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Marfan syndrome

 
Medical Encyclopedia: Marfan syndrome
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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 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.

— Rebecca J. Frey, PhD


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Dictionary: Mar·fan syndrome   (mär'făn) pronunciation
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n.
A genetic disorder principally affecting the connective tissues of the body, manifested in varying degrees by excessive bone elongation and joint flexibility and by abnormalities of the eye and cardiovascular system.

[After Antonin Bernard Jean Marfan (1858-1942), French pediatrician.]


Britannica Concise Encyclopedia: Marfan syndrome
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Rare hereditary disorder of connective tissue. Affected persons are tall, with long, thin limbs and spiderlike fingers (arachnodactyly). The lens of the eye is dislocated, and many have glaucoma or detached retina. Heart muscle abnormalities and various malfunctions and malformations occur; rupture of the aorta is the most common cause of death. Severity varies; affected individuals may die young or live essentially normal lives. The underlying abnormality cannot be cured, but some of the defects can be surgically corrected.

For more information on Marfan syndrome, visit Britannica.com.

Dental Dictionary: Marfan syndrome
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n.pr

Tall, thin stature, long, tapered fingers and toes (arachnodactyly), dislocation of the lens of the eye (ectopia lentis), and aneurysm leading to rupture of the aorta.

Children's Health Encyclopedia: Marfan Syndrome
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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.

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, andAnnotated 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 MedicalGuide 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. .

National Marfan Foundation, 22 Manhasset Avenue, Port Washington, NY, 11050-2023. (516) 883-8712, (800). 862-7326. .

Web Sites

Marfan Syndrome, National Institutes of Health. .

[Article by: Judith Sims, MS Rebecca J. Frey, PhD]


Sports Science and Medicine: Marfan's syndrome
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An inherited connective tissue disorder that can affect several organ systems. It may cause sudden cardiac death if the heart is affected. Anyone with a family history of Marfan's syndrome should be screened before taking part in sport or a strenuous activity.

Veterinary Dictionary: Marfan's syndrome
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Congenital defect in calves comparable to an inherited human defect; enlargement of the aortic root associated with a loud systolic murmur on the left side, long, thin limbs, joint laxity, lenticular displacement and opacity.

Wikipedia: Marfan syndrome
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"Marfan" redirects here. For the man who discovered the syndrome, see Antoine Marfan.
Marfan syndrome
Classification and external resources

Micrograph demonstrating myxomatous degeneration of the aortic valve - a common manifestation of Marfan syndrome.
ICD-10 Q87.4
ICD-9 759.82
OMIM 154700
DiseasesDB 7845
MedlinePlus 000418
eMedicine ped/1372 orthoped/414
MeSH D008382

Marfan syndrome (also called Marfan's syndrome) is a genetic disorder of the connective tissue.

It is sometimes inherited as a dominant trait. It is carried by a gene called FBN1, which encodes a connective protein called fibrillin-1.[1][2] People have a pair of FBN1 genes. Because it is dominant, people who have inherited one affected FBN1 gene from either parent will have Marfan's. This syndrome can run from mild to severe.

People with Marfan's are typically tall, with long limbs and long thin fingers.

The most serious complications are the defects of the heart valves and aorta. It may also affect the lungs, eyes, the dural sac surrounding the spinal cord, skeleton and the hard palate.

In addition to being a connective protein that forms the structural support for tissues outside the cell, the normal fibrillin-1 protein binds to another protein, transforming growth factor beta (TGF-β).[3] TGF-β has deleterious effects on vascular smooth muscle development and the integrity of the extracellular matrix. Researchers now believe that secondary to mutated fibrillin there is excessive TGF-β at the lungs, heart valves, and aorta, and this weakens the tissues and causes the features of Marfan syndrome. [4]Since angiotensin II receptor blockers (ARBs) also reduce TGF-β, they have tested this by giving ARBs (losartan, etc.) to a small sample of young, severely affected Marfan syndrome patients. In some patients, the growth of the aorta was indeed reduced.[5]

It is named after Antoine Marfan,[6] the French pediatrician who first described the condition in 1896 after noticing striking features in a 5-year-old girl.[7][8] The gene linked to the disease was first identified by Francesco Ramirez at the Mount Sinai Medical Center in New York City in 1991.[9]

Contents

Symptoms

Although there are no unique signs or symptoms of Marfan syndrome, the constellation of long limbs, dislocated lenses, and aortic root dilation is sufficient to make the diagnosis with confidence. There are more than 30 other clinical features that are variably associated with the syndrome, most involving the skeleton, skin, and joints. There is a great deal of clinical variability even within families that carry the identical mutation.

