Genetics of Marfan Syndrome
- Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD more...
Marfan syndrome (MFS) is an inherited connective tissue disorder, noteworthy for its worldwide distribution, relatively high prevalence, and clinical variability, as well as pleiotropic manifestations involving primarily the ocular, skeletal, and cardiovascular systems, some of which are life threatening. Although Marfan syndrome has historically always been considered as a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1, the study of Marfan mouse models and Marfan-related conditions has shifted our current understanding to a pathogenic model that involves dysregulation of the cytokine-transforming growth factor beta (TGF-β) signaling.[1, 2]
Marfan syndrome results from mutations in the fibrillin-1 (FBN1) gene on chromosome 15, which encodes for the glycoprotein fibrillin. Fibrillin is a major building block of microfibrils, which constitute the structural components of the suspensory ligament of the lens and serve as substrates for elastin in the aorta and other connective tissues. Abnormalities involving microfibrils weaken the aortic wall. Progressive aortic dilatation and eventual aortic dissection occur because of tension caused by left ventricular ejection impulses. Likewise, deficient fibrillin deposition leads to reduced structural integrity of the lens zonules, ligaments, lung airways, and spinal dura.
Production of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation. This pathogenetic mechanism has been termed dominant-negative because the mutant fibrillin-1 disrupts microfibril formation though the other fibrillin gene encodes normal fibrillin. This proposed mechanism is evinced by the fact that cultured skin fibroblasts from patients with Marfan syndrome produce greatly diminished and abnormal microfibrils.
FBN1 mutation causes several Marfanlike disorders, such as the mitral valve prolapse, aortic dilation, skin, and skeletal (MASS) phenotype or isolated ectopia lentis.
Recent studies have suggested that abnormalities in the transforming growth factor-beta ( TGFβ)-signaling pathway may represent a final common pathway for the development of the Marfan phenotype.  The gene defect ultimately leads to decreased and disordered incorporation of fibrillin into the connective tissue matrix.
The identification of mutations in transforming growth factor-beta receptor 2 ( TGF β R2) in patients with Marfan syndrome type II ( MFS2 mapped at 3p24.2-p25) provided direct evidence of abnormal TGFβ signaling in the pathogenesis of Marfan syndrome.
Abnormalities in TGF β R 2 and TGF β R1 were also reported to cause a new dominant syndrome similar to Marfan syndrome; it was associated with aortic aneurysm and congenital anomalies, including Loeys-Dietz aortic aneurysm syndrome (LDS) (Online Mendelian Inheritance in Man [OMIM] 609192).  These results define a new group of Marfan syndrome–related connective-tissue disorders, namely, TGFβ signalopathies, and include LDS I and LDS II ( TGFβR1 and TGFβR2) and the recently described SMAD3 and TGFβ2 disorders, which are being classified as Loeys-Dietz-like (or even types III and IV).
Shprintzen Goldberg syndrome (SGS) has also been found to be caused by pathogenic mutations in the SKI gene. There is quite a bit of overlap with Marfan syndrome and LDS, and it is also involved in the TGF pathway.
A second fibrillin gene, the FBN2 gene, is responsible for the congenital contractural arachnodactyly, known as Beals syndrome. 
Marfan syndrome affects about 1 in 10,000 individuals and perhaps as many as 1 in 3000-5000.
Estimates suggest that at least 200,000 people in the United States have Marfan syndrome or a related connective-tissue disorder.
This makes Marfan syndrome one of the most common single-gene malformation syndromes.
No geographic predilection is known.
Cardiovascular disease (aortic dilatation and dissection) is the major cause of morbidity and mortality.
Progression from mitral valve prolapse to mitral regurgitation, often in conjunction with tricuspid prolapse and regurgitation, is the most common cause of infant morbidity. If untreated, Marfan syndrome is highly lethal; the average age at death is 30-40 years.
Death after infancy usually involves ascending aortic dissection and chronic aortic regurgitation. Dissection generally occurs at the aortic root and is uncommon in childhood and adolescence.
Marfan syndrome is panethnic.
No sex predilection is known.
Marfan syndrome may be diagnosed prenatally, at birth, or well into adulthood. Neonatal presentation is associated with a more severe course than that associated with other presentations.
