Marfan syndrome is a genetic autosomal dominant disorder of the connective tissue characterized by unusually long limbs, great stature or long toes or fingers in proportion to height. The disease may also affect numerous other structures and organs — including the lungs, eyes, heart, blood vessels, dural sac surrounding the spinal cord, and hard palate. It is named after Antoine Marfan, the French pediatrician who first described it in 1896.
Marfan syndrome affects all races and both sexes equally, as the mutation has no bias for gender or geographic location. 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 and haploinsufficiency. It is associated with incomplete penetrance, therefore not all persons carrying the mutation develop the disease.
Marfan syndrome has been linked to a defect in the FBN1 gene on chromosome 15, which encodes a glycoprotein called fibrillin-1. Fibrillin is essential for the formation of the elastic fibers found in connective tissue, as it provides the scaffolding for tropoelastin. Elastic 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. Without the structural support provided by fibrillin many connective tissues are weakened, which can have severe consequences for support and stability.
A related disease has been found in mice, and the study of mouse fibrillin synthesis and secretion, and connective tissue formation, has begun to further our understanding of Marfan syndrome in humans. 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 binds TGFβ and inactivates it. In Marfan syndrome, reduced levels of fibrillin-1 allow activated TGFβ to damage the lungs and heart. A defect in the gene TGFβR2 on chromosome 3, a receptor protein of TGFβ, has also been related to Marfan syndrome. Marfan syndrome can often be confused with Loeys-Dietz syndrome, a similar connective tissue disorder resulting from mutations in the TGFβ receptor genes TGFβR1 and TGFβR2.
There are no signs or symptoms that are unique to Marfan syndrome. It is usually one sign or symptom that is apparent in an individual that leads doctors to look for other signs of the syndrome, and an eventual diagnosis. The connective tissue affected by Marfan syndrome is involved in diverse organs and tissues. Even in the same family, each affected individual might have a different combination of symptoms and a difference in severity.
The most readily visible signs may be associated with the skeletal system. Many individuals with Marfan syndrome grow to larger than normal height, and have long, slender limbs, fingers, and toes. An individual's arms can be disproportionately long compared to his or her height. In addition to affecting height and limb proportions, Marfan syndrome can produce other skeletal signs. 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 mouth palate, the need for orthodontics work, flat feet, stooped shoulders, and unexplained stretch marks on the skin. Some people with Marfans have speech impediments as a result of the high palates and small jaws.
Marfan syndrome can also seriously affect the eyes and vision. Nearsightedness or myopia and Astigmatism is common, but farsightedness can also be found in people with Marfan syndrome. Periodic eye exams of individuals with vision difficulties can lead to an ophthalmologist or optometrist discovering dislocation, or subluxation, of the crystalline lens in one or both eyes (ectopia lentis) by carefully observing these structures using a slit-lamp biomicroscope. Sometimes, no eye problems are apparent until the weakening of connective tissue in the eye causes detachment of the retina. Early onset glaucoma can be another complication.
The most serious conditions associated with Marfan syndrome primarily involve the cardiovascular system. Undue fatigue, shortness of breath, heart palpitations, racing heart beats, or pain in the left chest, back, shoulder, or arm, can bring an individual into the doctor's office. A heart murmur heard on a stethescope, an abnormal reading on an electrocardiogram, or symptoms of angina can lead a doctor to order an echocardiogram. The echocardiogram can reveal signs of leakage or prolapse of the mitral or aortic valves that control the flow of blood through the heart. 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.
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, and it can cause cyanosis and even death, if not treated. Marfan 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 extremeties, 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 a upright MRI of the lower spine. Dural ectasia that has progressed to the point of causing these symptoms would appear in a 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. The syndrome is treated by addressing each issue as it arises, and, in particular, considering prophylactic 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 failure of the aortic or other valve, 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 millimetres, 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 dependant 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 pneumothoraxes might require chest surgery. Moderately sized pneumothoraxes might need chest drain management for several days in hospital. Large pneumothoraxes are likely to be medical emergencies requiring emergency decompression.
Research in laboratory mice has suggested that the angiotensin II receptor antagonist losartan (marketed by Merck & Co, Inc. as Cozaar), 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.