Skeletal system

The most readily visible signs are associated with the skeletal system. Many individuals with Marfan syndrome grow to above average height. Some have long slender limbs with long fingers and toes (arachnodactyly). This condition of elongated limbs is known as dolichostenomelia. An individual's arms may be disproportionately long, with thin, weak wrists. In addition to affecting height and limb proportions, Marfan syndrome can produce other skeletal anomalies. Abnormal curvature of the spine (scoliosis) is common, as is abnormal indentation (pectus excavatum) or protrusion (pectus carinatum) of the sternum. Other signs include abnormal joint flexibility, a high palate, malocclusions, flat feet, hammer toes, stooped shoulders, unexplained stretch marks on the skin and thin wrists. It can also cause pain in the joints, bones and muscles in some patients. Some people with Marfan have speech disorders resulting from symptomatic high palates and small jaws. Early osteoarthritis may occur.

Eyes

Lens dislocation in Marfan's syndrome, the lens was kidney-shaped and was resting against the ciliary body.

Marfan syndrome can also seriously affect the eyes and vision. Nearsightedness and astigmatism are common, but farsightedness can also result. Subluxation (dislocation) of the crystalline lens in one or both eyes (ectopia lentis) (in 80% of patients) also occurs and may be detected by an ophthalmologist or optometrist using a slit-lamp biomicroscope. In Marfan's the dislocation is typically superotemporal whereas in the similar condition homocystinuria, the dislocation is inferonasal. Sometimes eye problems appear only after the weakening of connective tissue has caused detachment of the retina.[10] Early onset glaucoma can be another related problem.

Cardiovascular system

The most serious signs and symptoms associated with Marfan syndrome involve the cardiovascular system. Undue fatigue, shortness of breath, heart palpitations, racing heartbeats, or Angina pectoris with pain radiating to the back, shoulder, or arm. Cold arms, hands and feet can also be linked to Marfan's syndrome because of inadequate circulation. A heart murmur, abnormal reading on an EKG, or symptoms of angina can indicate further investigation. The signs of regurgitation from prolapse of the mitral or aortic valves (which control the flow of blood through the heart) result from cystic medial degeneration of the valves which is commonly associated with Marfan's syndrome (see mitral valve prolapse, aortic regurgitation). However, the major sign that would lead a doctor to consider an underlying condition is a dilated aorta or an aortic aneurysm. Sometimes, no heart problems are apparent until the weakening of the connective tissue (cystic medial degeneration) in the ascending aorta causes an aortic aneurysm or aortic dissection, a medical emergency. An aortic dissection is most often fatal and presents with pain radiating down the back, giving a tearing sensation.

Because of the underlying connective tissue abnormalities that cause Marfan syndrome, there is an increased incidence of dehiscence of prosthetic mitral valve.[11] Care should be taken to attempt repair of damaged heart valves rather than replacement.

During pregnancy, even in the absence of preconceived cardiovascular abnormality, women with Marfan syndrome are at significant risk of aortic dissection, which is often fatal even when rapidly treated. For this reason, women with Marfan syndrome should receive a thorough assessment prior to conception, and echocardiography should be performed every six to ten weeks during pregnancy, to assess the aortic root diameter. For most women, safe vaginal delivery is possible.[12]

Lungs

Marfan syndrome is a risk factor for spontaneous pneumothorax. In spontaneous unilateral pneumothorax, air escapes from a lung and occupies the pleural space between the chest wall and a lung. The lung becomes partially compressed or collapsed. This can cause pain, shortness of breath, cyanosis, and, if not treated, death. Marfan syndrome has also been associated with sleep apnea and idiopathic obstructive lung disease.