Most clinical features are specific to age, and some features may not manifest until relatively late in life. This feature may make diagnosis in a child difficult.
Bolar N, Van Laer L, Loeys BL. Marfan syndrome: from gene to therapy. Curr Opin Pediatr. 2012 Aug. 24(4):498-504. [Medline].
Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005 Mar. 37(3):275-81. [Medline].
Lee B, Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature. 1991. 352:337-339.
Pyeritz RE. The Marfan syndrome. Annu Rev Med. 2000. 51:481-510. [Medline].
Rose PS, Levy HP, Ahn NU, et al. A comparison of the Berlin and Ghent nosologies and the influence of dural ectasia in the diagnosis of Marfan syndrome. Genet Med. 2000 Oct. 2(5):278-82. [Medline].
Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul. 47(7):476-85. [Medline].
Faivre L, Collod-Beroud G, Ades L, et al. The new Ghent criteria for Marfan syndrome: what do they change?. Clin Genet. 2012 May. 81(5):433-42. [Medline].
Van de Velde S, Fillman R, Yandow S. Protrusio acetabuli in Marfan syndrome. History, diagnosis, and treatment. J Bone Joint Surg Am. 2006 Mar. 88(3):639-46. [Medline].
Jones KB, Sponseller PD, Erkula G, et al. Symposium on the musculoskeletal aspects of Marfan syndrome: meeting report and state of the science. J Orthop Res. 2007 Mar. 25(3):413-22. [Medline].
Lacassie HJ, Millar S, Leithe LG, et al. Dural ectasia: a likely cause of inadequate spinal anaesthesia in two parturients with Marfan's syndrome. Br J Anaesth. 2005 Apr. 94(4):500-4. [Medline].
Dean JC. Marfan syndrome: clinical diagnosis and management. Eur J Hum Genet. 2007 May 9. [Medline].
Tiecke F, Katzke S, Booms P, et al. Classic, atypically severe andneonatal Marfan syndrome: twelve mutations and genotype-phenotypecorrelations in FBN1 exons 24-40. Eur J Hum Genet. 2001. 9:13-21. [Medline]. [Full Text].
de Vries BB, Pals G, Odink R, Hamel BC. Homozygosity for a FBN1 missense mutation: clinical and molecular evidence for recessive Marfan syndrome. Eur J Hum Genet. 2007 Sep. 15(9):930-5. [Medline].
Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. 2012 Jan. 14(1):171-7. [Medline].
Gupta PA, Wallis DD, Chin TO, et al. FBN2 mutation associated with manifestations of Marfan syndrome and congenital contractural arachnodactyly. J Med Genet. 2004 May. 41(5):e56. [Medline].
Putnam EA, Zhang H, Ramirez F, Milewicz DM. Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet. 1995 Dec. 11(4):456-8. [Medline].
Callewaert B, Malfait F, Loeys B, De Paepe A. Ehlers-Danlos syndromes and Marfan syndrome. Best Pract Res Clin Rheumatol. 2008 Mar. 22(1):165-89. [Medline].
Zhu L, Vranckx R, Khau Van Kien P, et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006 Mar. 38(3):343-9. [Medline].
Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-betareceptor. New Engl J Med. 2006. 355:788-798.
Glesby MJ, Pyeritz RE. Association of mitral valve prolapse and systemic abnormalities of connective tissue. A phenotypic continuum. JAMA. 1989 Jul 28. 262(4):523-8. [Medline].
Montgomery RA, Geraghty MT, Bull E, Gelb BD, Johnson M, McIntosh I, et al. Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. Am J Hum Genet. 1998 Dec. 63(6):1703-11. [Medline].
Lieberman ER, Gomperts ED, Shaw KN, Landing BH, Donnell GN. Homocystinuria: clinical and pathologic review, with emphasis on thrombotic features, including pulmonary artery thrombosis. Perspect Pediatr Pathol. 1993. 17:125-47. [Medline].
Sood S, Eldadah ZA, Krause WL, McIntosh I, Dietz HC. Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome. Nat Genet. 1996 Feb. 12(2):209-11. [Medline].
Raymond FL, Tarpey PS, Edkins S, et al. Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus. Am J Hum Genet. 2007 May. 80(5):982-7. [Medline].
