Connective tissue is made up of proteins. The genetic defect that causes Marfan syndrome is a mutation in a gene known as FBN1. This gene affects a protein called fibrillin-1. The abnormal fibrillin-1 protein leads to an increase in the activity of a growth factor, called transforming growth factor-beta (TGF-beta), and eventually leads to problems with connective tissue throughout the body. This, in turn, creates the features and medical problems associated with Marfan syndrome. Because connective tissue is found throughout the body, Marfan syndrome can affect many different parts of the body (see below):
Some Marfan features can be more dangerous than others. One example is an increase in the size of the aorta, which is the main blood vessel that carries blood away from the heart to the rest of the body. When the aorta expands, it is called an aortic aneurysm. An aortic aneurysm may lead to a tear in the aorta (acute aortic dissection), which is life-threatening. Surgery to replace the enlarged aorta with an artificial graft can prevent aortic dissection. The eyes, mitral valve, skeleton, lungs, skin, nervous system, and the lining of the dural sac may also be affected. Marfan syndrome does not affect intelligence.
About 1 in 5,000 people have Marfan syndrome, including men and women of all races and ethnic groups. About 3 out of 4 people with Marfan syndrome inherit it, meaning they get the genetic mutation from a parent who has it. But some people with Marfan syndrome are the first in their family to have the condition. When this happens, it is called a spontaneous mutation. If you have Marfan syndrome, each child you have has a 50% chance of also having this condition.
Figure 2 - Long arms are often present in Marfan syndrome
Figure 5 - Sunken chest (pectus excavatum) in Marfan syndrome
Figure 3 - Long fingers (which are often hyperflexible) in Marfan syndrome
Figure 6 - Facial features in Marfan syndrome:
Figure 4 - X-ray example of a curved spine (scoliosis)
Figure 7 - Highly-arched and tall palate and crowded teeth in an individual with Marfan syndrome
Figure 9 - Echocardiogram demonstrating an aortic root aneurysm (arrow)
Figure 10 - Lens dislocation (ectopia lentis) in Marfan syndrome. The suspensory ligament holding the lens in place is stretched (arrow).
Figure 11 - CT scan demonstrating lumbosacral dural ectasia (arrow)
It is important you go to a doctor experienced with Marfan syndrome for a diagnosis. Your doctor will examine many parts of your body as part of a complete physical exam. Your doctor will also ask you questions about your medical and family history. This may include information about any family member who may have Marfan syndrome, an early heart-related or unexplained death, or a history of aortic aneurysm or dissection.
You should also have tests to identify Marfan features that cannot be seen during the physical exam, including:
Genetic testing may also provide helpful information. If you have a family history of Marfan syndrome, genetic testing can help show which of your family members have Marfan syndrome and need additional care. This is useful in young children who may not yet show signs of Marfan syndrome.
Figure 12 - Genetic Pedigree of a Family with Marfan Syndrome
This example (Figure 12) demonstrates that an individual affected by Marfan syndrome (in black) may pass the gene for Marfan syndrome to his or her children. If someone in the family does not have Marfan syndrome (in white), that unaffected individual cannot pass on a trait for Marfan syndrome as he or she does not carry the mutated gene. (See Genetic testing for HTAD link).
Some of the outward features of Marfan syndrome can be found in other disorders related to Marfan syndrome, such as Loeys-Dietz syndrome or isolated thoracic aortic aneurysms. For this reason, genetic testing may be helpful when a diagnosis cannot be determined through an exam, family history, and imaging tests alone or when lens dislocation (ectopia lentis) is not present and features suggesting an alternative diagnosis are present. Knowing the precise diagnosis is critical to the follow up monitoring and treatment plan.
While Marfan syndrome cannot be cured, with diagnosis, monitoring and treatment you can live a long, full life. Working with your doctors will help you manage this condition. Everyone with Marfan syndrome is different, depending on how severe or mild their features are.
In general, you can expect some things you need to think about every day, such as medications and some limitations on physical activity and lifestyle. Then, there are routine doctor appointments, which may be yearly or more often, as well as other tests to make sure that your signs and symptoms are not changing. Sometimes, when symptoms progress or the testing shows a change in the condition (such as significant enlargement of the aorta or leaking of the mitral valve), your doctor will recommend surgery. In most cases, you will have time to plan for surgery; in some cases, immediate surgery may be needed.
Understanding how Marfan syndrome is treated will help you. We encourage you to learn as much as you can about the recommended management for Marfan syndrome so you can be prepared.
People with Marfan syndrome are always at risk for growth or enlargement of the aorta. This growth mostly happens closest to the heart and just above the aortic valve, called the aortic root. The size of your aorta is watched by an echocardiogram which is done at least once a year. You may need these tests more often if your aorta is large or getting to the point where doctors think you may need surgery. Some people need yearly CT or MRI scans (see testing section) to follow the aorta.