Central nervous system

Another condition that can reduce the quality of life for an individual, though not life-threatening, is dural ectasia, the weakening of the connective tissue of the dural sac, the membrane that encases the spinal cord. Dural ectasia can be present for a long time without producing any noticeable symptoms. Symptoms that can occur are lower back pain, leg pain, abdominal pain, other neurological symptoms in the lower extremities, or headaches. Such symptoms usually diminish when the individual lies flat on his or her back. These types of symptoms might lead a doctor to order an X-ray of the lower spine. Dural ectasia is usually not visible on an X-ray in the early phases. A worsening of symptoms and the lack of finding any other cause should eventually lead a doctor to order an upright MRI of the lower spine. Dural ectasia that has progressed to the point of causing these symptoms would appear in an upright MRI image as a dilated pouch that is wearing away at the lumbar vertebrae.[10] Other spinal issues associated with Marfan include degenerative disk disease and spinal cysts. Marfan syndrome is also associated with dysautonomia.

Pathogenesis

Marfan syndrome is caused by mutations in the FBN1 gene on chromosome 15,[13] which encodes a glycoprotein called fibrillin-1, a component of the extracellular matrix. The Fibrillin 1 protein is essential for the proper formation of the extracellular matrix including the biogenesis and maintenance of elastic fibers. The extracellular matrix is critical for both the structural integrity of connective tissue but also serves as a reservoir for growth factors.[14] Elastin fibers are found throughout the body but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye; consequently, these areas are among the worst affected.

A transgenic mouse has been created carrying a single copy of a mutant fibrillin 1, a mutation similar to that found in the human fibrillin 1 gene that is known to cause Marfan syndrome. This mouse strain recapitulates many of the features of the human disease and promises to provide insights into the pathogenesis of the disease. Reducing the level of normal fibrillin-1 causes a Marfan-related disease in mice.[15]

Transforming growth factor beta (TGFβ) plays an important role in Marfan syndrome. Fibrillin-1 indirectly binds a latent form of TGFβ keeping it sequestered and unable to exert its biological activity. The simplest model of Marfan syndrome suggests that reduced levels of fibrillin-1 allow TGFβ levels to rise due to inadequate sequestration. Although it is not proven how elevated TGFβ levels are responsible for the specific pathology seen with the disease, an inflammatory reaction releasing proteases that slowly degrade the elastin fibers and other components of the extracellular matrix is known to occur. The importance of the TGFβ pathway was confirmed with the discovery of a similar syndrome Loeys-Dietz syndrome involving the TGFβR2 gene on chromosome 3, a receptor protein of TGFβ.[16] Marfan syndrome has often been confused with Loeys-Dietz syndrome, because of the considerable clinical overlap between the two syndromes.[17]

Diagnosis

Diagnostic criteria of Marfan syndrome were agreed internationally in 1996.[18] A diagnosis of Marfan syndrome is based on family history and a combination of major and minor indicators of the disorder, rare in the general population, that occur in one individual. For example: four skeletal signs with one or more signs in another body system such as ocular and cardiovascular in one individual. The following conditions may result from Marfan syndrome but may also occur in people without any known underlying disorder.


Differential diagnosis

The following disorders have similar signs and symptoms of Marfan syndrome:

Management

There is no cure for Marfan syndrome, but life expectancy has increased significantly over the last few decades, and clinical trials are underway for a promising new treatment.[29] The syndrome is treated by addressing each issue as it arises, and, in particular, considering preventive medication, even for young children, to slow progression of aortic dilation.

