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{{Infobox_Disease
| Name = Marfan syndrome
| Image = Marfansyndrome.jpg
| Caption
| DiseasesDB = 7845
| ICD10 = {{ICD10|Q|87|4|q|80}}
| ICD9
| ICDO
| OMIM = 154700
| MedlinePlus = 000418
| eMedicineSubj = ped
| eMedicineTopic = 1372
| eMedicine_mult = {{eMedicine2|orthoped|414}}
| MeshID = C17.300.500
}}
'''Marfan syndrome''' is an [[autosomal dominant]] genetic disorder of the [[connective tissue]] characterized by disproportionately long [[limb]]s, long thin fingers, a relatively tall stature, and a predisposition to cardiovascular abnormalities, specifically those affecting the [[heart valves]] and [[aorta]]. The [[disease]] may also affect numerous other structures and organs — including the [[lung]]s, [[eye]]s, dural sac surrounding the [[spinal cord]], and [[hard palate]]. It is named after [[Antoine Marfan]], the [[France|French]] [[pediatrician]] who first described it in 1899.
==
Marfan syndrome affects males and females equally,<ref name="marorg">{{Cite web|url=http://www.marfan.org/nmf/GetSubContentRequestHandler.do?sub_menu_item_content_id=6&menu_item_id=3|title=The role of heredity and family history|accessdate=2007-01-11|publisher=National Marfan Foundation|year=1999}}</ref> and the mutation shows no geographical bias. Estimates indicate that approximately 60 000 (1 in 5000, or 0.02% of the population)<ref name="marorg"/> to 200 000<ref name="mednet">{{Cite web|url=http://www.medicinenet.com/script/main/art.asp?articlekey=63689|title=New, Deadly Relative of Marfan's Syndrome Discovered|accessdate=2007-01-11|publisher=MedicineNet.com|year=2006}}</ref> 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 mutation|de novo]]'' [[genetic mutation]]s<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease| last=Cotran| coauthors=Kumar, Collins| publisher=W.B Saunders Company| ___location=Philadelphia| id=0-7216-7335-X}}</ref> — such spontaneous mutations occur in about 1 in 20 000 births. Marfan syndrome is also an example of [[dominant negative mutation]] and [[haploinsufficiency]].<ref name="Judge_et_al_2004">{{cite journal | last = Judge | first = Daniel P. | coauthors = Nancy J. Biery, Douglas R. Keene, Jessica Geubtner, Loretha Myers, David L. Huso, Lynn Y. Sakai, Harry C. Dietz | title = Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. | journal = The Journal of Clinical Investigation | volume = 114 | issue = 2 | pages = 172-181 | doi = 10.1172/JCI200420641 | id = PMID 15254584 | url = http://www.jci.org/cgi/content/full/114/2/172 | accessdate = 2007-02-15}}</ref><ref name="Judge_et_al_2005">{{cite journal | last = Judge | first = Daniel P. | coauthors = Harry C. Dietz | title = Marfan's syndrome. | journal = Lancet | volume = 366 | issue = 9501 | pages = 1965-76 | year = 2005 | doi = 10.1016/S0140-6736(05)67789-6. | id = PMID 16325700 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16325700 | accessdate = 2007-02-15}}</ref> It is associated with [[incomplete penetrance]], therefore not all persons carrying the mutation develop the disease.
== Pathogenesis ==
Marfan syndrome has been linked to a defect in the ''FBN1'' [[gene]] on [[chromosome]] 15,<ref>{{cite journal | author = McKusick V | title = The defect in Marfan syndrome. | journal = Nature | volume = 352 | issue = 6333 | pages = 279-81 | year = 1991 | id = PMID 1852198}}</ref> which [[Genetics|encodes]] a [[glycoprotein]] called [[fibrillin]]-1. Fibrillin is essential for the formation of the [[elastic fiber]]s found in connective tissue, as it provides the scaffolding for [[tropoelastin]].<ref name="robspath">{{cite book | title=Robbins Pathologic Basis of Disease| last=Cotran| coauthors=Kumar, Collins| publisher=W.B Saunders Company| ___location=Philadelphia| id=0-7216-7335-X}}</ref> Elastic fibers are found throughout the body but are particularly abundant in the [[aorta]], [[ligament]]s and the [[Zonule of Zinn|ciliary zonule]]s 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 [[mouse|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.<ref name="micefib">{{cite journal | author=Lygia Pereira, ''et al.''| title=Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1| journal=Proceedings of the National Academy of Sciences| year=1999| volume=96| issue=7| page=3819-3823| url=http://www.pnas.org/cgi/content/full/96/7/3819}}</ref>
[[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.<ref name="tgf2beta">{{Cite web|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=gene&dopt=full_report&list_uids=7048|title=TGFBR2 transforming growth factor, beta receptor II|accessdate=2007-01-11|publisher=NCBI|year=2007|author=Entrez Gene|format=Entrez gene entry}}</ref> 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''.<ref name="loeysdietz">{{Cite web|url=http://www.marfan.org/nmf/GetContentRequestHandler.do?menu_item_id=84|title=Related Disorders: Loeys-Dietz |accessdate=2007-01-11|publisher=National Marfan Foundation}}</ref>
==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 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 may be disproportionately long. In addition to affecting height and limb proportions, Marfan syndrome can produce other skeletal signs. Abnormal curvature of the [[Vertebral column|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 disorder|speech impediments]] resulting from symptomatic high palates and small jaws.
===Eyes===
Marfan syndrome can also seriously affect the eyes and vision. [[myopia|Nearsightedness]] and [[astigmatism]] are common, but farsightedness can also result. Periodic eye exams can lead to an [[ophthalmologist]] or [[optometrist]] discovering dislocation, or [[subluxation]], of the crystalline [[lens (anatomy)|lens]] in one or both eyes ([[ectopia lentis]]) by carefully observing these structures using a [[Slit lamp|slit-lamp]] biomicroscope. This can be differentiated from the similar condition [[homocystinuria]], where the dislocation is inferonasal; in Marfan's the dislocation is superotemporal. Sometimes eye problems appear only after the weakening of connective tissue has caused [[retinal detachment|detachment of the retina]].<ref name="mayo-gen">{{Cite web|url=http://www.mayoclinic.com/health/marfan-syndrome/DS00540/DSECTION=2|title=Marfan Syndrome|accessdate=2007-01-12|publisher=Mayo Clinic}}</ref> Early onset [[glaucoma]] can be another complication.
===Cardiovascular system===
The most serious conditions associated with Marfan syndrome involve the cardiovascular system. Undue fatigue, shortness of breath, [[heart palpitations]], [[tachycardia|racing heartbeats]], or [[angina|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 [[heart valve|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 [[aorta|ascending aorta]] causes an [[aortic aneurysm]] or even [[aortic dissection]]. 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 recieve 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.<ref name="emed">{{Cite web|url=http://www.emedicine.com/ped/fulltopic/topic1372.htm#section~Miscellaneous|title=Marfan Syndrome, special concerns|accessdate=2007-06-25}}</ref>
===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
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 [[lumbar|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]].<ref name="mayo-gen" /> 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. 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 [[Cardiac arrhythmia|arrythmias]], minimizing the [[heart rate]], and minimizing [[blood pressure]]. [[Beta blocker]]s have been used to control [[Cardiac arrhythmia|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 antagonist]]s, 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.<ref name="mayo-heart">{{Cite web|url=http://www.mayoclinic.org/marfan-syndrome/heartsurgery.html|title=Heart Surgery for Marfan Syndrome|accessdate=2007-01-12|publisher=Mayo Clinic}}</ref> 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]]).<ref name="chkd">{{Cite web|url=http://www.chkd.org/services/nussprocedure/Overview.aspx|title=Overview of the Nuss Procedure for Pectus Excavatum|accessdate=2007-01-12|publisher=Children's Hospital of The King's Daughters}}</ref> 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.<ref name="spine">{{Cite web|url=http://www.spineuniverse.com/displayarticle.php/article922.html|title=Dural Ectasia in the Marfan Spine: Symptoms and Treatment|accessdate=2007-01-12|publisher=Scoliosis Research Society}}</ref> 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 tube|chest drain]] management for several days in hospital. Large pneumothoraxes are likely to be medical emergencies requiring emergency decompression.
Research in laboratory [[mouse|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.<ref name="scimag">{{Cite journal | last = Habashi | first = Jennifer P. | coauthors = 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 | date = [[April 7]], [[2006]] | title = Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome | volume = 312 | issue = 5770 | pages = 117 - 121 | doi = 10.1126/science.1124287 | url = http://www.sciencemag.org/cgi/content/full/312/5770/117 | abstract = http://www.sciencemag.org/cgi/content/abstract/sci;312/5770/117 | news = http://www.news-medical.net/?id=17249}}</ref> 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.<ref name="trial">{{Cite web|url=http://www.marfan.org/nmf/GetSubContentRequestHandler.do?sub_menu_item_content_id=147&menu_item_id=91|title=Atenolol vs. Losartan in Individuals with Marfan Syndrome Clinial Trial|accessdate=2007-01-12|publisher=National Marfan Foundation}}</ref>
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 known or believed to have had Marfan syndrome:
* [[Euell Gibbons]], outdoorsman & health food proponent.
* [[Flo Hyman]], silver medal in Women's Volleyball (1984 Olympics)<ref name="flo">{{Cite web|url=http://www.volleyhall.org/hyman.html|title=Flo Hyman|accessdate=2007-01-11|publisher=Volleyball Hall of Fame}}</ref>
* [[Jonathan Larson]], Tony Award-winning playwright ([[Rent (musical)|Rent]]); he died in 1996 of [[aortic dissection]] on the eve of his musical's premiere<ref name="larson">{{Cite web|url=http://www.wnbc.com/drmaxgomez/5421112/detail.html|title=Marfan's Syndrome Is Deadly, Elusive|accessdate=2007-01-11|publisher=WNBC.com}}</ref>
* [[Robert Johnson (musician)|Robert Johnson]], blues singer and guitarist<ref name="robertj">{{Cite journal | last = Connel | first = David | date = [[September 2]], [[2006]] | title=Retrospective blues: Robert Johnson—an open letter to Eric Clapton | journal = British Medical Journal | volume = 333 | issue = 7566 | pages = 489 | url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1557967|accessdate=2007-01-11}}</ref>
*[[Mike Dunleavy]], professional basketball player for the [[Portland Trailblazers]]
* [[Vincent Schiavelli]], actor<ref name="schiavelli">{{Cite web|url=http://www.marfan.org/nmf/PreviewPressReleaseInfoRequestHandler.do?press_release_id=24|title=NMF Mourns the Loss of its Honorary Co-Chair, Vincent Schiavelli|accessdate=2007-01-11|publisher=National Marfan Foundation}}</ref>
* [[Sir John Tavener]],<ref name="bbc">Richard Morrison, ''99 Names for God: John Tavener turns his back on Orthodoxy'', BBC Music, November 2004, page 30</ref> contemporary British composer
* Bradford Cox, frontman of the punk rock band [[Deerhunter]]<ref name="deerhunter">{{Cite web|url=http://www.pitchforkmedia.com/article/feature/43085-interview-deerhunter|title=Pitchfork Feature: Interview: Deerhunter}}</ref>
* [[Joey Ramone]], of the punk rock band [[The Ramones]].
===Spurious or conjectural claims===
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.
* [[Akhenaten]], Egyptian Pharaoh, who was the father of King [[Tutankhamun]] (spurious claim based on early Amarna art style. Tutankhamun, who didn't have syndrome, was also portrayed this way)<ref name="pharaoh">{{Cite web|url=http://www.marfan.ca/pharaoh.html|title=Did Akhenaten Suffer from Marfan's Syndrome?|accessdate=2007-01-11|publisher=Canadian Marfan Association}}</ref>
* [[Osama bin Laden]] may suffer from Marfan Syndrome (speculation based on tall size, use of cane and rumoured heart-disease; almost certainly in error)<ref>http://archive.salon.com/people/feature/2001/11/09/marfan/index.html</ref>
* [[Charles de Gaulle]] (conjectural)<ref>http://archive.salon.com/people/feature/2001/11/09/marfan/index.html</ref>
* [[Nicollo Paganini]] (Conjectural) <ref>[http://tafkac.org/celebrities/paganini_stories_myths.html], main reference being an article in the AMA journal by Dr. Myron R. Shoenfeld dated 2 January, 1978.</ref>
* It was once believed that [[Abraham Lincoln]] suffered from Marfan Sydrome, although recent research has argued that he probably didn't.
* [[Johnny Appleseed]], a pioneer nurseryman in America living during the 18th century; he has become an almost mythical popular culture icon in America.
==Related disorders==
The following disorders have similar signs and symptoms of Marfan syndrome:
*[[Arachnodactyly|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:
<div style="width:30%; float:left; padding:0 3% 0 0; border:none; overflow:hidden; clear:left;">
*[[Aortic aneurysm|Aortic aneurysm or dilitation]]
*[[Arachnodactyly]]
*[[Bicuspid aortic valve]]
*[[Cysts]]
*[[Craniosynostosis]]
*[[Cystic medial necrosis]]
*[[Dural ectasia]]
*[[Ectopia lentis]]
</div>
<div style="width:30%; float:left; padding:0 3% 0 0; border:none; overflow:hidden; ">
*[[Flat feet]]
*[[Gigantism]]
*[[Glaucoma]]
*[[Hernias]]
*[[Hyperflex|Hypermobility of the joints]]
*[[Malocclusion]]
*[[Mitral valve prolapse]]
*[[Myopia]]
</div>
<div class="editmode" style="width:30%; float:left; padding:0 3% 0 0; border:none; overflow:hidden; ">
*[[COPD|Obstructive lung disease]]
*[[Osteoarthritis]]
*[[Pectus carinatum]] or [[pectus excavatum|excavatum]]
*[[Pneumothorax]]
*[[Retinal detachment]]
*[[Scoliosis]]
*[[Sleep apnea]]
*[[Stretch marks]]
</div><br clear="left" />
==References==
{{reflist|2}}
==External links==
*[http://marfanworld.org/ International Federation of Marfan Syndrome Organisations]
*[http://www.marfan.org/ National Marfan Foundation (USA)]
*[http://www.marfan.org.za/diagnosis.html Marfan diagnosis criteria]
*[http://www.ncbi.nlm.nih.gov/disease/Marfan.html National Institute for Health Marfan syndrome page (USA)]
*[http://www.medicinenet.com/marfan_syndrome/index.htm Marfan Syndrome Center at medicinenet.com]
*[http://marfansyndrome.researchtoday.net/ Marfan Syndrome Research] - recent literature on Marfan Syndrome
*[http://www.supportmarfan.com Marfan support]
*[http://www.marfan.ca/ Canadian Marfan Association]
*[http://www.marfan.org.uk/ Marfan Association UK]
*[http://www.marfan.org.mx/ Marfan de Mexico]
*[http://www.marfan.no/ Norwegian Marfan Organization]
*[http://www.marfanlife.net Marfan Life blog] - mostly links to news articles about Marfan Syndrome
*[http://www.marfanlife.net/lists/ Marfan-List] - email discussion list for people and families with Marfan Syndrome
*[http://www.marfan.org.za/ South African Marfan Syndrome Organisation] - support group for Africa
*[http://www.medstudents.com.br/original/revisao/marfan/marfan.htm Eye Findings in Marfan's syndrome]
[[Category:Cardiology]]
[[Category:Diseases involving the fasciae]]
[[Category:Genetic disorders]]
[[Category:Syndromes]]
[[ar:متلازمة مارفان]]
[[de:Marfan-Syndrom]]
[[es:Síndrome de Marfan]]
[[fr:Syndrome de Marfan]]
[[ko:마르팡 증후군]]
[[it:Sindrome di Marfan]]
[[he:תסמונת מרפן]]
[[nl:Syndroom van Marfan]]
[[ja:マルファン症候群]]
[[nn:Marfans syndrom]]
[[pl:Zespół Marfana]]
[[pt:Síndrome de Marfan]]
[[ru:Синдром Марфана]]
[[sr:Марфанов синдром]]
[[fi:Marfanin oireyhtymä]]
[[sv:Marfans syndrom]]
[[uk:Синдром Марфана]]
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