Genetic: Marfan Syndrome
Genetic: Marfan Syndrome
Marfan syndrome, or MFS, is a disorder of the connective tissue caused by a mutation in the FBN1 gene on chromosome 15. Because connective tissue occurs throughout the human body, Marfan syndrome affects the patient's eyes, circulatory system, skin, and lungs as well as the bones and muscles. The disorder is named for Antoine Marfan (1858–1942), a French pediatrician who first described it in a five-year-old girl. The gene responsible for MFS was identified in 1991 by Francesco Ramirez, a researcher at Mount Sinai Medical Center in New York.
Marfan syndrome is a hereditary connective tissue disorder caused by mutations in the FBN1 gene. This gene is responsible for the production of elastic fibers in connective tissue and for the proper timing of the release of growth factors. People with defective FBN1 genes are not affected with equal severity, however; at least 137 different mutations of the gene have been identified. Some people may have only a few of the characteristic features of MFS, while at the other extreme, some babies are born with a severe form of the syndrome that progresses rapidly to early death from heart problems.
The classic signs of Marfan syndrome are long, thin arms and legs, bone overgrowth, and loose joints or poor muscle tone. The most common symptoms of MFS, however, are eye disorders, such as an increased risk of cataracts, dislocation of the lens of the eye, nearsightedness, and glaucoma. These affect more than 50 percent of patients. Skeletal deformities are another common characteristic, particularly scoliosis (abnormal curvature of the spine) and deformities of the ribs and breastbone.
The most damaging health problems associated with Marfan syndrome, however, are those involving the heart and circulatory system. The weakness of the connective tissue in patients with MFS leads to damaged heart valves, a weakened aorta (the large blood vessel that carries blood away from the heart), enlargement of the pulmonary artery (which carries blood from the heart to the lungs), or an aortic dissection.
An aortic dissection is a medical emergency that occurs when a tear in the wall of the aorta allows blood being pumped from the heart under pressure to force its way between the layers of tissue that form the aorta. The separation of the tissue layers can lead to a complete rupture of the aorta and rapid death.
MFS affects about one in every 5,000 persons in the United States. It occurs with equal frequency in both sexes and in all races and ethnic groups. It is estimated that as many as 200,000 people in the United States have some form of Marfan syndrome. Many cases are not diagnosed, however, because the affected person may have only mild symptoms of the disorder.
Marfan syndrome is inherited in what geneticists call an autosomal dominant pattern. That means that only one copy of a defective FBN1 gene is needed to produce the condition. Although Marfan syndrome does run in families, between 25 and 30 percent of diagnosed cases involve new mutations of the FBN1 gene in patients with no family history of MFS.
Marfan syndrome appears to be equally common in all countries around the world.
The cause of Marfan syndrome is a mutation in the FBN1 gene on chromosome 15. There are nearly 140 mutations of this gene that have been identified as of 2008. The gene governs the production of a protein called fibrillin-1, which helps to form tiny threadlike filaments that become part of the fibers in connective tissue. The tiny filaments also control the release of growth factors, which are protein molecules that stimulate the growth and multiplication of cells. In normal circumstances, the filaments release these growth factors at the proper time; but in Marfan syndrome, the filaments release the growth factors too soon. The
defective fibrillin-1 produced by a mutated FBN1 gene will thus result not only in weakened connective tissue but also in the unusual height and long arms characteristic of MFS patients.
Did Abraham Lincoln have Marfan Syndrome?
In 1959, a doctor named Harold Schwartz advanced the theory that Abraham Lincoln suffered from Marfan syndrome. Lincoln had some of the physical features associated with MFS: he was tall (6 feet 4 inches [2 meters]) and thin (160–170 pounds [73–77 kilograms]). Lincoln was also loose-jointed, shuffled when he walked, and had to wear eyeglasses. Dr. Schwartz then discovered that Lincoln shared a great-great-grandfather with a man known to have Marfan syndrome, which seemed to confirm the diagnosis.
However, Lincoln had no other signs of the disorder. His visual problem was not myopia, but farsightedness. In addition, he did not suffer from the chest pains, fatigue, and lung problems typical of MFS. In 2007 a cardiologist named John Sotos published a book in which he speculates that Lincoln actually suffered from something much less common, but much more serious than Marfan syndrome—a type of hereditary cancer called multiple endocrine neoplasia type 2B, or MEN 2B. People with MEN 2B develop cancers in hormone-producing organs like the thyroid or the adrenal gland. Sotos thinks that Lincoln'smotherand two of his sons may have also died from MEN 2B.
The historical riddle could be solved by a DNA test. It is known that Lincoln's doctor kept a few locks
of his hair and some bloodstained clothing after his assassination, and that the federal government has stored eight fragments from Lincoln's skull. It is not known, however, whether those in charge of these remains would be willing to give up a sample for DNA analysis.
The symptoms in organ systems most commonly affected by MFS are:
- Visual: High risk of cataracts (clouding of the lens), glaucoma (high fluid pressure inside the eye), myopia (nearsightedness), and dislocation of the lens of the eye.
- Circulatory: High risk of widening (resulting in an aneurysm) or dissection of the aorta; defects in heart valves leading to heart murmurs, shortness of breath, tiring easily, chest pain, and a very fast or irregular heart rate.