Regular checkups by a cardiologist are needed to monitor the health of the heart valves and the aorta. The goal of treatment is to slow the progression of aortic dilation and damage to heart valves by eliminating arrythmias, minimizing the heart rate, and minimizing blood pressure. Beta blockers have been used to control arrythmias and slow the heart rate. Other medications might be needed to further minimize blood pressure without slowing the heart rate, such as ACE inhibitors and angiotensin II receptor antagonists, also known as angiontensin receptor blockers (ARBs). If the dilation of the aorta progresses to a significant diameter aneurysm, causes a dissection or a rupture, or leads to failure of the aortic or other valve, then surgery (possibly a composite aortic valve graft [CAVG] or valve-sparing procedure) becomes necessary. Although aortic graft surgery (or any vascular surgery) is a serious undertaking it is generally successful if undertaken on an elective basis.[30] Surgery in the setting of acute aortic dissection or rupture is considerably more problematic. Elective aortic valve/graft surgery is usually considered when aortic root diameter reaches 50 millimeters (2.0 inches), but each case needs to be specifically evaluated by a qualified cardiologist. New valve-sparing surgical techniques are becoming more common.[31] As Marfan patients live longer, other vascular repairs are becoming more common, e.g. repairs of descending thoractic aortic aneurysms and aneurysms of vessels other than the aorta.

The skeletal and ocular manifestations of Marfan syndrome can also be serious, although not life-threatening. These symptoms are usually treated in the typical manner for the appropriate condition, such as with various kinds of pain medication or muscle relaxants. It is also common for patients to receive treatment from a physiotherapist, using TENS therapy, ultrasound and skeletal adjustment.[citation needed] This can also affect height, arm length, and life span. A physiotherapist can also help improve function and prevent injuries in individuals with Marfan's. The Nuss procedure is now being offered to people with Marfan syndrome to correct 'sunken chest' or (pectus excavatum).[32] Because Marfan may cause spinal abnormalities that are asymptomatic, any spinal surgery contemplated on a Marfan patient should only follow detailed imaging and careful surgical planning, regardless of the indication for surgery.

Clinical trials have been conducted of the drug acetazolamide in the treatment of symptoms of dural ectasia. The treatment has demonstrated significant functional improvements in some sufferers.[33] Other medical treatments, as well as physical therapy, are also available.

Treatment of a spontaneous pneumothorax is dependent on the volume of air in the pleural space and the natural progression of the individual's condition. A small pneumothorax might resolve without active treatment in one to two weeks. Recurrent pneumothoraces might require chest surgery. Moderately sized pneumothoraces might need chest drain management for several days in a hospital. Large pneumothoraces are likely to be medical emergencies requiring emergency decompression.

Research in laboratory mice has suggested that the angiotensin II receptor antagonist losartan, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome.[34] A large clinical trial sponsored by the National Institutes of Health comparing the effects of losartan and atenolol on the aortas of Marfan patients was scheduled to begin in early 2007, coordinated by Johns Hopkins.[35]

Genetic counseling and specialized clinics are available at many academic medical centers for affected persons and family members.

Epidemiology

Marfan syndrome affects males and females equally,[36] and the mutation shows no geographical bias. Estimates indicate that approximately 60,000 (1 in 5,000, or 0.02% of the population)[36] to 200,000[37] Americans have Marfan syndrome. Each parent with the condition has a 50% risk of passing the genetic defect on to any child due to its autosomal dominant nature. Most individuals with Marfan syndrome have another affected family member, but approximately 15–30% of all cases are due to de novo genetic mutations[14]—such spontaneous mutations occur in about 1 in 20,000 births. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.[38][39] It is associated with variable expressivity; incomplete penetrance has not been definitively documented.

Well-known people

Prominent figures who have been diagnosed with Marfan syndrome include:

Speculative claims concerning historical figures

The diagnosis of Marfan syndrome was not available until well into the 20th century, but there has been speculation on whether historical figures may have had it, based on sparse medical records, descriptions, and images. Ancient figures include Akhenaten, Egyptian pharaoh, based on his image in early Amarna art.[47] Musicians and composers Niccolò Paganini[48] and Sergei Rachmaninoff[49] are thought by some to have had the disease. A 1962 theory that Abraham Lincoln had Marfan syndrome has little currency today.[50][51] According to a 2007 theory, it is more likely that he had a different disorder, multiple endocrine neoplasia type 2B, that caused skeletal features almost identical to Marfan syndrome.[52]

References

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External links


v • d • e
Congenital abnormality · multiple abnormalities (Q87, 759.7)
Craniofacial
Short stature
Limbs
Overgrowth
Laurence-Moon-Bardet-Biedl
Combined/other,
known locus
Combined/other,
unknown locus

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