow bacteria to enter the bloodstream. Penicillin and amoxicillin are the antibiotics most often used.

Surgical treatment. Surgery may be necessary if the width of the child's aorta increases rapidly or reaches a critical size (about 2 inches [5 cm]). The most common surgical treatment involves replacing the child's aortic valve and several inches of the aorta itself with a composite graft, which is a prosthetic heart valve sewn into one end of a Dacron tube. This surgery has been performed widely since about 1985; most children who have had a composite graft have not needed additional surgery. Children who have had a valve replaced must take an anticoagulant medication, usually warfarin (Coumadin), in order to minimize the possibility of a clot forming on the prosthetic valve.

Musculoskeletal system

Children diagnosed with Marfan should be checked for scoliosis by their pediatricians at each annual physical examination. The doctor simply asks the child to bend forward while the back is examined for changes in the curvature. In addition, the child's spine should be x rayed in order to measure the extent of scoliosis or kyphosis. The curve is measured in degrees by the angle between the vertebrae as seen on the x ray. Curves of 20 degrees or less are not likely to become worse. Curves between 20 and 40 degrees are likely to increase in children or adolescents. Curves of 40 degrees or more are highly likely to worsen, even in an adult, because the spine is so badly imbalanced that the force of gravity will increase the curvature.

Scoliosis between 20 and 40 degrees in children is usually treated with a back brace. The child must wear this appliance about 23 hours a day until growth is complete. If the spinal curvature increases to 40 or 50 degrees, the child may require surgery in order to prevent lung problems, back pain, and further deformity. Surgical treatment of scoliosis involves straightening the spine with metal rods and fusing the vertebrae in the straightened position.

Spondylolisthesis is treated with a brace in mild cases. If the slippage is more than 30 degrees, the slipped vertebra may require surgical realignment.

Dural ectasia can be distinguished from other causes of back pain on an MRI. Mild cases are usually not treated. Medication or spinal shunting to remove some of the spinal fluid are used to treat severe cases.

Pectus excavatum and pectus carinatum can be treated by surgery. In pectus excavatum, the deformed breastbone and ribs are raised and straightened by a metal bar. After four to six months, the bar is removed in an outpatient procedure.

Protrusio acetabulae may require artificial hip joint surgery in adult life, if the arthritic pains are severe.

Pain in the feet or limbs is usually treated with a mild analgesic such as acetaminophen . Children with Marfan should consider wearing shoes with low heels, special cushions, or orthotic inserts. Foot surgery is rarely necessary.

Visual and dental concerns

Children with Marfan should have a thorough eye examination, including a slit-lamp examination, to test for dislocation of the lens as well as nearsightedness. Dislocation can be treated by a combination of special glasses and daily use of one percent atropine sulfate ophthalmic drops, or by surgery.

Because children with Marfan are at increased risk of glaucoma, they should have the fluid pressure inside the eye measured every year as part of an eye examination. Glaucoma can be treated with medications or with surgery.

Cataracts are treated with increasing success by implant surgery. It is important, however, to seek treatment at medical centers with eye surgeons familiar with the possible complications of cataract surgery in children with Marfan syndrome.

All children with Marfan should be taught to recognize the signs of retinal detachment (sudden blurring of vision in one eye becoming progressively worse without pain or redness) and ask their parents to seek professional help immediately.

Children with Marfan should be evaluated by their dentist at each checkup for crowding of the teeth and possible misalignment and referred to an orthodontist if necessary.

Athletic activities and occupational choice

Children with Marfan should avoid sports or occupations that require heavy weight lifting, rough physical contact, or rapid changes in atmospheric pressure (e.g., scuba diving). Weight lifting increases blood pressure, which in turn may enlarge the aorta. Rough physical contact may cause retinal detachment. Sudden changes in air pressure may produce pneumothorax. Regular noncompetitive physical exercise , however, is beneficial for children with Marfan. Good choices include brisk walking, shooting baskets, and slow-paced tennis.

KEY TERMS

Arachnodactyly —A condition characterized by abnormally long and slender fingers and toes.

Ectopia lentis —Dislocation of the lens of the eye. It is one of the most important single indicators in diagnosing Marfan syndrome.

Fibrillin —A protein that is an important part of the structure of the body's connective tissue. In Marfan's syndrome, the gene responsible for fibrillin has mutated, causing the body to produce a defective protein.

Hypermobility —Unusual flexibility of the joints, allowing them to be bent or moved beyond their normal range of motion.

Kyphosis —An extreme, abnormal outward curvature of the spine, with a hump at the upper back.

Pectus carinatum —An abnormality of the chest in which the sternum (breastbone) is pushed outward. It is sometimes called "pigeon breast."

Pectus excavatum —An abnormality of the chest in which the sternum (breastbone) sinks inward; sometimes called "funnel chest."

Scoliosis —An abnormal, side-to-side curvature of the spine.

Social and lifestyle issues

Smoking is particularly harmful for children and adolescents with Marfan because it increases their risk of emphysema.

Children and adolescents with Marfan may benefit from supportive counseling regarding appearance, particularly if their symptoms are severe enough to cause them to withdraw from social activities.

Prognosis

The prognosis for children with Marfan has improved markedly in recent years. By 1995, the life expectancy of people with the syndrome increased to 72 years, up from 48 years in 1972. This dramatic improvement is attributed to new surgical techniques, improved diagnosis, and new techniques of medical treatment.

The most important single factor in improving the child's prognosis is early diagnosis. The earlier that a child can benefit from the new techniques and lifestyle modifications, the more likely he or she is to have a longer life expectancy.

Prevention

Marfan syndrome that occurs because of spontaneous new mutations (15% to 25% of the cases) cannot be prevented. However, for prospective parents with a family history of Marfan syndrome, genetic counseling is recommended. Also, older fathers are more likely to have new mutations appear in chromosome 15.

Parental concerns

Families may wish to seek counseling regarding the effects of the syndrome on relationships within the family. Many people respond with guilt, fear , or blame when a genetic disorder is diagnosed in the family, or they may overprotect the affected member. Support groups are often good sources of information about Marfan; they can offer helpful suggestions about living with it as well as emotional support.

Resources

BOOKS

Marfan Syndrome: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References. San Diego, CA: Icon Health Publications, 2004.

The Official Patient's Sourcebook on Klinefelter Syndrome. San Diego, CA: Icon Health Publications, 2002.

PM Medical Health News. 21st Century Complete Medical Guide to Marfan Syndrome: Authoritative Government Documents, Clinical References, and Practical Information for Patients and Physicians. CD-ROM. Washington, DC: Progressive Management, 2004.

Pyeritz, Reed E., and Cheryll Gasner. The Marfan Syndrome. New York: National Marfan Syndrome, 1999.

Robinson, Peter. Marfan Syndrome. New York: Kluwer Academic Publishers, 2004.

ORGANIZATIONS

Alliance of Genetic Support Groups, 4301 Connecticut Avenue, Washington, DC, 20008. (202) 652-5553. <http:www.geneticalliance.org>.

National Marfan Foundation, 22 Manhasset Avenue, Port Washington, NY, 11050-2023. (516) 883-8712, (800). 862-7326. <http:www.marfan.org>.

WEB SITES

Marfan Syndrome, National Institutes of Health. <http://www.nlm.nih.gov/medlineplus/marfansyndrome.html>.

Judith Sims, MS Rebecca J. Frey, PhD

Marfan syndrome

Definition

Marfan syndrome is an inherited disorder of the connective tissue that causes abnormalities of the patient's eyes, cardiovascular system, and musculoskeletal system. It is named for the French pediatrician, Antoine Marfan (1858-1942), who first described it in 1896. Marfan syndrome is sometimes called arachnodactyly, which means "spider-like fingers" in Greek, since one of the characteristic signs of the disease is disproportionately long fingers and toes. It is estimated that one person in every 3,000-5,000 has Marfan syndrome, or about 50,000 people in the United States. Marfan syndrome is one of the more common inheritable disorders.

Description

Marfan syndrome affects three major organ systems of the body: the heart and circulatory system, the bones and muscles, and the eyes. The genetic mutation responsible for Marfan was discovered in 1991. It affects the body's production of fibrillin, which is a protein that is an important part of connective tissue. Fibrillin is the primary component of the microfibrils that allow tissues to stretch repeatedly without weakening. Because the patient's fibrillin is abnormal, his or her connective tissues are looser than usual, which weakens or damages the support structures of the entire body.

The most common external signs associated with Marfan syndrome include excessively long arms and legs, with the patient's arm span being greater than his or her height. The fingers and toes may be long and slender, with loose joints that can bend beyond their normal limits. This unusual flexibility is called hypermobility. The patient's face may also be long and narrow, and he or she may have a noticeable curvature of the spine. It is important to note, however, that Marfan patients vary widely in the external signs of their disorder and in their severity; even two patients from the same family may look quite different. Most of the external features of Marfan syndrome become more pronounced as the patient gets older, so that diagnosis of the disorder is often easier in adults than in children. In many cases, the patient may have few or very minor outward signs of the disorder, and the diagnosis may be missed until the patient develops vision problems or cardiac symptoms.

Marfan syndrome by itself does not affect a person's intelligence or ability to learn. There is, however, some clinical evidence that children with Marfan have a slightly higher rate of attention-deficit and hyperactivity disorder (ADHD) than the general population. In addition, a child with undiagnosed nearsightedness related to Marfan may have difficulty seeing the blackboard or reading printed materials, and thus do poorly in school.

Genetic profile

Marfan syndrome is caused by a single gene for fibrillin on chromosome 15, which is inherited in most cases from an affected parent. Between 15% and 25% of cases result from spontaneous mutations. Mutations of the fibrillin gene (FBNI) are unique to each family affected by Marfan, which makes rapid genetic diagnosis impossible, given present technology. The syndrome is an autosomal dominant disorder, which means that someone who has it has a 50% chance of passing it on to any offspring.

Another important genetic characteristic of Marfan syndrome is variable expression. This term means that the mutated fibrillin gene can produce a variety of symptoms of very different degrees of severity, even in members of the same family.

Demographics

Marfan syndrome affects males and females equally, and appears to be distributed equally among all races and ethnic groups. The rate of mutation of the fibrillin gene, however, appears to be related to the age of the patient's father; older fathers are more likely to have new mutations appear in chromosome 15.

Signs and symptoms

Cardiac and circulatory abnormalities

The most important complications of Marfan syndrome are those affecting the heart and major blood vessels; some are potentially life-threatening. About 90% of Marfan patients will develop cardiac complications.

• Aortic enlargement. This is the most serious potential complication of Marfan syndrome. Because of the abnormalities of the patient's fibrillin, the walls of the aorta (the large blood vessel that carries blood away from the heart) are weaker than normal and tend to stretch and bulge out of shape. This stretching increases the likelihood of an aortic dissection, which is a tear or separation between the layers of tissue that make up the aorta. An aortic dissection usually causes severe pain in the abdomen, back, or chest, depending on the section of the aorta that is affected. Rupture of the aorta is a medical emergency requiring immediate surgery and medication.
• Aortic regurgitation. A weakened and enlarged aorta may allow some blood to leak back into the heart during each heartbeat; this condition is called aortic regurgitation. Aortic regurgitation occasionally causes shortness of breath during normal activity. In serious cases, it causes the left ventricle of the heart to enlarge and may eventually lead to heart failure.
• Mitral valve prolapse. Between 75% and 85% of patients with Marfan syndrome have loose or "floppy" mitral valves, which are the valves that separate the chambers of the heart. When these valves do not cover the opening between the chambers completely, the condition is called mitral valve prolapse. Complications of mitral valve prolapse include heart murmurs and arrhythmias. In rare cases, mitral valve prolapse can cause sudden death.
• Infective endocarditis. Infective endocarditis is an infection of the endothelium, the tissue that lines the heart. In patients with Marfan syndrome, it is the abnormal mitral valve that is most likely to become infected.
• Other complications. Some patients with Marfan syndrome develop cystic disease of the lungs or recurrent spontaneous pneumothorax, a condition in which air accumulates in the space around the lungs. Many patients will also eventually develop emphysema.

Musculoskeletal abnormalities

Marfan syndrome causes an increase in the length of the patient's bones, with decreased support from the ligaments that hold the bones together. As a result, the patient may develop various deformities of the skeleton or disorders related to the relative looseness of the ligaments.

Disorders of the spine

• Scoliosis . Scoliosis, or curvature of the spine, is a disorder in which the vertebrae that make up the spine twist out of line from side to side into an S-shape or a spiral. It is caused by a combination of the rapid growth of children with Marfan, and the looseness of the ligaments that help the spine to keep its shape.
• Kyphosis is an abnormal outward curvature of the spine, sometimes called hunchback when it occurs in the upper back. Patients with Marfan syndrome may develop kyphosis either in the upper (thoracic) spine or the lower (lumbar) spine.
• Spondylolisthesis. Spondylolisthesis is the medical term for a forward slippage of one vertebra on the one below it. It produces an ache or stiffness in the lower back.
• Dural ectasia. The dura is the tough, fibrous outermost membrane covering the brain and the spinal cord. The weak dura in patients with Marfan syndrome swells or bulges under the pressure of the spinal fluid. This swelling is called ectasia. In most cases, dural ectasia occurs in the lower spine, producing low back ache, a burning feeling, or numbness or weakness in the legs.

