Marfan syndrome

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.

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

Disorders of the chest and lower body

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:

Other disorders

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.

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Marfan syndrome,

n.pr a hereditary disorder of connective tissue characterized by tall stature, elongated extremities, subluxation of the lens, dilation of the ascending aorta, and “pigeon breast.” It is inherited as an autosomal dominant trait.