You may be given medications to slow the rate of aortic growth. These medications include beta blockers (such as atenolol or metoprolol) to lessen the stress on the aortic wall or angiotensin receptor blockers (ARBs such as losartan or irbesartan) which are believed to block the overactive growth factor (TGF-β) in Marfan syndrome. The US Food and Drug Administration (FDA) also recently warned that people with Marfan syndrome and other aortic aneurysm conditions should avoid commonly used antibiotics called fluoroquinolones (includes Avelox, Cipro, Factive, Levaquin, and Ofloxacin). The reason for this recommendation is that recent medical studies have shown that people who have taken a fluoroquinolone are twice as likely to have an aortic aneurysm or dissection than those who have not taken one of these drugs.
Once the aorta reaches 5 cm, aortic root replacement surgery is recommended (Figure 13). This is open heart surgery. Heart surgeons will replace the aortic root with a graft. In this surgery, your own aortic valve may be sewn inside the graft (a valve sparing root replacement) (Figure 14), or you may receive an artificial valve along with the graft (a Bentall procedure) (Figure 15). If you are given a new valve, it will likely be a mechanical valve. A mechanical valve requires treatment with a blood thinner (anticoagulant) called warfarin. In some cases, aortic root replacement surgery is performed when your aortic size is less than 5 cm, like if you have a family history of aortic dissection (when the wall of the aorta tears) or if the aorta is growing very rapidly.
You may experience leaking (regurgitation) of the mitral valve. In Marfan syndrome, it is common for one or both of the mitral valve leaflets to move backwards into the upper chamber of the heart when the heart beats (mitral valve prolapse). This problem may also require heart surgery to correct.
Figure 13 - CT scan demonstrating an aortic root aneurysm (arrow) measuring 5 centimeters
Figure 14 - Valve-sparing root replacement procedure. A. aortic root aneurysm (arrow); B. the aneurysm is removed; C. the aortic valve is reimplanted within the surgical graft; D. the graft is sewn to the normal aorta distally (courtesy of Craig Miller, MD)
Figure 15 - Composite aortic valve and root replacement (Bentall procedure). A mechanical aortic valve prosthesis (arrow) is at the proximal end of the graft and the coronary arteries are reattached to the graft (courtesy of Mayo Clinic)
Nearly every activity can be done at different intensity levels, and no recommendation applies to every case. For example, shooting baskets in the driveway is different from playing a full-court basketball game. Biking ten miles in one hour on a level course is different from doing a triathlon.
Figure 16 - Low-intensity, low-impact exercise is usually recommended
You need to discuss physical activities and activity levels with your physician so you can safely exercise. As you get older, you should keep talking with your doctor about exercise as your health may change.
Pregnancy increases stress on the heart and blood vessels. This can be especially dangerous in women with Marfan syndrome. While there is no clear way to know if you can have a low-risk pregnancy, several points should be considered:
If you have an artificial aortic valve, you should talk to your doctor about the risks of warfarin on the developing fetus. If you have had aortic root surgery, your risks during pregnancy may be lower. However, this does not remove all risk since other parts of the aorta can enlarge and tear (dissect) related to pregnancy.
If you do get pregnant, it will be considered high-risk (a term doctors use).You should be monitored by a cardiologist and a maternal-fetal medicine specialist or high-risk obstetrician during your pregnancy. During pregnancy, your aorta should be evaluated by echocardiography at least every three months. Before getting pregnant, your entire aorta should be scanned with CT/MRI. These tests will give doctors a better picture of your whole aorta.
Delivery should be by the least stressful method possible. We do not yet know whether a controlled vaginal delivery or a Cesarean section (C-section) is less stressful for women with Marfan syndrome. You and your doctors should talk about the best delivery method for you. It is important you work with doctors who are familiar with Marfan syndrome. C-section is not absolutely necessary because of Marfan syndrome, but may be indicated for any of the usual reasons that would apply to any pregnancy. If possible, you may want to try to have children earlier in life and when the aorta is not enlarged.
Certain medications you take cannot be used during pregnancy as they increase the risk of birth defects and fetal loss. These include:
The beta blocker metoprolol is low-risk during pregnancy. Atenolol is not recommended during pregnancy. Lower spine (lumbosacral) disease and enlargement of the sac around the spine (dural ectasia) may affect the use of an epidural. Pre-delivery discussion with your doctors is recommended.
In addition to careful assessment of the risk for women contemplating pregnancies, couples in whom the underlying genetic defect is known may consider prenatal or pre-implantation diagnostics.
In both cases, it is necessary to know the specific mutation in the gene leading to Marfan syndrome as well as having dedicated pre-conception counseling.