Disorders of the chest and lower body

• Pectus excavatum. Pectus excavatum is a malformation of the chest in which the patient's breastbone, or sternum, is sunken inward. It can cause difficulties in breathing, especially if the heart, spine, and lung have been affected by Marfan. It also usually causes concerns about appearance.
• Pectus carinatum. In other patients with Marfan syndrome the sternum is pushed outward and narrowed. Although pectus carinatum does not cause breathing difficulties, it can cause embarrassment about appearance. A few patients may have a pectus excavatum on one side of their chest and a pectus carinatum on the other.
• Foot disorders. Patients with Marfan syndrome are more likely to develop pes planus (flat feet) or socalled "claw" or "hammer" toes than people in the general population. They are also more likely to have chronic pain in their feet.
• Protrusio acetabulae. The acetabulum is the socket of the hip joint. In patient's with Marfan syndrome, the acetabulum becomes deeper than normal during growth for reasons that are not yet understood. Although protrusio acetabulae does not cause problems during childhood and adolescence, it can lead to a painful form of arthritis in adult life.

Disorders of the eyes and face

Although the visual problems that are related to Marfan syndrome are rarely life-threatening, they are important in that they may be the patient's first indication of the disorder. Eye disorders related to the syndrome include the following:

• Myopia (nearsightedness). Most patients with Marfan develop nearsightedness, usually in childhood.
• Ectopia lentis. Ectopia lentis is the medical term for dislocation of the lens of the eye. Between 65% and 75% of patients with Marfan syndrome have dislocated lenses. This condition is an important indication for diagnosis of the syndrome because there are relatively few other disorders that produce it.
• Glaucoma . This condition is much more prevalent in patients with Marfan syndrome than in the general population.
• Cataracts. Patients with Marfan are more likely to develop cataracts, and to develop them much earlier in life, sometimes as early as 40 years of age.
• Retinal detachment. Patients with Marfan syndrome are more vulnerable to this disorder because of the weakness of their connective tissues. Untreated retinal detachment can cause blindness. The danger of retinal detachment is an important reason for patients to avoid contact sports or other activities that could cause a blow on the head or being knocked to the ground.
• Other facial problems. Patients with Marfan syndrome sometimes develop dental problems related to crowding of the teeth caused by a high-arched palate and a narrow jaw.

Other disorders

• Striae. Striae are stretch marks in the skin caused by rapid weight gain or growth; they frequently occur in pregnant women, for example. Patients with Marfan often develop striae over the shoulders, hips, and lower back at an early age because of rapid bone growth. Although the patient may be self-conscious about the striae, they are not a danger to health.
• Obstructive sleep apnea. Obstructive sleep apnea refers to partial obstruction of the airway during sleep, causing irregular breathing and sometimes snoring. In patients with Marfan syndrome, obstructive sleep apnea is caused by the unusual flexibility of the tissues lining the patient's airway. This disturbed breathing pattern increases the risk of aortic dissection.

Diagnosis

Presently, there is no objective diagnostic test for Marfan syndrome, in part because the disorder does not produce any measurable biochemical changes in the patient's blood or body fluids, or cellular changes that could be detected from a tissue sample. Although researchers in molecular biology are currently investigating the FBNI gene through a process called mutational analysis, it is presently not useful as a diagnostic test because there is evidence that there can be mutations in the fibrillin gene that do not produce Marfan syndrome. Similarly, there is no reliable prenatal test, although some physicians have used ultrasound to try to determine the length of fetal limbs in at-risk pregnancies.

The diagnosis is made by taking a family history and a thorough examination of the patient's eyes, heart, and bone structure. The examination should include an echocardiogram taken by a cardiologist, a slit-lamp eye examination by an ophthalmologist, and a work-up of the patient's spinal column by an orthopedic specialist. In terms of the cardiac examination, a standard electrocardiogram (EKG) is not sufficient for diagnosis; only the echocardiogram can detect possible enlargement of the aorta. The importance of the slit-lamp examination is that it allows the doctor to detect a dislocated lens, which is a significant indication of the syndrome.

The symptoms of Marfan syndrome in some patients resemble the symptoms of homocystinuria , which is an inherited disorder marked by extremely high levels of homocystine in the patient's blood and urine. This possibility can be excluded by a urine test.

In other cases, the diagnosis remains uncertain because of the mildness of the patient's symptoms, the absence of a family history of the syndrome, and other variables. These borderline conditions are sometimes referred to as marfanoid syndromes.

Treatment and management

The treatment and management of Marfan syndrome is tailored to the specific symptoms of each patient. Some patients find that the syndrome has little impact on their overall lifestyle; others have found their lives centered on the disorder.

Cardiovascular system

After a person has been diagnosed with Marfan syndrome, he or she should be monitored with an echocardiogram every six months until it is clear that the aorta is not growing larger. After that, the patient should have an echocardiogram once a year. If the echocardiogram does not allow the physician to visualize all portions of the aorta, CT (computed tomography) or MRI (magnetic resonance imaging) may be used. In cases involving a possible aortic dissection, the patient may be given a TEE (transesophageal echocardiogram).

