(or 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. 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. Parents have a 50/50 chance of passing on the gene to their children.
People with Marfan's are typically tall, with long limbs and long thin fingers.
The most serious complication is defects of the heart valves and aorta. It may also affect the lungs, eyes, dural sac surrounding the spinal cord, skeleton and hard palate.
In addition to being a connective protein that forms the structural support for tissues outside the cell, fibrillin-1 binds to another protein, Transforming growth factor beta (TGF-β). TGF-β can cause inflammation. Researchers now believe that the inflammatory effects of TGF-β, at the lungs, heart valves, and aorta, weaken the tissues and cause the features of Marfan syndrome. Since angiotensin II receptor blockers (ARBs) also reduce TGF-β, they have tested this by giving ARBs (losartan, etc.) to young Marfan syndrome patients, and the growth of the aorta was indeed reduced.
It is named after Antoine Marfan, the French pediatrician who first described the condition in 1896 after noticing striking features in a 5 year old girl. The gene linked to the disease was first identified by Francesco Ramirez at the Mount Sinai Medical Center in New York City in 1991.
Marfan syndrome affects males and females equally, and the mutation shows no geographical bias. Estimates indicate that approximately 60 000 (1 in 5000, or 0.02% of the population) to 200 000 Americans have Marfan syndrome. Each parent with the condition has a 50% chance of passing it on to a 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
— such spontaneous mutations occur in about 1 in 20 000 births. Marfan syndrome is also an example of dominant negative mutation
. It is associated with variable expressivity. Incomplete penetrance
has not been definitively documented.
Marfan syndrome is caused by mutations in the FBN1 gene
15, which encodes
-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. Elastin fibers are found throughout the body but are particularly abundant in the aorta
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. It has been found that simply reducing the level of normal fibrillin-1 causes a Marfan-related disease in mice.
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 TGFb levels to rise due to inadequate sequestration. Although it is not proven how elevated TGFb levels would be 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 TGFb 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. Marfan syndrome has often been confused with Loeys-Dietz syndrome, because of the considerable clinical overlap between the two syndromes.
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 thirty 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.
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 fingers and toes that are also abnormally long and slender (arachnodactyly
). This long, slender body habitus and long, slender limbs are 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 signs. Abnormal curvature of the spine
) is common, as is abnormal indentation (pectus excavatum
) or protrusion (pectus carinatum
) of the sternum
. Other signs include abnormal joint flexibility, a high palate
, flat feet
, hammer toes
, stooped shoulders, unexplained stretch marks
on the skin and thin wrists. Some people with Marfan have speech disorders
resulting from symptomatic high palates and small jaws.
Marfan syndrome can also seriously affect the eyes and vision. Nearsightedness
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
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
. Early onset glaucoma
can be another complication.
The most serious conditions associated with Marfan syndrome involve the cardiovascular system. Undue fatigue, shortness of breath, heart palpitations
, racing heartbeats
, or pain in the left chest, back, shoulder, or arm
, can bring a person into the doctor's office. Cold arms, hands and feet can also be seriously linked to marfan syndrome
because of a loss of blood circulation. A heart murmur
heard on a stethoscope
, an abnormal reading on an electrocardiogram
, or symptoms of angina
can lead a doctor to order an echocardiogram
. This can reveal signs of leakage or prolapse
of the mitral or aortic valves
that control the flow of blood through the heart. (See mitral valve prolapse
.) 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 in the ascending aorta
causes an aortic aneurysm
or even aortic dissection
Because of the underlying connective tissue abnormalities that cause Marfan syndrome, there is an increased incidence of dehiscence of prosthetic mitral valve. 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 acute aortic dissection, which can be lethal if untreated. For this reason, women with Marfan syndrome should receive a thorough assessment prior to conception, and echocardiography should be performed every 6-10 weeks during pregnancy, to assess the aortic root diameter. Most women however tolerate pregnancy well and safe vaginal delivery is possible.
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
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
. Other spinal issues associated with Marfan include degenerative disk disease and spinal cysts.
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. 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. 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. 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. This can also affect height, arm length, and life span. The Nuss procedure is now being offered to people with Marfan syndrome to correct 'sunken chest' or (pectus excavatum). 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. 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 1 to 2 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. A large clinical trial sponsored by the National Institutes of Health comparing the effects of losartan and atenolol on the aortas of Marfan patients is scheduled to begin in early 2007, coordinated by Johns Hopkins.
Genetic counseling and specialized clinics are available at many academic medical centers for affected persons and family members.
Well known people
Below is a list of prominent figures who have been diagnosed with Marfan syndrome:
There are a number of historical persons believed to have suffered from Marfan's syndrome, but as proper Marfan diagnosis was not available before well into the 20th century most such claims can only be considered as speculation based on sparse medical records and pictures.
Symptoms and diagnosis
The following conditions may result from Marfan syndrome but may also occur in people without any known underlying disorder. 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 disorders have similar signs and symptoms of Marfan syndrome: