Marfan's syndrome

Revision as of 14:02, 26 November 2010 by C Michael Gibson (talk | contribs)
Jump to navigation Jump to search
Marfan syndrome
ICD-10 Q87.4
ICD-9 759.82
OMIM 154700
DiseasesDB 7845
MedlinePlus 000418
eMedicine ped/1372  orthoped/414
MeSH C17.300.500

WikiDoc Resources for Marfan's syndrome

Articles

Most recent articles on Marfan's syndrome

Most cited articles on Marfan's syndrome

Review articles on Marfan's syndrome

Articles on Marfan's syndrome in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Marfan's syndrome

Images of Marfan's syndrome

Photos of Marfan's syndrome

Podcasts & MP3s on Marfan's syndrome

Videos on Marfan's syndrome

Evidence Based Medicine

Cochrane Collaboration on Marfan's syndrome

Bandolier on Marfan's syndrome

TRIP on Marfan's syndrome

Clinical Trials

Ongoing Trials on Marfan's syndrome at Clinical Trials.gov

Trial results on Marfan's syndrome

Clinical Trials on Marfan's syndrome at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Marfan's syndrome

NICE Guidance on Marfan's syndrome

NHS PRODIGY Guidance

FDA on Marfan's syndrome

CDC on Marfan's syndrome

Books

Books on Marfan's syndrome

News

Marfan's syndrome in the news

Be alerted to news on Marfan's syndrome

News trends on Marfan's syndrome

Commentary

Blogs on Marfan's syndrome

Definitions

Definitions of Marfan's syndrome

Patient Resources / Community

Patient resources on Marfan's syndrome

Discussion groups on Marfan's syndrome

Patient Handouts on Marfan's syndrome

Directions to Hospitals Treating Marfan's syndrome

Risk calculators and risk factors for Marfan's syndrome

Healthcare Provider Resources

Symptoms of Marfan's syndrome

Causes & Risk Factors for Marfan's syndrome

Diagnostic studies for Marfan's syndrome

Treatment of Marfan's syndrome

Continuing Medical Education (CME)

CME Programs on Marfan's syndrome

International

Marfan's syndrome en Espanol

Marfan's syndrome en Francais

Business

Marfan's syndrome in the Marketplace

Patents on Marfan's syndrome

Experimental / Informatics

List of terms related to Marfan's syndrome

Editors-In-Chief: William James Gibson, C. Michael Gibson, M.S., M.D.

Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [1]

Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.

Overview

Marfan syndrome (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. 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 complication is 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, 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.[1]

Differential Diagnosis

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

Etymology

In 1896, French pediatrician Antoine-Bernard Jean Marfan described a five year old girl, Gabrielle P, with skeletal features characteristic of Marfan Syndrome1, pieds d’aragne (French, spider feet) and dolichostenomalie (French, longheadedness meaning long limbs). In 1902, Emile Charles Achard described a similar syndrome, reporting scoliosis and arachnodactyly (abnormally long and slender fingers) as essential features2. Salle contributed the observation in 1912 that patients with arachnodactyly had thickened mitral leaflets, ocular abnormalities and increase in eosinophilic cells in the pituitary3,4. The observation that ectopic lens was associated with other symptoms was first made by Boerger in 19145 . Weve established the autosomal dominant inheritance of the disease, still known as arachnodactyly, in 19316. Weve postulated that the syndrome arose from a defect in mesenchymal tissue and thus designated the syndrome dystrophia mesodermalis congenita typus Marfanis. Association of the syndrome with aortic dilation and dissection, the major causes of mortality in individuals with Marfan Syndrome were identified in 1943 by RW Baer et al. as well as Etter and Glover7,8. Harry C Deitz finally established the molecular basis of Marfan Syndrome in his landmark 1991 Nature paper, showing that dysregulation of TGF-beta signaling is responsible for the observed manifestations9.

Epidemiology

Marfan syndrome affects males and females equally,[2] and the mutation shows no geographical bias. Estimates indicate that approximately 60 000 (1 in 5000, or 0.02% of the population)[2] to 200 000[3] 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[4] — such spontaneous mutations occur in about 1 in 20 000 births. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.[5][6] It is associated with variable expressivity. Incomplete penetrance, has not been definitively documented.

Pathogenesis

Marfan syndrome has been linked to a defect in the FBN1 gene on chromosome 15,[7] 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.[4] 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.[8]

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.[9] 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.[10]

Related disorders

The following conditions that can result from having Marfan's syndrome and may also occur in people without any known underlying disorder. what leads doctors to a diagnosis of marfan syndrome is family history and a combination of major and minor indicators of the disorder that occur in one individual which is a rare manifestation in general population. Example: four skeletal signs with one or more signs in another body system such as ocular and cardiovascular in one individual.