MEDICATIONS A patient may be given drugs called beta-blockers to slow down the rate of aortic enlargement and decrease the risk of dissection by lowering the blood pressure and decreasing the forcefulness of the heartbeat. The most commonly used beta-blockers in patients with Marfan syndrome are propranolol (Inderal) and atenolol (Tenormin). Patients who are allergic to beta-blockers may be given a calcium blocker such as verapamil.

Because patients with Marfan syndrome are at increased risk for infective endocarditis, they must take a prophylactic dose of an antibiotic before having dental work or minor surgery, as these procedures may allow bacteria to enter the bloodstream. Penicillin and amoxicillin are the antibiotics most often used.

SURGICAL TREATMENT Surgery may be necessary if the width of the patient's aorta increases rapidly or reaches a critical size (about 2 in, 5 cm). The most common surgical treatment involves replacing the patient's aortic valve and several inches of the aorta itself with a composite graft, which is a prosthetic heart valve sewn into one end of a Dacron tube. This surgery has been performed widely since about 1985; most patients who have had a composite graft have not needed additional surgery.

Patients who have had a valve replaced must take an anticoagulant medication, usually warfarin (Coumadin), in order to minimize the possibility of a clot forming on the prosthetic valve.

Musculoskeletal system

Children diagnosed with Marfan syndrome should be checked for scoliosis by their pediatricians at each annual physical examination. The doctor simply asks the child to bend forward while the back is examined for changes in the curvature. In addition, the child's spine should be x rayed in order to measure the extent of scoliosis or kyphosis. The curve is measured in degrees by the angle between the vertebrae as seen on the x ray. Curves of 20° or less are not likely to become worse. Curves between 20° and 40° are likely to increase in children or adolescents. Curves of 40° or more are highly likely to worsen, even in an adult, because the spine is so badly imbalanced that the force of gravity will increase the curvature.

Scoliosis between 20° and 40° in children is usually treated with a back brace. The child must wear this appliance about 23 hours a day until growth is complete. If the spinal curvature increases to 40° or 50°, the patient may require surgery in order to prevent lung problems, back pain, and further deformity. Surgical treatment of scoliosis involves straightening the spine with metal rods and fusing the vertebrae in the straightened position.

Spondylolisthesis is treated with a brace in mild cases. If the slippage is more than 30°, the slipped vertebra may require surgical realignment.

Dural ectasia can be distinguished from other causes of back pain on an MRI. Mild cases are usually not treated. Medication or spinal shunting to remove some of the spinal fluid are used to treat severe cases.

Pectus excavatum and pectus carinatum can be treated by surgery. In pectus excavatum, the deformed breastbone and ribs are raised and straightened by a metal bar. After four to six months, the bar is removed in an outpatient procedure.

Protrusio acetabulae may require surgery in adult life to provide the patient with an artificial hip joint, if the arthritic pains are severe.

Pain in the feet or limbs is usually treated with a mild analgesic such as acetaminophen. Patients with Marfan syndrome should consider wearing shoes with low heels, special cushions, or orthotic inserts. Foot surgery is rarely necessary.

Visual and dental concerns

Patients with Marfan syndrome should have a thorough eye examination, including a slit-lamp examination, to test for dislocation of the lens as well as nearsightedness. Dislocation can be treated by a combination of special glasses and daily use of 1% atropine sulfate ophthalmic drops, or by surgery.

Because patients with Marfan syndrome are at increased risk of glaucoma, they should have the fluid pressure inside the eye measured every year as part of an eye examination. Glaucoma can be treated with medications or with surgery.

Cataracts are treated with increasing success by implant surgery. It is important, however, to seek treatment at medical centers with eye surgeons familiar with the possible complications of cataract surgery in patients with Marfan syndrome.

All persons with Marfan syndrome should be taught to recognize the signs of retinal detachment (sudden blurring of vision in one eye becoming progressively worse without pain or redness) and to seek professional help immediately.

Children with Marfan syndrome should be evaluated by their dentist at each checkup for crowding of the teeth and possible misalignment, and referred to an orthodontist if necessary.

People with Marfan syndrome should avoid sports or occupations that require heavy weight lifting, rough physical contact, or rapid changes in atmospheric pressure (e.g., scuba diving). Weight lifting increases blood pressure, which in turn may enlarge the aorta. Rough physical contact may cause retinal detachment. Sudden changes in air pressure may produce pneumothorax. Regular noncompetitive physical exercise, however, is beneficial for patients with Marfan syndrome. Good choices include brisk walking, shooting baskets, and slow-paced tennis.

