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==Background==
==Background==
In 1896, French pediatrician Antoine-Bernard Jean Marfan described a five year old girl, Gabrielle P, with skeletal features characteristic of Marfan Syndrome <ref>Marfan A. Un cas de déformation congénitgale des quatres membres, plus prononcée aux extremités, caractérisée par l'allongement des os avec un certain degré d'amincissiment. . Bulletins et memoires de la Société medicale des hôpitaux de Paris 1896;13:220-8.</ref>, 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 features <ref name="pmid13590978">{{cite journal |author=BOYER BE, MARTIN MM |title=Marfan's syndrome; report of a case manifesting a giant bone cyst of the mandible and multiple (110) basal cell carcinomata |journal=[[Plastic and Reconstructive Surgery and the Transplantation Bulletin]] |volume=22 |issue=3 |pages=257–63 |year=1958 |month=September |pmid=13590978 |doi= |url= |issn= |accessdate=2010-12-22}}</ref>.  Salle contributed the observation in 1912 that patients with arachnodactyly had thickened mitral leaflets, ocular abnormalities and increase in eosinophilic cells in the pituitary <ref>Salle V. Grosse der Extremitaten mit einem an Akromegalie erinnernden Symptomenkomplex. J Kinderheilk 1912;75:540.</ref>, <ref name="pmid14360720">{{cite journal |author=BLACK HH, LANDAY LH |title=Marfan's syndrome; report on five cases in one family |journal=[[A.M.A. American Journal of Diseases of Children]] |volume=89 |issue=4 |pages=414–20 |year=1955 |month=April |pmid=14360720 |doi= |url= |issn= |accessdate=2010-12-22}}</ref>.  The observation that ectopic lens was associated with other symptoms was first made by Boerger in 1914 <ref>Boerger F. Ueber zwei Falle von Arachnodaktylie. Monatsschr Kinderheilk 1914;13:335.</ref>.  Weve established the autosomal dominant inheritance of the disease, still known as arachnodactyly, in 1931 <ref>Weve H. Ueber Arachnodaktylie (Dystrophia mesodermalis congenita, Typus Marfan). Archiv für Augenheilkunde, Wiesbaden 1931;104:1-46.</ref>. 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 Glover <ref>Baer RW, Taussig, H. B., Oppenheimer, E. H. Congenital aneurysmal dilatation of the aorta associated with arachnodactyly. Bull Johns Hopkins Hosp 1943.</ref>, <ref>Major Lewis E. Etter; L. Pellman Glover MD. ARACHNODACTYLY COMPLICATED BY DISLOCATED LENS AND DEATH FROM RUPTURE OF DISSECTING ANEURYSM OF AORTA. Journal of the American Medical Association 1943;123:88-9.</ref>.  Harry C Deitz finally established the molecular basis of Marfan Syndrome in his landmark 1991 Nature paper, showing that mutations in the FBN1 gene are responsible for the disease <ref name="pmid1852208">{{cite journal |author=Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM |title=Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene |journal=[[Nature]] |volume=352 |issue=6333 |pages=337–9 |year=1991 |month=July |pmid=1852208 |doi=10.1038/352337a0 |url=http://dx.doi.org/10.1038/352337a0 |issn= |accessdate=2010-12-22}}</ref>.
In 1896, French pediatrician Antoine-Bernard Jean Marfan described a five year old girl, Gabrielle P, with skeletal features characteristic of Marfan Syndrome <ref>Marfan A. Un cas de déformation congénitgale des quatres membres, plus prononcée aux extremités, caractérisée par l'allongement des os avec un certain degré d'amincissiment. . Bulletins et memoires de la Société medicale des hôpitaux de Paris 1896;13:220-8.</ref>, 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 features <ref name="pmid13590978">{{cite journal |author=BOYER BE, MARTIN MM |title=Marfan's syndrome; report of a case manifesting a giant bone cyst of the mandible and multiple (110) basal cell carcinomata |journal=[[Plastic and Reconstructive Surgery and the Transplantation Bulletin]] |volume=22 |issue=3 |pages=257–63 |year=1958 |month=September |pmid=13590978 |doi= |url= |issn= |accessdate=2010-12-22}}</ref>.  Salle contributed the observation in 1912 that patients with arachnodactyly had thickened [[mitral leaflet]]s, ocular abnormalities and increase in [[eosinophilic]] cells in the [[pituitary]] <ref>Salle V. Grosse der Extremitaten mit einem an Akromegalie erinnernden Symptomenkomplex. J Kinderheilk 1912;75:540.</ref>, <ref name="pmid14360720">{{cite journal |author=BLACK HH, LANDAY LH |title=Marfan's syndrome; report on five cases in one family |journal=[[A.M.A. American Journal of Diseases of Children]] |volume=89 |issue=4 |pages=414–20 |year=1955 |month=April |pmid=14360720 |doi= |url= |issn= |accessdate=2010-12-22}}</ref>.  The observation that ectopic lens was associated with other symptoms was first made by Boerger in 1914 <ref>Boerger F. Ueber zwei Falle von Arachnodaktylie. Monatsschr Kinderheilk 1914;13:335.</ref>.  Weve established the [[autosomal dominant inheritance]] of the disease, still known as arachnodactyly, in 1931 <ref>Weve H. Ueber Arachnodaktylie (Dystrophia mesodermalis congenita, Typus Marfan). Archiv für Augenheilkunde, Wiesbaden 1931;104:1-46.</ref>. 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 Glover <ref>Baer RW, Taussig, H. B., Oppenheimer, E. H. Congenital aneurysmal dilatation of the aorta associated with arachnodactyly. Bull Johns Hopkins Hosp 1943.</ref>, <ref>Major Lewis E. Etter; L. Pellman Glover MD. ARACHNODACTYLY COMPLICATED BY DISLOCATED LENS AND DEATH FROM RUPTURE OF DISSECTING ANEURYSM OF AORTA. Journal of the American Medical Association 1943;123:88-9.</ref>.  Harry C Deitz finally established the molecular basis of Marfan Syndrome in his landmark 1991 Nature paper, showing that [[mutations]] in the [[FBN1 gene]] are responsible for the disease <ref name="pmid1852208">{{cite journal |author=Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM |title=Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene |journal=[[Nature]] |volume=352 |issue=6333 |pages=337–9 |year=1991 |month=July |pmid=1852208 |doi=10.1038/352337a0 |url=http://dx.doi.org/10.1038/352337a0 |issn= |accessdate=2010-12-22}}</ref>.


==Pathophysiology==
==Pathophysiology==
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.  
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.  


Marfan syndrome is inherited as a [[Autosomal dominant|dominant]] trait.  In so far as the pattern of inheritance is [[Dominance (genetics)|dominant]],   people who have inherit just one affected FBN1 gene from either parent   will develop Marfan syndrome. This expression of the syndrome can range  from mild to severe.  
Marfan syndrome is inherited as a [[Autosomal dominant|dominant]] trait.  In so far as the pattern of inheritance is [[Dominance (genetics)|dominant]], people who have inherit just one affected FBN1 gene from either parent will develop Marfan syndrome. This expression of the syndrome can range  from mild to severe.  


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.<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>
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 is associated with 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>


High levels of [[Transforming growth factor]] beta (TGFβ) are associated with inflammation and also play an important role in Marfan syndrome. Ordinarily, Fibrillin-1 binds TGFβ and inactivates it. In Marfan syndrome, reduced levels of  fibrillin-1 allow activated TGFβ to damage the lungs and heart. Researchers now believe that the inflammatory effects of TGF-β, on the lungs, heart valves, and aorta weaken the connective tissues and cause the features of Marfan syndrome. In so far as [[angiotensin II receptor blocker]]s ([[Angiotensin II receptor antagonists|ARBs]]) reduce TGF-β, these agents  have been administered  to young Marfan syndrome patients, and the expansion of the aorta was indeed reduced.<ref>{{cite journal |author=Pyeritz RE |title=A small molecule for a large disease |journal=N. Engl. J. Med. |volume=358 |issue=26 |pages=2829–31 |year=2008 |month=June |pmid=18579819 |doi=10.1056/NEJMe0804008}}</ref>
High levels of [[Transforming growth factor]] beta ([[TGFβ]]) are associated with inflammation and also play an important role in Marfan syndrome. Ordinarily, [[Fibrillin-1]] binds [[TGFβ]] and inactivates it. In Marfan syndrome, reduced levels of  fibrillin-1 allow activated TGFβ to damage the lungs and heart. Researchers now believe that the inflammatory effects of TGF-β, on the lungs, heart valves, and aorta weaken the [[connective tissue]]s and cause the features of Marfan syndrome. In so far as [[angiotensin II receptor blocker]]s ([[Angiotensin II receptor antagonists|ARBs]]) reduce TGF-β, these agents  have been administered  to young Marfan syndrome patients, and the expansion of the aorta was indeed reduced.<ref>{{cite journal |author=Pyeritz RE |title=A small molecule for a large disease |journal=N. Engl. J. Med. |volume=358 |issue=26 |pages=2829–31 |year=2008 |month=June |pmid=18579819 |doi=10.1056/NEJMe0804008}}</ref>


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|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|publisher=National Marfan Foundation}}</ref>
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|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|publisher=National Marfan Foundation}}</ref>


==Differential Diagnosis==
==Differential Diagnosis==
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==Etymology==
==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.
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==
==Epidemiology==
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==Genetics==
==Genetics==


Marfan syndrome is an autosomal dominant disorder caused by mutations in the Fibrillin-1 gene encoding an extracellular matrix protein which constitutes an essential component of microfibrils, critical in formation of elastin.  Engvall first isolated the protein from human fibroblast cell culture in 1986, demonstrated its function as a component of extracellular microfibrils and its widespread expression through connective tissue in many organ systems <ref name="pmid3536967">{{cite journal |author=Sakai LY, Keene DR, Engvall E |title=Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils |journal=[[The Journal of Cell Biology]] |volume=103 |issue=6 Pt 1 |pages=2499–509 |year=1986 |month=December |pmid=3536967 |pmc=2114568 |doi= |url=http://www.jcb.org/cgi/pmidlookup?view=long&pmid=3536967 |issn= |accessdate=2010-12-22}}</ref>.  Early linkage studies of families with Marfan syndrome mapped the gene to 15q21.1 <ref name="pmid2402262">{{cite journal |author=Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L |title=Location on chromosome 15 of the gene defect causing Marfan syndrome |journal=[[The New England Journal of Medicine]] |volume=323 |issue=14 |pages=935–9 |year=1990 |month=October |pmid=2402262 |doi=10.1056/NEJM199010043231402 |url=http://dx.doi.org/10.1056/NEJM199010043231402 |issn= |accessdate=2010-12-22}}</ref>, surprising some investigators who suspected defects in the Elastin gene were causal.  Subsequent mutational analysis of FBN1 in patients with Marfan system revealed identical missense mutations in two unrelated patients9.  Many linkage studies have been performed and demonstrate that most families have private mutations.  The FBN1 gene is very large, consisting of 65 exons.  It encodes a 350 kiloDalton protein and is highly conserved between different species.   
Marfan syndrome is an [[autosomal dominant]] disorder caused by mutations in the Fibrillin-1 gene encoding an extracellular matrix protein which constitutes an essential component of microfibrils, critical in formation of elastin.  Engvall first isolated the protein from human fibroblast cell culture in 1986, demonstrated its function as a component of extracellular microfibrils and its widespread expression through connective tissue in many organ systems <ref name="pmid3536967">{{cite journal |author=Sakai LY, Keene DR, Engvall E |title=Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils |journal=[[The Journal of Cell Biology]] |volume=103 |issue=6 Pt 1 |pages=2499–509 |year=1986 |month=December |pmid=3536967 |pmc=2114568 |doi= |url=http://www.jcb.org/cgi/pmidlookup?view=long&pmid=3536967 |issn= |accessdate=2010-12-22}}</ref>.  Early linkage studies of families with Marfan syndrome mapped the gene to 15q21.1 <ref name="pmid2402262">{{cite journal |author=Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L |title=Location on chromosome 15 of the gene defect causing Marfan syndrome |journal=[[The New England Journal of Medicine]] |volume=323 |issue=14 |pages=935–9 |year=1990 |month=October |pmid=2402262 |doi=10.1056/NEJM199010043231402 |url=http://dx.doi.org/10.1056/NEJM199010043231402 |issn= |accessdate=2010-12-22}}</ref>, surprising some investigators who suspected defects in the Elastin gene were causal.  Subsequent mutational analysis of FBN1 in patients with Marfan system revealed identical [[missense mutations]] in two unrelated patients9.  Many [[linkage studies]] have been performed and demonstrate that most families have private mutations.  The FBN1 gene is very large, consisting of 65 [[exons]].  It encodes a 350 kiloDalton protein and is highly conserved between different species.   