- Skeletal: Overgrowth of the long bones of the body; loose joints; abnormally shaped mouth with crowded teeth; scoliosis (curvature of the spine); breastbone that either curves inward or protrudes outward; flat feet; long, narrow skull.
- Nervous system: Weakening of the membrane that covers the spinal cord. This defect can lead to pain in the abdomen or legs in middle age.
Other symptoms that some patients with MFS experience include:
- High risk of sleep apnea
- Speech problems caused by the high arch in the roof of the mouth
- Stretch marks in the skin that are not due to weight loss or pregnancy
- Learning disabilities
- Cold hands or feet
The diagnosis of Marfan syndrome is complicated for several reasons. One is that there is no single genetic test that can identify all the known mutations of the FBN1 gene. Another is that some of the symptoms of MFS are also found in other connective tissue disorders. A third reason is that some symptoms are age-specific; that is, the affected person may have to reach his or her full height for the abnormal growth pattern to be clear, or to reach adulthood to develop some of the eye disorders associated with MFS. It is not unusual for young adult athletes to die from undiagnosed Marfan syndrome; Flo Hyman (1954–1986), who won a silver medal in volleyball in the 1984 Olympics, died suddenly of an aortic dissection during a volleyball game in 1986.
The diagnosis of Marfan syndrome is therefore based on a combination of the patient's symptoms, family history, and any information that may be obtained through genetic testing. There are several different sets of criteria that the patient's doctor may follow to arrive at the diagnosis. The four symptoms that are weighted most heavily are dilation of the
aorta; dislocation of the lens of the eye; weakening of the membrane covering the spinal cord; and four or more of the skeletal changes associated with MFS.
The following tests are usually ordered as part of the diagnostic process:
- A complete physical examination that includes measuring the ratio of the patient's arm length to his or her height.
- An eye examination with a slit lamp to check for dislocation of the lens or a detached retina.
- A test for glaucoma. This test involves measuring the pressure of the fluid inside the eyeball.
- Electrocardiogram (ECG). This test measures the rhythm of the heart.
- Imaging studies of the aorta. Both computed tomography (CT) scans and magnetic resonance imaging (MRI) can be used to see whether the patient's aorta is enlarged or has begun to dissect.
- Echocardiogram. This is a test that uses ultrasound waves to produce two-dimensional images of the heart and its blood vessels.
Treatment of Marfan syndrome requires a team of specialists rather than just one doctor. The usual pattern is to treat health problems as they arise. A child diagnosed with MFS, for example, will usually need to see an ophthalmologist (eye doctor), pediatrician, orthodontist, and cardiologist (heart specialist). Adolescents may need to be treated by an orthopaedic surgeon if they have developed scoliosis or chest deformities. A neurologist may be consulted to treat complications involving the spinal cord.
To slow down the dilation of the aorta, even children are now given beta blockers, which are medications that cause the heart to beat more slowly and with less force. If the aorta enlarges to a certain size (about 2 inches [5 centimeters]), it is usually treated surgically. The surgeon will replace the weakened part of the aorta with a tube of synthetic material. Surgery may also be done to replace damaged or defective heart valves or to correct scoliosis or chest deformities.
People diagnosed with MFS must be careful to have regular eye examinations, echocardiograms, and other checkups intended to prevent
the complications of the disease. They must also make a number of lifestyle adjustments, such as not smoking because of the possibility of severe lung damage. They are advised to avoid contact sports, weight lifting, and competitive sports like marathon running, although swimming, yoga, and walking are recommended forms of healthy exercise. Women with Marfan syndrome who choose to start a family must be carefully monitored throughout pregnancy because of the additional strain that pregnancy places on a woman's heart.
The prognosis for MFS patients has been greatly improved by early diagnosis and treatment. Without treatment, most patients with Marfan syndrome die in their early thirties from heart problems or aortic dissection. In the early 2000s, however, the life expectancy of people with MFS has been increased to sixty to seventy years, thanks to modern heart medications and surgical techniques.
WORDS TO KNOW
Aneurysm: A swelling or balloon-like bulge in a blood vessel caused by weakness in the vessel's wall.
Aorta: The large artery that carries blood away from the heart to the rest of the body.
Aortic dissection: A tear in the wall of the aorta that allows blood to seep between the layers of apart.
Beta blockers: A group of drugs given to treat abnormal heart rhythms and reduce the risk of aortic dilation in MFS patients.
Scoliosis: Abnormal curvature of the spine from of side to side.
Marfan syndrome cannot be completely prevented because new mutations of the FBN1 gene will continue to arise. However, people with a family history of MFS should consider genetic counseling because it takes only one copy of the defective gene to produce Marfan syndrome. A parent who has Marfan syndrome has a 50 percent chance of having a child with the disorder.
Researchers are presently studying the ways in which the FBN1 gene affects the development of connective tissue, hoping that better understanding may yield clues to new treatments. Other scientists are studying new drugs that may prevent or reduce heart complications in patients with Marfan syndrome. One specific drug that is receiving careful attention is losartan, a drug originally developed to treat high blood pressure.
SEE ALSO Cataracts; Glaucoma; Myopia; Scoliosis; Sleep apnea
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