Social and lifestyle issues

Smoking is particularly harmful for patients with Marfan because it increases their risk of emphysema.

Until very recently, women with Marfan syndrome were advised to avoid pregnancy because of the risk of aortic enlargement or dissection. The development of beta-blockers and echocardiograms, however, allows doctors now to monitor patients throughout pregnancy. It is recommended that patients have an echocardiogram during each of the three trimesters of pregnancy. Normal, vaginal delivery is not necessarily more stressful than a Caesarian section, but patients in prolonged labor may have a Caesarian birth to reduce strain on the heart. A pregnant woman with Marfan syndrome should also receive genetic counseling regarding the 50% risk of having a child with the syndrome.

Children and adolescents with Marfan syndrome may benefit from supportive counseling regarding appearance, particularly if their symptoms are severe and causing them to withdraw from social activities. In addition, families may wish to seek counseling regarding the effects of the syndrome on relationships within the family. Many people respond with guilt, fear, or blame when a genetic disorder is diagnosed in the family, or they may overprotect the affected member. Support groups are often good sources of

information about Marfan syndrome; they can offer helpful suggestions about living with it as well as emotional support.

Prognosis

The prognosis for patient's with Marfan syndrome has improved markedly in recent years. As of 1995, the life expectancy of people with the syndrome had increased to 72 years; up from 48 years in 1972. This dramatic improvement is attributed to new surgical techniques, improved diagnosis, and new techniques of medical treatment.

The most important single factor in improving the patient's prognosis is early diagnosis. The earlier that a patient can benefit from the new techniques and lifestyle modifications, the more likely he or she is to have a longer life expectancy.

Resources

BOOKS

Beers, Mark H., and Robert Berkow, eds. Pediatrics. Whitehouse Station, NJ: Merck Research Laboratories, 1999.

Pyeritz, Reed E., and Cheryll Gasner. The Marfan Syndrome. New York: National Marfan Syndrome, 1999.

Thoene, Jess G. "Marfan Syndrome." In Physician's Guide to Rare Diseases. 2nd ed. Montvale, NJ: Dowden Publishing Company, Inc., 1995.

Wynbrandt, James, and Mark D. Ludman. "Marfan Syndrome." In The Encyclopedia of Genetic Disorders and Birth Defects. New York and Oxford: Facts on File, 1991.

PERIODICALS

DePaepe, A., et al. "Revised diagnostic criteria for the Marfan syndrome." American Journal of Medical Genetics 62 (1996): 417–26.

Shores, J., et al. "Progression of Aortic Dilatation and the Benefit of Long-Term β-Adrenergic Blockade in Marfan's Syndrome" New England Journal of Medicine 330 (1994): 1335–41.

Silverman, D., et al. "Life expectancy in the Marfan syndrome." American Journal of Cardiology 75 (1995): 157–60.

ORGANIZATION

Alliance of Genetic Support Groups. 4301 Connecticut Avenue, Washington, DC, 20008. (202) 652-5553. <http://www.geneticalliance.org>.

National Marfan Foundation. 382 Main Street, Port Washington, NY, 11050. (516) 883-8712. <http://www.marfan.org>.

Rebecca J. Frey, PhD

Marfan Syndrome

Symptoms

History

Cause and treatment

Resources

Marfan syndrome is a 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 of the disease is about one in 10,000 persons, and the disorder is inherited with variable expression. This term means that each individual may have a different combination of the possible clinical features that characterize the disorder. There is no cure for the disorder.

Symptoms

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.

History

Former U.S. President Abraham Lincoln (1809–1865) was thought to have Marfan syndrome in that he manifested several key clinical features. However, it was not until after he died, in 1896, when French pediatrician Antoine Marfan (1858–1942) first described a specific cluster of skeletal abnormalities in a five year old girl who was thin, and had long limbs and abnormally long fingers and toes. Marfan compared the girl’s long digits to the legs of a spider, which gave the condition its medical name, arachnodacryly, from the Greek word for spider, arachne.

Marfan’s findings had been suggested 20 years earlier by an eye doctor in Cincinnati, Ohio, who described a tremor in the irises of a brother and sister with long limbs and exceptionally flexible joints—all subsequently shown to be characteristic symptoms of Marfan’s syndrome. Later, observers noted that Marfan’s patients also are often tall and thin, with a long and narrow face, and may have a curved spine and a protruding or sunken breastbone. Most serious, it was found that the heart valves in Marfan’s patients tend to leak, and the aorta—the body’s largest artery—tends to enlarge and develop aneurysms, weak spots that may suddenly and fatally burst.

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 its functional significance studied.