Familial mutations of the FBN1 gene account for 75% of cases of Marfan syndrome and their corresponding phenotype is inherited in a dominant fashion.  Over 500 different FBN1 mutations have been detected in Marfan syndrome patients <ref name="pmid9399842">{{cite journal |author=Collod-Béroud G, Béroud C, Ades L, Black C, Boxer M, Brock DJ, Holman KJ, de Paepe A, Francke U, Grau U, Hayward C, Klein HG, Liu W, Nuytinck L, Peltonen L, Alvarez Perez AB, Rantamäki T, Junien C, Boileau C |title=Marfan Database (third edition): new mutations and new routines for the software |journal=[[Nucleic Acids Research]] |volume=26 |issue=1 |pages=229–3 |year=1998 |month=January |pmid=9399842 |pmc=147226 |doi= |url= |issn= |accessdate=2010-12-22}}</ref>.  56% of these mutations are missense mutations, most often by creating or substituting  a cysteine in a cbEGF domain critical for calcium binding <ref name="pmid21063442">{{cite journal |author=Hilhorst-Hofstee Y, Hamel BC, Verheij JB, Rijlaarsdam ME, Mancini GM, Cobben JM, Giroth C, Ruivenkamp CA, Hansson KB, Timmermans J, Moll HA, Breuning MH, Pals G |title=The clinical spectrum of complete FBN1 allele deletions |journal=[[European Journal of Human Genetics : EJHG]] |volume= |issue= |pages= |year=2010 |month=November |pmid=21063442 |doi=10.1038/ejhg.2010.174 |url=http://dx.doi.org/10.1038/ejhg.2010.174 |issn= |accessdate=2010-12-22}}</ref>.  Missense mutations are clustered in loci with cbEGF domains and typically cause moderate to severe phenotype <ref name="pmid8406497">{{cite journal |author=Dietz HC, McIntosh I, Sakai LY, Corson GM, Chalberg SC, Pyeritz RE, Francomano CA |title=Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome |journal=[[Genomics]] |volume=17 |issue=2 |pages=468–75 |year=1993 |month=August |pmid=8406497 |doi=10.1006/geno.1993.1349 |url=http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(83)71349-2 |issn= |accessdate=2010-12-22}}</ref>.  Other documented mutations include nonsense, frameshift and splice site mutations.  Complete deletions of a FBN1 allele are very rare.  90% of FBN1 mutations are private to an individual or family10.  The incredibly diverse set of mutations that cause the syndrome suggest that these mutations generally reflect loss-of-function cause a dominant negative phenotype.  Haploinsufficiency and other theories have been proposed to account for the dominant negative phenomenon which will be detailed later.
Familial mutations of the FBN1 gene account for 75% of cases of Marfan syndrome and their corresponding phenotype is inherited in a dominant fashion.  Over 500 different FBN1 mutations have been detected in Marfan syndrome patients <ref name="pmid9399842">{{cite journal |author=Collod-Béroud G, Béroud C, Ades L, Black C, Boxer M, Brock DJ, Holman KJ, de Paepe A, Francke U, Grau U, Hayward C, Klein HG, Liu W, Nuytinck L, Peltonen L, Alvarez Perez AB, Rantamäki T, Junien C, Boileau C |title=Marfan Database (third edition): new mutations and new routines for the software |journal=[[Nucleic Acids Research]] |volume=26 |issue=1 |pages=229–3 |year=1998 |month=January |pmid=9399842 |pmc=147226 |doi= |url= |issn= |accessdate=2010-12-22}}</ref>.  56% of these mutations are missense mutations, most often by creating or substituting  a cysteine in a cbEGF domain critical for calcium binding <ref name="pmid21063442">{{cite journal |author=Hilhorst-Hofstee Y, Hamel BC, Verheij JB, Rijlaarsdam ME, Mancini GM, Cobben JM, Giroth C, Ruivenkamp CA, Hansson KB, Timmermans J, Moll HA, Breuning MH, Pals G |title=The clinical spectrum of complete FBN1 allele deletions |journal=[[European Journal of Human Genetics : EJHG]] |volume= |issue= |pages= |year=2010 |month=November |pmid=21063442 |doi=10.1038/ejhg.2010.174 |url=http://dx.doi.org/10.1038/ejhg.2010.174 |issn= |accessdate=2010-12-22}}</ref>.  Missense mutations are clustered in loci with cbEGF domains and typically cause moderate to severe phenotype <ref name="pmid8406497">{{cite journal |author=Dietz HC, McIntosh I, Sakai LY, Corson GM, Chalberg SC, Pyeritz RE, Francomano CA |title=Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome |journal=[[Genomics]] |volume=17 |issue=2 |pages=468–75 |year=1993 |month=August |pmid=8406497 |doi=10.1006/geno.1993.1349 |url=http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(83)71349-2 |issn= |accessdate=2010-12-22}}</ref>.  Other documented mutations include nonsense, frameshift and [[splice site mutation]]s.  Complete deletions of a FBN1 [[allele]] are very rare.  90% of FBN1 mutations are private to an individual or family10.  The incredibly diverse set of mutations that cause the syndrome suggest that these mutations generally reflect loss-of-function cause a dominant negative phenotype.  [[Haploinsufficiency]] and other theories have been proposed to account for the dominant negative phenomenon which will be detailed later.


No FBN1 mutation can be identified in 10% of Marfan syndrome patients <ref>Michael J Wright HMC. Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders. In: UptoDate; 2010.</ref>.  In this subset of patients, mutations in the transforming growth factor-beta receptor 2 (TGFBR2) are causal.  Families with TGFBR2 mutations display autosomal dominant inheritance with variable penetrance.   
No FBN1 mutation can be identified in 10% of Marfan syndrome patients <ref>Michael J Wright HMC. Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders. In: UptoDate; 2010.</ref>.  In this subset of patients, mutations in the transforming growth factor-beta receptor 2 (TGFBR2) are causal.  Families with TGFBR2 mutations display autosomal dominant inheritance with variable [[penetrance]].   




Revision as of 15:20, 23 December 2010

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

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

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

Assistant Editor-In-Chief: Cassandra Abueg, M.P.H. [2]

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 [3] 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 connective tissue disorder most often caused by defects in the Fibrillin-1 gene (FBN1). Patients with Marfan's syndrome are at significant risk of skeletal, cardiovascular and ocular complications. People with Marfan's are typically tall, with long limbs and long thin fingers.

Background

In 1896, French pediatrician Antoine-Bernard Jean Marfan described a five year old girl, Gabrielle P, with skeletal features characteristic of Marfan Syndrome [1], 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 features [2]. Salle contributed the observation in 1912 that patients with arachnodactyly had thickened mitral leaflets, ocular abnormalities and increase in eosinophilic cells in the pituitary [3], [4]. The observation that ectopic lens was associated with other symptoms was first made by Boerger in 1914 [5]. Weve established the autosomal dominant inheritance of the disease, still known as arachnodactyly, in 1931 [6]. 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 Glover [7], [8]. Harry C Deitz finally established the molecular basis of Marfan Syndrome in his landmark 1991 Nature paper, showing that mutations in the FBN1 gene are responsible for the disease [9].

Pathophysiology

Marfan syndrome has been linked to a defect in the FBN1 gene on chromosome 15,[10] 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.[11] 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.

Marfan syndrome is inherited as a dominant trait. In so far as the pattern of inheritance is dominant, people who have inherit just one affected FBN1 gene from either parent will develop Marfan syndrome. This expression of the syndrome can range from mild to severe.

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 is associated with a Marfan-related disease in mice.[12]

High levels of Transforming growth factor beta (TGFβ) are associated with inflammation and also play an important role in Marfan syndrome. Ordinarily, Fibrillin-1 binds TGFβ and inactivates it. In Marfan syndrome, reduced levels of fibrillin-1 allow activated TGFβ to damage the lungs and heart. Researchers now believe that the inflammatory effects of TGF-β, on the lungs, heart valves, and aorta weaken the connective tissues and cause the features of Marfan syndrome. In so far as angiotensin II receptor blockers (ARBs) reduce TGF-β, these agents have been administered to young Marfan syndrome patients, and the expansion of the aorta was indeed reduced.[13]

A defect in the gene TGFβR2 on chromosome 3, a receptor protein of TGFβ, has also been related to Marfan syndrome.[14] 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.[15]

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,[16] and the mutation shows no geographical bias. Estimates indicate that approximately 60 000 (1 in 5000, or 0.02% of the population)[16] to 200 000[17] 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[11] — such spontaneous mutations occur in about 1 in 20 000 births. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency.[18][19] It is associated with variable expressivity. Incomplete penetrance, has not been definitively documented.

The prevalence of Marfan syndrome is 1 case per 3000 to 5000 individuals or .033 % (upper estimate) [20]. Neither location nor ethnicity appear to impact this statistic. Populations of certain athletes such as basketball and volleyball players have been shown to have an increased incidence of Marfan syndrome (~0.5%) [21], perhaps due to skeletal abnormalities associated with the syndrome. While patients now have nearly normal life expectancies, in previous decades, patients’ life expectancies were significantly shortened by the risks of aortic dissection, valvular failure and congestive heart failure. Together, these cardiovascular complications accounted for 90% of the mortality associated with Marfan syndrome such that in the 1970s, an affected individual would be expected to live only two-thirds as long as his unaffected counterparts [22].

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. [23]

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. [23]

In Marfan's the dislocation is typically superotemporal whereas in the similar condition homocystinuria, the dislocation is inferonasal.[23]

Sometimes eye problems appear only after the weakening of connective tissue has caused detachment of the retina.[23] 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.[24] 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.[25]

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

Diagnosis

Several standards of diagnostic criteria for Marfan syndrome have been proposed. In 1986, the Berlin nosology was established which represented a consensus on clinical features diagnostic of Marfan syndrome with an emphasis on skeletal features [26]. Advances in molecular testing and the realization that many individuals diagnosed with Marfan syndrome according to the Berlin nosology did not have mutations in the FBN1 gene, led to the establishment of the Ghent nosology in1996, a new set of criteria with stricter diagnostic requirements [27]. The Ghent nosology remains the current standard for diagnosis, although a revised version of the guidelines was published in 201015. The criteria are divided into major and minor manifestations which have allowed physicians to correctly diagnose 95% of patients as confirmed by molecular analysis of the FBN1 gene [28]. The new criteria establish aortic root aneurysm and ectopia lentis as the principal clinical features of the disease and stress cardiovascular manifestations.

The major criteria for diagnosis of Marfan syndrome are ectopia lentis, aortic root dilation/dissection, dural ectasia, or a combination of more than 4 out of 8 major skeletal features (Table 1). In an individual with no known family history of Marfan syndrome and in the absence of any known FBN1 mutations, major involvement of two organs systems (e.g. skeletal, cardiovascular, ocular) and minor involvement of a third system is required for diagnosis. However, if the patient has a known FBN1 mutation or affected relative, major involvement of only one system and minor involvement of another is sufficient for diagnosis (Table 1). Major manifestations of the cardiovascular system include ascending aortic dilation involving the sinuses of valsalva or dissection of the ascending aorta. Ectopia Lentis is the sole major criterion for involvement of the ocular system, and dural ectasia in the lumbosacral region diagnosed by CT or MRI is the criterion for major involvement of the dura. Having a known FBN1 mutation or a relative who independently satisfies criteria for diagnosis satisfies major involvement of family/genetic history. Physical examination for Marfan syndrome requires extensive evaluation of the skeletal system. Patients must fulfill four of the eight following criteria for major involvement of the skeletal system: pectus carinatum, pectus ex cavatum requiring surgery, reduced upper to lower segment ratio, wrist and thumb signs (Figure 1). Minor criteria for the various systems including pulmonary and skin/integument can be found in the supplement.

Diagnostic Criteria
Skeletal System
Major Criterion. Presence of at least 4of the following manifestations.

• pectus carinatum

• pectus ex cavatum requiring surgery

• reduced upper to lower segment ratio or arm span to height ratio greater than 1.05

• wrist and thumb signs

• scoliosis of > 20" or spondylolisthesis

• reduced extension at the elbows (< 170")

• medial displacementof the medial malleolus causing pes planus protmsio acetabulae of any degree (ascertained on radiographs)

Minor criteria.

• pectus excavatum of moderate severity

• joint hypermobility

• highly arched palate with crowding of teeth

• facial appearance (dolichocephaly, malar hypo- plasia,enophthalmos,retrognathia,down-Slanting palpebral fissures)

Ocular System
Major criterion. • Ectopia lentis
Minor criteria.

• abnormally flat cornea (as measured by keratometry)

• increased axial length of globe (as measured by ultrasound)

• hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis

Cardiovascular System
Major criteria.

• dilatation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva; or

• dissection of the ascending aorta

Minor criteria.

• Mitral valve prolapsed

• Mitral valve prolapsed with or without mitral valve regurgitation;

• dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause, below the age of 40 years;

• calcification of the mitral annulus below the age of 40 years; or dilatation or dissection of the descending thoracic or abdominal aorta below the age of 50 years

Pulmonary System
Minor criteria.

• spontaneous pneumothorax [Hall et al., 19841]

• apical blebs (ascertained by chest radiography)

Skin and Integument
Minor criteria.

• striaeatrophicae (stretchmarks) not associated with marked weight changes, pregnancy or repetitive stress

• recurrent or incisional herniae

Dura
Major criterion.

• Lumbosacral dural ectasia by CT or MRI

Family/Genetic History
Major criteria. • having a parent, child or sib who meets these diagnostic criteria independently;

• presence of a mutation in FBNl known to cause the Marfan syndrome;

• presence of a haplotype around FBNl, inherited by descent, known to be associated with unequivocal- ly diagnosed Marfan syndrome in the family

Adapted from De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417-26.


Molecular diagnostics, namely DNA sequencing can be extremely informative for the diagnosis of Marfan syndrome. A 2008 study showed that while only 79% of known probands could be diagnosed with Marfan syndrome using clinical criteria, 90% of these individuals could be diagnosed using the international criteria when sequencing data was added. In children, this figure leapt from 56% to 85% with sequencing data. The increased diagnostic sensitivity conferred by genetic information promises to be especially useful in children who have not developed clinical manifestations, but in whom new pharmacological interventions may be successful. Currently, laboratories offer complete sequencing of the 65 exon FBN1 gene for approximately $1700.00 [29]. The high costs of these diagnostics have delayed the widespread use of molecular diagnostics in the approach to patients suspected of Marfan syndrome. Increasingly less expensive sequencing technologies promise to increase reliance on individual genetic data for diagnosis in the future.

Image A: Skeletal exam of Marfan syndrome. Thumb sign, positive if the thumb protrudes from the clenched fist. Image B: Skeletal exam of Marfan syndrome. Wrist Sign, positive if thumb and first phalange can overlap when encircling wrist.

[30]

Genetics

Marfan syndrome is an autosomal dominant disorder caused by mutations in the Fibrillin-1 gene encoding an extracellular matrix protein which constitutes an essential component of microfibrils, critical in formation of elastin. Engvall first isolated the protein from human fibroblast cell culture in 1986, demonstrated its function as a component of extracellular microfibrils and its widespread expression through connective tissue in many organ systems [31]. Early linkage studies of families with Marfan syndrome mapped the gene to 15q21.1 [32], surprising some investigators who suspected defects in the Elastin gene were causal. Subsequent mutational analysis of FBN1 in patients with Marfan system revealed identical missense mutations in two unrelated patients9. Many linkage studies have been performed and demonstrate that most families have private mutations. The FBN1 gene is very large, consisting of 65 exons. It encodes a 350 kiloDalton protein and is highly conserved between different species.

Familial mutations of the FBN1 gene account for 75% of cases of Marfan syndrome and their corresponding phenotype is inherited in a dominant fashion. Over 500 different FBN1 mutations have been detected in Marfan syndrome patients [33]. 56% of these mutations are missense mutations, most often by creating or substituting a cysteine in a cbEGF domain critical for calcium binding [34]. Missense mutations are clustered in loci with cbEGF domains and typically cause moderate to severe phenotype [35]. Other documented mutations include nonsense, frameshift and splice site mutations. Complete deletions of a FBN1 allele are very rare. 90% of FBN1 mutations are private to an individual or family10. The incredibly diverse set of mutations that cause the syndrome suggest that these mutations generally reflect loss-of-function cause a dominant negative phenotype. Haploinsufficiency and other theories have been proposed to account for the dominant negative phenomenon which will be detailed later.

No FBN1 mutation can be identified in 10% of Marfan syndrome patients [36]. In this subset of patients, mutations in the transforming growth factor-beta receptor 2 (TGFBR2) are causal. Families with TGFBR2 mutations display autosomal dominant inheritance with variable penetrance.


Molecular Biology/Pathogenesis

How FBN1 and TGFBR2 mutations cause the syndrome is not well understood. Early data suggests that the mechanism of pathogenesis may involve altered calcium binding FBN1 proteins, as suggested by the predominance of mutations in putative calcium binding regions of the FBN1 gene. The gene contains 47 tandemly repeated calcium binding epidermal growth factor-like domains (cbEGF). These domains contain six cysteine residues that are spaced in a conserved fashion and function to both coordinate calcium binding and form disulfide linkages which govern protein folding. Mutations in cbEGF domains make the Fibrillin-1 proteins more vulnerable to proteolytic degradation and cleavage [37],[38].

The dominant negative inheritance of the disorder suggests mechanisms for molecular pathogenesis. Indeed, other diseases of connective tissue have an established pathway of dominant negative pathology such as osteogenesis imperfecta, a disorder caused by defects in the collagen-1 gene. Because collagen assembles from several monomers, a defect in one protein can disrupt the folding and thus function of the entire assembly, a phenomenon called interference. Similarly, microfibrils are composed of several fibrillin monomers and it is suspected that interference may occur in Marfan syndrome. More complex interactions may be at play as well. Many patients show dramatically decreased expression of FBN1, far below a simple halving that would be expected from loss of one allele. Further, patients with a mild phenotype have been identified who express very low levels of the mutant allele.

Conversely, there is a great deal of evidence suggesting that haploinsufficiency of FBN1 causes the disease. In a mouse model, transgenic expression of a missense mutant FBN1 gene which caused vascular hallmarks of disease with only one normal allele did not cause disease in mice with two normal alleles [39]. A second mouse study showed that mice with loss of one FBN1 allele displayed aortic manifestations of the disease, and transgenic expression of a wild-type FBN1 in these same mice was able to rescue the normal phenotype [40]. Finally, a 2010 report of 10 patients with full deletions of one copy of the FBN1 gene showed that seven of these patients fulfilled the Ghent criteria, while the others were quite young at examination but still displayed facial and skeletal manifestations of the disease .

Increased TGF-β signaling is reflected by higher concentrations of the cytokine in both Marfan syndrome patients (6 fold increase in concentration) and mice with FBN1 mutations. Marfan syndrome mice treated with losartan, an angiotensin II type I blocker which attenuates TGF-β activation, experienced a significant reduction in plasma TGF-β concentration. This finding was also replicated in Marfan Sydrome patients. Promisingly, aortic root diameter was also significantly reduced in mice receiving losartan [41].

Current efforts aim at identifying molecular events occurring downstream of TGF-β signaling as possible therapeutic targets. TGF-β dependent activation of matrix metalloproteinases 2 and 9 has been implicated in disease pathogenesis. Data from mouse models shows that the matrix metalloproteinase antagonist doxycycline can slow aortic root growth [42].

Treatment

Medical therapy for Marfan syndrome focuses on measures to delay the progression of cardiovascular complications of the disease. Once sufficient progression has occurred, surgical interventions become necessary. The most dangerous manifestation of the disease is aortic dissection which must be carefully managed. Aortic diameter can be measured using echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI). While internal diameter can be measured with echocardiography, CT or MRI are required for measurement of the external vessel diameter which is normally 2 to 4 mm larger than the internal artery diameter. When possible, it is recommended that MRI be used to assess diameter in order to minimize patient exposure to radiation. The most important measurement is the diameter at the sinuses of valsalva, a location particularly prone to dissection in patients with the syndrome. After diagnosis, patients must be followed and the aortic size monitored every 6 months as recommended by the 2010 ACC/AHA/AATS guidelines for thoracic aortic disease. If the diameter is stable and less than 45mm, annual imaging is sufficient. However, if the diameter is greater than 45mm or the diameter is growing appreciably more frequent imaging is necessary.

Drug therapies for Marfan syndrome focus on decreasing the mechanical forces to which the aorta is exposed. Beta blockers are the standard of care for adults. These drugs decrease myocardial contractility and as an extension, decrease blood pressure. In 1994, a study was published comparing the beta blocker propanol to placebo. Patients receiving propanol experienced a significant four-fold reduction in aortic root dilation and significantly decreased mortality in the middle of the study (around 5 years). However, at the end of the study, there was no significant difference between the groups in mortality. Evidence for use of beta blockers in children is less clear.

Recent studies of Losartan in children have proven promising in preventing cardiovascular complication of the syndrome. A 2008 study of 18 children with severe aortic root dilation who failed treatment with other medical therapy were treated with losartan. The rate of aortic root dilation was dramatically reduced after the initiation of therapy (3.54+/- 2.87 mm per year versus 0.46 +/-0.62 mm per year, p<.001). These findings have not yet been confirmed in a randomized trial. Clinical trials are currently underway comparing standard beta blocker therapy (Atenolol, Nebivolol) to therapy with Angiotensin Receptor Blockers (Losartan) [43], [44].

Even with the advent of new therapies based on angiotensin receptor blockade, patients are still at risk of aortic dissection It is recommended that most patients do not engage in vigorous physical activity. Contact sports such as football, ice hockey are strongly discouraged in addition to surfing and snorkeling. Activities that increase intrathoracic pressure such as weight lifting are also strongly discouraged. Exercise of low to moderate intensity, four to six metabolic equivalents, is permissible [45].