Symptoms

There are no signs or symptoms that are unique to Marfan syndrome. It is usually a single apparent sign or symptom that leads doctors to look for others and eventually to diagnose the syndrome, which affects connective tissue in diverse organs and systems. Even affected individuals in the same family might exhibit various combinations and severities of symptoms.

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 fingers and toes that are also abnormally long and slender (arachnodactyly). An individual's arms may be disproportionately long. 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 palate, malocclusions, flat feet, stooped shoulders, and unexplained stretch marks on the skin. Some people with Marfans have speech disorders resulting from symptomatic high palates and small jaws.

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. [11]

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. [11]

In Marfan's the dislocation is typically superotemporal whereas in the similar condition homocystinuria, the dislocation is inferonasal.[11]

Sometimes eye problems appear only after the weakening of connective tissue has caused detachment of the retina.[11] Early onset glaucoma can be another related problem.

Cardiovascular system

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 an individual into the doctor's office. 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.[12] 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.[13]

  • A typical aortic root in Marfan's syndrome.

<googlevideo>-760162053984535443&hl=en</googlevideo>

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.[11] Other spinal issues associated with Marfan include degenerative disk disease and spinal cysts.

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.[14] 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 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 millimetres, but each case needs to be specifically evaluated by a qualified cardiologist. New valve-sparing surgical techniques are becoming more common.[15] 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).[16] 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.[17] 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, which appears to block TGF-beta activity, can slow or halt the formation of aortic aneurysms in Marfan syndrome.[18] 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.[19]

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

References

  1. Pyeritz RE (2008). "A small molecule for a large disease". N. Engl. J. Med. 358 (26): 2829–31. doi:10.1056/NEJMe0804008. PMID 18579819. Unknown parameter |month= ignored (help)
  2. 2.0 2.1 "The role of heredity and family history". National Marfan Foundation. 1999.
  3. "New, Deadly Relative of Marfan's Syndrome Discovered". MedicineNet.com. 2006.
  4. 4.0 4.1 Cotran. Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company. 0-7216-7335-X. Unknown parameter |coauthors= ignored (help)
  5. Judge, Daniel P. "Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome". The Journal of Clinical Investigation. 114 (2): 172–181. doi:10.1172/JCI200420641. PMID 15254584. Unknown parameter |coauthors= ignored (help)
  6. Judge, Daniel P. (2005). "Marfan's syndrome". Lancet. 366 (9501): 1965–76. doi:10.1016/S0140-6736(05)67789-6. Check |doi= value (help). PMID 16325700. Unknown parameter |coauthors= ignored (help)
  7. McKusick V (1991). "The defect in Marfan syndrome". Nature. 352 (6333): 279–81. PMID 1852198.
  8. Lygia Pereira; et al. (1999). "Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1". Proceedings of the National Academy of Sciences. 96 (7): 3819-3823.
  9. Entrez Gene (2007). "TGFBR2 transforming growth factor, beta receptor II" (Entrez gene entry). NCBI.
  10. "Related Disorders: Loeys-Dietz". National Marfan Foundation.
  11. 11.0 11.1 11.2 11.3 11.4 "Marfan Syndrome". Mayo Clinic. Retrieved January 12 2007. Unknown parameter |dateformat= ignored (help); Check date values in: |accessdate= (help)
  12. Braunwald's Heart Disease ~ A Textbook of Cardiovascular Medicine, Seventh Edition. United States of America: Elseview Saunders. 2005. p. 1894. ISBN 0-7216-0509-5. Unknown parameter |coauthors= ignored (help)
  13. "Marfan Syndrome, special concerns".
  14. Freeman, Elaine (2007) "A Silver Bullet for Blake", Johns Hopkins Magazine, Fall, 2007.
  15. "Heart Surgery for Marfan Syndrome". Mayo Clinic.
  16. "Overview of the Nuss Procedure for Pectus Excavatum". Children's Hospital of The King's Daughters.
  17. "Dural Ectasia in the Marfan Spine: Symptoms and Treatment". Scoliosis Research Society.
  18. Habashi, Jennifer P. (April 7, 2006). "Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome". 312 (5770): 117–121. doi:10.1126/science.1124287. Unknown parameter |news= ignored (|newspaper= suggested) (help); Unknown parameter |abstract= ignored (help); Unknown parameter |coauthors= ignored (help)
  19. "Atenolol vs. Losartan in Individuals with Marfan Syndrome Clinial Trial". National Marfan Foundation.

External links

Template:Phakomatoses and other congenital malformations not elsewhere classified Template:SIB

ar:متلازمة مارفان de:Marfan-Syndrom ko:마르팡 증후군 it:Sindrome di Marfan he:תסמונת מרפן nl:Syndroom van Marfan nn:Marfans syndrom sr:Марфанов синдром fi:Marfanin oireyhtymä sv:Marfans syndrom uk:Синдром Марфана


Template:WikiDoc Sources