Cause and treatment

In 1991, researchers discovered that a defective gene on chromosome 15 causes the syndrome. The severity of the disease will vary depending on the type of mutation, which affects the production of a protein call fibrillin, which is a protein that plays a role in the characteristically elastic properties of connective tissue. As a result, individuals with the syndrome apparently have insufficient amounts tiny fibers, which provide strength and elasticity to normal connective tissue. The biochemical abnormality that leads to Marfan syndrome is not well understood. Biochemical defects are thought to involve the synthesis, secretion and

KEY TERMS

Aorta —The major blood vessel leaving the heart and carrying blood to numerous other smaller vessels that branch off and deliver blood to the entire body.

Connective tissue —A biochemically distinct group of the body’s tissues, which provide structural support for other body tissues. Examples of connective tissue include bone and cartilage.

Mitral valve —A one way gateway for blood leaving the heart, located at the aorta.

incorporation of fibrillin into connective tissue. Research is under way to identify the various mutations that cause the disorder.

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 wing-span, 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.

Patients of Marfan’s syndrome must be regularly monitored via echocardiography to check the size of the aorta and may need to be medicated with beta blockers, which reduce stress on the aorta by lowering the heart rate and contraction strength. The lifespan of a Marfan’s syndrome patient is shortened, with survival likely only into the sixties. The results of undiagnosed or unmonitored Marfan’s can be tragic, as in the case of Flo Hyman, a 6-foot-5-inch (about two meters) Olympic volleyball star who died of an aorta rupture while on tour; her Marfan’s was discovered only by autopsy.

See also Circulatory system; Gene mutation; Genetic disorders; Genetic engineering; Genetics.

Resources

BOOKS

Marfan Syndrome: Obstetric Issues. Port Washington, NY: National Marfan Foundation, 2004.

Nussbaum, Robert L., Roderick R. McInnes, Huntington F. Willard. Genetics in Medicine. Philadelphia, PA: Saunders, 2001.

Pveritz, Reed E., and Cheryll Gasner. The Marfan Syndrome. Port Washington, NY: National Marfan Foundation, 2001.

Rimoin, David L. Emery and Rimoin’s Principles and Practice of Medical Genetics. New York: Churchill Livingstone, 2002.

Robinson, Peter, N., and Maurice Godrey. Marfan Syndrome: A Primer for Clinicians and Scientists. Georgetown, TX: Landes Bioscience; New York: Kluwer Academic/Plenum, 2004.

PERIODICALS

McKusick, Victor A. “The Cardiovascular Aspects of Marfan’s Syndrome.” Circulation 11 (1955): 321–342.

OTHER

Doctor Zebra. “The Medical History of President Abraham Lincoln.” September 28, 2002. <http://www.doctorzebra.com/prez/g16.htm> (accessed November 30, 2006).

National Marfan Foundation (NMF). “Home page of NMF.” February 19, 2002. <http://www.marfan.org/nmf/index.jsp> (November 22, 2002).

Bryan Cobb

Marfan Syndrome

What Is Marfan Syndrome?

What Causes Marfan Syndrome?

What Are the Signs and Symptoms of Marfan Syndrome?

How Is Marfan Syndrome Diagnosed?

How Is Marfan Syndrome Treated and Prevented?

Resource

Marfan syndrome involves the body’s connective tissue and is characterized by abnormalities in the skeleton, hearty and eyes. It is caused by an abnormal gene* that usually is inherited. People with Marfan syndrome are generally taller than average, have little body fat, and have long, thin fingers.

KEYWORDS

for searching the Internet and other reference sources

Circulation

Heredity

Myopia

Skeletal disorders

*genes

are chemicals in the body that help determine a person’s characteristics, such as hair or eye color. They are inherited from a person’s parents and are contained in the chromosomes found in the cells of the body

What Is Marfan Syndrome?

Marfan syndrome was first described in 1896 by the French physician Antonine Marfan. Some famous people of the past, such as Abraham Lincoln, who was very tall and lanky, and the brilliant violinist Niccolo Paganini, who had very long fingers, are believed by some to have had Marfan syndrome. Today, the disorder has received attention in the media largely as a result of health problems and deaths among very tall athletes, such as some basketball and volleyball players. Still, the disorder is rare.

Marfan syndrome affects only about 1 to 2 persons of every 10,000. In the United States, it has been estimated that 40,000 or more people have the disorder. It affects men and women in equal numbers, as well as people of all racial and ethnic groups. Marfan syndrome can affect the heart and aorta*, the eyes, and the skeleton.

*aorta

is the main artery that carries blood from the heart to the body

What Causes Marfan Syndrome?