Patients at high risk of aortic dissection may be counseled to undergo prophylactic aortic root replacement procedure. The 2010 ACC/AHA/AATS recommendations for indications for surgery include external diameter >50mm, rapid dilation (>5mm/year), a family history of aortic dissection at smaller diameters, the presence of aortic regurgitation, or extension of dilation beyond the sinuses of valsalva [46], [47]. The gold standard surgical intervention remains the technique described by Bentall and De Bono in 1968. The aortic root and valve are replaced with a composite Dacron graft and artificial valve. Patients treated with this procedure must take anticoagulants for the remainder of their lives. More recently, two valve-sparing procedures have been practiced: the aortic root remodeling procedure and the aortic valve reimplantation procedure. In the remodeling procedure, a graft is created containing three neosinuses and sutured slightly superior to the native valve. The reimplantation procedure reimplants the native valve into the Dakon graft and is thought to prevent future dilation, but is more technically demanding.


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.[48] 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.[49] 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).[50] 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.[51] 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.[52] 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.[53]

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

References

  1. ↑ Marfan A. Un cas de déformation congénitgale des quatres membres, plus prononcée aux extremités, caractérisée par l'allongement des os avec un certain degré d'amincissiment. . Bulletins et memoires de la Société medicale des hôpitaux de Paris 1896;13:220-8.
  2. ↑ BOYER BE, MARTIN MM (1958). "Marfan's syndrome; report of a case manifesting a giant bone cyst of the mandible and multiple (110) basal cell carcinomata". Plastic and Reconstructive Surgery and the Transplantation Bulletin. 22 (3): 257–63. PMID 13590978. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  3. ↑ Salle V. Grosse der Extremitaten mit einem an Akromegalie erinnernden Symptomenkomplex. J Kinderheilk 1912;75:540.
  4. ↑ BLACK HH, LANDAY LH (1955). "Marfan's syndrome; report on five cases in one family". A.M.A. American Journal of Diseases of Children. 89 (4): 414–20. PMID 14360720. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  5. ↑ Boerger F. Ueber zwei Falle von Arachnodaktylie. Monatsschr Kinderheilk 1914;13:335.
  6. ↑ Weve H. Ueber Arachnodaktylie (Dystrophia mesodermalis congenita, Typus Marfan). Archiv für Augenheilkunde, Wiesbaden 1931;104:1-46.
  7. ↑ Baer RW, Taussig, H. B., Oppenheimer, E. H. Congenital aneurysmal dilatation of the aorta associated with arachnodactyly. Bull Johns Hopkins Hosp 1943.
  8. ↑ Major Lewis E. Etter; L. Pellman Glover MD. ARACHNODACTYLY COMPLICATED BY DISLOCATED LENS AND DEATH FROM RUPTURE OF DISSECTING ANEURYSM OF AORTA. Journal of the American Medical Association 1943;123:88-9.
  9. ↑ Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM (1991). "Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene". Nature. 352 (6333): 337–9. doi:10.1038/352337a0. PMID 1852208. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  10. ↑ McKusick V (1991). "The defect in Marfan syndrome". Nature. 352 (6333): 279–81. PMID 1852198.
  11. ↑ 11.0 11.1 Cotran. Robbins Pathologic Basis of Disease. Philadelphia: W.B Saunders Company. 0-7216-7335-X. Unknown parameter |coauthors= ignored (help)
  12. ↑ 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.
  13. ↑ 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)
  14. ↑ Entrez Gene (2007). "TGFBR2 transforming growth factor, beta receptor II" (Entrez gene entry). NCBI.
  15. ↑ "Related Disorders: Loeys-Dietz". National Marfan Foundation.
  16. ↑ 16.0 16.1 "The role of heredity and family history". National Marfan Foundation. 1999.
  17. ↑ "New, Deadly Relative of Marfan's Syndrome Discovered". MedicineNet.com. 2006.
  18. ↑ 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)
  19. ↑ 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)
  20. ↑ Judge DP, Dietz HC (2005). "Marfan's syndrome". Lancet. 366 (9501): 1965–76. doi:10.1016/S0140-6736(05)67789-6. PMC 1513064. PMID 16325700. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  21. ↑ Kinoshita N, Mimura J, Obayashi C, Katsukawa F, Onishi S, Yamazaki H (2000). "Aortic root dilatation among young competitive athletes: echocardiographic screening of 1929 athletes between 15 and 34 years of age". American Heart Journal. 139 (4): 723–8. PMID 10740158. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  22. ↑ Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA (1972). "Life expectancy and causes of death in the Marfan syndrome". The New England Journal of Medicine. 286 (15): 804–8. doi:10.1056/NEJM197204132861502. PMID 5011789. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  23. ↑ 23.0 23.1 23.2 23.3 23.4 "Marfan Syndrome". Mayo Clinic. Retrieved January 12 2007. Unknown parameter |dateformat= ignored (help); Check date values in: |accessdate= (help)
  24. ↑ 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)
  25. ↑ "Marfan Syndrome, special concerns".
  26. ↑ Beighton P, de Paepe A, Danks D, Finidori G, Gedde-Dahl T, Goodman R, Hall JG, Hollister DW, Horton W, McKusick VA (1988). "International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986". American Journal of Medical Genetics. 29 (3): 581–94. doi:10.1002/ajmg.1320290316. PMID 3287925. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  27. ↑ De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE (1996). "Revised diagnostic criteria for the Marfan syndrome". American Journal of Medical Genetics. 62 (4): 417–26. doi:10.1002/(SICI)1096-8628(19960424)62:4<417::AID-AJMG15>3.0.CO;2-R. PMID 8723076. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  28. ↑ Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM (2010). "The revised Ghent nosology for the Marfan syndrome". Journal of Medical Genetics. 47 (7): 476–85. doi:10.1136/jmg.2009.072785. PMID 20591885. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  29. ↑ . (Accessed November 22, 2010, at http://www.bcm.edu/pediatrics/index.cfm?Realm=99992426&This_Template=FBN1.)