Genetic counseling: Marfan Syndrome
Well known people
Below is a list of prominent figures known or believed to have had Marfan syndrome:
- Akhenaten, Egyptian Pharaoh, who was possibly the father of King Tutankhamun
- Flo Hyman, silver medal in Women's Volleyball (1984 Olympics)
- Jonathan Larson, Tony Award-winning playwright (Rent); his death in 1996 of aortic dissection was covered in the media
- Robert Johnson, blues singer and guitarist
- Vincent Schiavelli, actor
- Abraham Lincoln
The following disorders have similar signs and symptoms of Marfan syndrome:
- Congenital Contractural Arachnodactyly (CCA) or Beals Syndrome
- Ehlers-Danlos syndrome
- Loeys-Dietz syndrome
- MASS phenotype
- Stickler syndrome
The following conditions that can result from having Marfan syndrome may also occur in people without any known underlying disorder:
- ↑ 1.0 1.1 (1999). The role of heredity and family history. National Marfan Foundation. URL accessed on 2007-01-11.
- ↑ (2006). New, Deadly Relative of Marfan's Syndrome Discovered. MedicineNet.com. URL accessed on 2007-01-11.
- ↑ 3.0 3.1 Cotran; Kumar, Collins. Robbins Pathologic Basis of Disease, Philadelphia: W.B Saunders Company. 0-7216-7335-X.
- ↑ Judge, Daniel P., Nancy J. Biery, Douglas R. Keene, Jessica Geubtner, Loretha Myers, David L. Huso, Lynn Y. Sakai, Harry C. Dietz. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome.. The Journal of Clinical Investigation 114 (2): 172-181. PMID 15254584.
- ↑ Judge, Daniel P., Harry C. Dietz (2005). Marfan's syndrome.. Lancet 366 (9501): 1965-76. PMID 16325700.
- ↑ McKusick V (1991). The defect in Marfan syndrome.. Nature 352 (6333): 279-81. PMID 1852198.
- ↑ Lygia Pereira, et al. (1999). Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proceedings of the National Academy of Sciences 96 (7).
- ↑ Entrez Gene (2007). TGFBR2 transforming growth factor, beta receptor II. (Entrez gene entry) NCBI. URL accessed on 2007-01-11.
- ↑ Related Disorders: Loeys-Dietz. National Marfan Foundation. URL accessed on 2007-01-11.
- ↑ 1996 Revised Criteria for the Marfan Syndrome. URL accessed on 2007-01-11.
- ↑ 11.0 11.1 Marfan Syndrome. Mayo Clinic. URL accessed on 2007-01-12.
- ↑ Heart Surgery for Marfan Syndrome. Mayo Clinic. URL accessed on 2007-01-12.
- ↑ Overview of the Nuss Procedure for Pectus Excavatum. Children's Hospital of The King's Daughters. URL accessed on 2007-01-12.
- ↑ Dural Ectasia in the Marfan Spine: Symptoms and Treatment. Scoliosis Research Society. URL accessed on 2007-01-12.
- ↑ Habashi, Jennifer P., Daniel P. Judge, Tammy M. Holm, Ronald D. Cohn, Bart L. Loeys, Timothy K. Cooper, Loretha Myers, Erin C. Klein, Guosheng Liu, Carla Calvi, Megan Podowski, Enid R. Neptune, Marc K. Halushka, Djahida Bedja, Kathleen Gabrielson, Daniel B. Rifkin, Luca Carta, Francesco Ramirez, David L. Huso, and Harry C. Dietz (April 7, 2006). Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome 312 (5770): 117 - 121.
- ↑ Atenolol vs. Losartan in Individuals with Marfan Syndrome Clinial Trial. National Marfan Foundation. URL accessed on 2007-01-12.
- ↑ Did Akhenaten Suffer from Marfan's Syndrome?. Canadian Marfan Association. URL accessed on 2007-01-11.
- ↑ Flo Hyman. Volleyball Hall of Fame. URL accessed on 2007-01-11.
- ↑ Marfan's Syndrome Is Deadly, Elusive. WNBC.com. URL accessed on 2007-01-11.
- ↑ Connel, David (September 2, 2006). Retrospective blues: Robert Johnson—an open letter to Eric Clapton. British Medical Journal 333 (7566): 489.
- ↑ NMF Mourns the Loss of its Honorary Co-Chair, Vincent Schiavelli. National Marfan Foundation. URL accessed on 2007-01-11.
- International Federation of Marfan Syndrome Organisations
- National Marfan Foundation (USA)
- National Institute for Health Marfan syndrome page (USA)
- Marfan Syndrome Center at medicinenet.com
- Marfan Syndrome Research - recent literature on Marfan Syndrome
- Marfan support
- Canadian Marfan Association
- Marfan Association UK
- Marfan de Mexico
- Norwegian Marfan Organization
- Marfan Life blog - mostly links to news articles about Marfan Syndrome
- Marfan-List - email discussion list for people and families with Marfan Syndrome
- South African Marfan Syndrome Organisation - support group for Africa
- Eye Findings in Marfan's syndrome
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