For many years, it had been known that Marfan syndrome was inherited. It had been observed that if someone had the disorder, each of his or her children would have about a 50 percent chance of developing it as well. However, it was not known what gene or genes were responsible for the disorder.

Then, in the early 1990s, researchers found that the condition is caused by a single abnormal gene. This gene is involved in the production of a type of protein, called fibrillin, which gives connective tissue its strength. Connective tissue is the material that holds in place all the structures of the body. When the gene is defective, it causes critical changes in fibrillin that may weaken and loosen the connective tissue. This effect, in turn, causes the wide range of features, such as tall stature and loose joints, that are found in Marfan syndrome. It is not as yet known just how alterations in the genes produce these features.

Although anyone born to a parent with Marfan syndrome has a 50-50 chance of inheriting the disorder, an estimated 25 percent of people with Marfan syndrome do not have a parent who has it. This is because a person can have the defective gene owing to a spontaneous mutation, or change, in the normal gene.

What Are the Signs and Symptoms of Marfan Syndrome?

The characteristic signs and symptoms of Marfan syndrome usually do not begin to become apparent until about age 10. When they do emerge, they may involve any or all of three parts of the body: the skeleton, the circulatory system (heart and blood vessels), and the eyes.

The Skeleton

A person who has Marfan syndrome usually (but not always) grows to be very tall and thin. The fingers also tend to be long and thin, or “spidery.” The head is sometimes elongated too, and the chest may have a caved-in look. The joints tend to be supple and loose, and are prone to becoming dislocated. Sometimes there may be scoliosis (sko-lee-O-sis), a side-to-side curvature of the spine.

The Circulatory System

The most serious features of Marfan syndrome involve the heart and aorta, the main artery that carries blood directly from the heart to the body. A characteristic defect in one of the valves of the heart (mitral valve) can cause irregular heart rhythm. Weakness in the aorta can allow it to widen, eventually leading to the development of an aneurysm (AN-yoo-riz-um), a weakness or bulge. If undiscovered or untreated, the weak spot in the aorta can rupture, causing severe internal hemorrhage and death, without warning.

The Eyes

A common symptom of Marfan syndrome is myopia (my-O-pee-uh), or nearsightedness. In addition, in about half of individuals with the disorder, there is dislocation of the lens of the eye, which can make cataracts (clouding of the lens of the eye) more likely to develop.

How Is Marfan Syndrome Diagnosed?

Marfan syndrome can be difficult to diagnose. As yet no single laboratory test can identify it. Some people with the condition do not have all of its characteristic signs. Conversely, most people who are tall, lanky, and nearsighted do not have Marfan syndrome. (Again, the disorder is rare.)

Accurate diagnosis is made from a combination of one’s family history and a complete physical examination that focuses on the skeleton, heart and aorta, and the eyes. An echocardiogram (ek-o-KAR-de-o-gram), a picture of the heart produced by using sound waves, can detect abnormalities in the heart and aorta. Eye doctors can look for possible lens dislocations.

The recent identification of the gene that causes Marfan syndrome, and of fibrillin as the component of connective tissue affected by the gene, will likely aid in future diagnosis.

How Is Marfan Syndrome Treated and Prevented?

Treatment and prevention of complications depend upon the individual symptoms of the person affected by the syndrome. Main aspects include annual echocardiograms to watch for enlargement of the aorta and to monitor heart function, and continuing eye examinations to detect lens dislocation. Medications called beta-blockers may be prescribed to lower blood pressure to help prevent aneurysms from developing in the aorta. Braces can be used to correct spinal curvature.

Abraham Lincoln

Abraham Lincoln had elongated fingers and was very tall (6 feet, 4 inches), which are attributes that are among the most visible and easily recognized signs of Marfan syndrome. For this reason, some experts believe that he may have had the disorder. However, because the syndrome was not medically known in his day, and because many others with these characteristics do not have it, no one knows for sure. Today, people growing up with Marfan syndrome might find encouragement in knowing that Abraham Lincoln may have had some of the difficulties that they have experienced, and that he overcame them.

In terms of lifestyle, strenuous sports may have to be avoided to reduce the risk of damage to the aorta. Genetic counseling is advisable for anyone thinking about having children, because of the risk that children will inherit the condition. Although there is no cure for Marfan syndrome, working closely with one’s doctor in an ongoing monitoring and treatment program can greatly improve the outlook for long life.

See also

Aneurysm

Cataracts

Genetic Diseases

Nearsightedness

Scoliosis

Resource

The National Marfan Foundation website has links to support groups and other resources.
http://www.marfan.org/

The National Institutes of Health posts information about Marfan syndrome on its website.
http://www.nih.gov/niams/healthinfo/marfan.htm