  30. ↑ Cocco G (2001). "Images in cardiology: The "thumb and wrist sign" in Marfan syndrome". Heart (British Cardiac Society). 86 (6): 602. PMC 1730018. PMID 11711445. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  31. ↑ Sakai LY, Keene DR, Engvall E (1986). "Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils". The Journal of Cell Biology. 103 (6 Pt 1): 2499–509. PMC 2114568. PMID 3536967. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  32. ↑ Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L (1990). "Location on chromosome 15 of the gene defect causing Marfan syndrome". The New England Journal of Medicine. 323 (14): 935–9. doi:10.1056/NEJM199010043231402. PMID 2402262. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  33. ↑ Collod-Béroud G, Béroud C, Ades L, Black C, Boxer M, Brock DJ, Holman KJ, de Paepe A, Francke U, Grau U, Hayward C, Klein HG, Liu W, Nuytinck L, Peltonen L, Alvarez Perez AB, Rantamäki T, Junien C, Boileau C (1998). "Marfan Database (third edition): new mutations and new routines for the software". Nucleic Acids Research. 26 (1): 229–3. PMC 147226. PMID 9399842. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  34. ↑ Hilhorst-Hofstee Y, Hamel BC, Verheij JB, Rijlaarsdam ME, Mancini GM, Cobben JM, Giroth C, Ruivenkamp CA, Hansson KB, Timmermans J, Moll HA, Breuning MH, Pals G (2010). "The clinical spectrum of complete FBN1 allele deletions". European Journal of Human Genetics : EJHG. doi:10.1038/ejhg.2010.174. PMID 21063442. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  35. ↑ Dietz HC, McIntosh I, Sakai LY, Corson GM, Chalberg SC, Pyeritz RE, Francomano CA (1993). "Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome". Genomics. 17 (2): 468–75. doi:10.1006/geno.1993.1349. PMID 8406497. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  36. ↑ Michael J Wright HMC. Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders. In: UptoDate; 2010.
  37. ↑ Reinhardt DP, Mechling DE, Boswell BA, Keene DR, Sakai LY, Bächinger HP (1997). "Calcium determines the shape of fibrillin". The Journal of Biological Chemistry. 272 (11): 7368–73. PMID 9054436. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  38. ↑ Reinhardt DP, Ono RN, Sakai LY (1997). "Calcium stabilizes fibrillin-1 against proteolytic degradation". The Journal of Biological Chemistry. 272 (2): 1231–6. PMID 8995426. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  39. ↑ Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL, Sakai LY, Dietz HC (2004). "Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome". The Journal of Clinical Investigation. 114 (2): 172–81. doi:10.1172/JCI20641. PMC 449744. PMID 15254584. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  40. ↑ Pereira L, Andrikopoulos K, Tian J, Lee SY, Keene DR, Ono R, Reinhardt DP, Sakai LY, Biery NJ, Bunton T, Dietz HC, Ramirez F (1997). "Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome". Nature Genetics. 17 (2): 218–22. doi:10.1038/ng1097-218. PMID 9326947. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  41. ↑ Matt P, Schoenhoff F, Habashi J, Holm T, Van Erp C, Loch D, Carlson OD, Griswold BF, Fu Q, De Backer J, Loeys B, Huso DL, McDonnell NB, Van Eyk JE, Dietz HC (2009). "Circulating transforming growth factor-beta in Marfan syndrome". Circulation. 120 (6): 526–32. doi:10.1161/CIRCULATIONAHA.108.841981. PMC 2779568. PMID 19635970. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  42. ↑ Chung AW, Yang HH, Radomski MW, van Breemen C (2008). "Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9". Circulation Research. 102 (8): e73–85. doi:10.1161/CIRCRESAHA.108.174367. PMID 18388324. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  43. ↑ Gambarin FI, Favalli V, Serio A, Regazzi M, Pasotti M, Klersy C, Dore R, Mannarino S, Viganò M, Odero A, Amato S, Tavazzi L, Arbustini E (2009). "Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations". Journal of Cardiovascular Medicine (Hagerstown, Md.). 10 (4): 354–62. doi:10.2459/JCM.0b013e3283232a45. PMID 19430350. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  44. ↑ Lacro RV, Dietz HC, Wruck LM, Bradley TJ, Colan SD, Devereux RB, Klein GL, Li JS, Minich LL, Paridon SM, Pearson GD, Printz BF, Pyeritz RE, Radojewski E, Roman MJ, Saul JP, Stylianou MP, Mahony L (2007). "Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome". American Heart Journal. 154 (4): 624–31. doi:10.1016/j.ahj.2007.06.024. PMID 17892982. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  45. ↑ Michael J Wright HMC. Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders. In: UptoDate; 2010.
  46. ↑ Cañadas V, Vilacosta I, Bruna I, Fuster V (2010). "Marfan syndrome. Part 2: treatment and management of patients". Nature Reviews. Cardiology. 7 (5): 266–76. doi:10.1038/nrcardio.2010.31. PMID 20351702. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  47. ↑ Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE, Eagle KA, Hermann LK, Isselbacher EM, Kazerooni EA, Kouchoukos NT, Lytle BW, Milewicz DM, Reich DL, Sen S, Shinn JA, Svensson LG, Williams DM (2010). "2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine". Circulation. 121 (13): e266–369. doi:10.1161/CIR.0b013e3181d4739e. PMID 20233780. Retrieved 2010-12-22. Unknown parameter |month= ignored (help)
  48. ↑ Freeman, Elaine (2007) "A Silver Bullet for Blake", Johns Hopkins Magazine, Fall, 2007.
  49. ↑ "Heart Surgery for Marfan Syndrome". Mayo Clinic.
  50. ↑ "Overview of the Nuss Procedure for Pectus Excavatum". Children's Hospital of The King's Daughters.
  51. ↑ "Dural Ectasia in the Marfan Spine: Symptoms and Treatment". Scoliosis Research Society.
  52. ↑ 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)
  53. ↑ "Atenolol vs. Losartan in Individuals with Marfan Syndrome Clinial Trial". National Marfan Foundation.

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