Schwartz CE, Tarpey PS, Lubs HA, et al. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet. 2007 Jul. 44(7):472-7. [Medline].
Faivre L, Masurel-Paulet A, Collod-Béroud G, Callewaert BL, Child AH, Stheneur C, et al. Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations. Pediatrics. 2009 Jan. 123(1):391-8. [Medline].
von Kodolitsch Y, Robinson PN. Marfan syndrome: an update of genetics, medical and surgical management. Heart. 2007 Jun. 93(6):755-60. [Medline].
Frobel AK, Hulpke-Wette M, Schmidt KG, Laer S. Beta-blockers for congestive heart failure in children. Cochrane Database Syst Rev. 2009 Jan 21. CD007037. [Medline].
Williams A, Davies S, Stuart AG, Wilson DG, Fraser AG. Medical treatment of Marfan syndrome: a time for change. Heart. 2008 Apr. 94(4):414-21. [Medline].
Pyeritz RE. Marfan syndrome: 30 years of research equals 30 years of additional life expectancy. Heart. 2009 Mar. 95(3):173-5. [Medline].
Yetman AT, Bornemeier RA, McCrindle BW. Usefulness of enalapril versus propranolol or atenolol for prevention of aortic dilation in patients with the Marfan syndrome. Am J Cardiol. 2005 May 1. 95(9):1125-7. [Medline].
Ahimastos AA, Aggarwal A, D'Orsa KM, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA. 2007 Oct 3. 298(13):1539-47. [Medline].
Chung AW, Yang HH, Radomski MW, van Breemen C. 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. Circ Res. 2008 Apr 25. 102(8):e73-85. [Medline].
Chung AW, Au Yeung K, Sandor GG, Judge DP, Dietz HC, van Breemen C. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in the thoracic aortic aneurysm in Marfan syndrome. Circ Res. 2007 Aug 31. 101(5):512-22. [Medline].
Kharrazi FD, Rodgers WB, Coran DL, Kasser JR, Hall JE. Protrusio acetabuli and bilateral basicervical femoral neck fractures in a patient with Marfan syndrome. Am J Orthop. 1997 Oct. 26(10):689-91. [Medline].
[Guideline] Harris EJ, Vanore JV, Thomas JL, et al. Diagnosis and treatment of pediatric flatfoot. J Foot Ankle Surg. 2004 Nov-Dec. 43(6):341-73. [Medline].
Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008 Jun 26. 358(26):2787-95. [Medline]. [Full Text].
Pees C, Laccone F, Hagl M, Debrauwer V, Moser E, Michel-Behnke I. Usefulness of losartan on the size of the ascending aorta in an unselected cohort of children, adolescents, and young adults with Marfan syndrome. Am J Cardiol. 2013 Nov 1. 112 (9):1477-83. [Medline].
Chen H. Genetic Diagnosis and Counseling. 2nd ed. New York, NY: Springer; 2012. Vol 2: 1309-26.
Stout M. The Marfan syndrome: implications for athletes and their echocardiographic assessment. Echocardiography. 2009 Oct. 26(9):1075-81. [Medline].
Ageno W, Crotti S, Turpie AG. The safety of antithrombotic therapy during pregnancy. Expert Opin Drug Saf. 2004 Mar. 3(2):113-8. [Medline].
Meijboom LJ, Vos FE, Timmermans J, Boers GH, Zwinderman AH, Mulder BJ. Pregnancy and aortic root growth in the Marfan syndrome: a prospective study. Eur Heart J. 2005 May. 26(9):914-20. [Medline].
Goland S, Elkayam U. Cardiovascular problems in pregnant women with marfan syndrome. Circulation. 2009 Feb 3. 119(4):619-23. [Medline].
Goland S, Barakat M, Khatri N, Elkayam U. Pregnancy in Marfan syndrome: maternal and fetal risk and recommendations for patient assessment and management. Cardiol Rev. 2009 Nov-Dec. 17(6):253-62. [Medline].
Boileau C, Jondeau G, Mizuguchi T, Matsumoto N. Molecular genetics of Marfan syndrome. Curr Opin Cardiol. 2005 May. 20(3):194-200. [Medline].
Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008 Jun 26. 358(26):2787-95. [Medline].
Chen H. Marfan syndrome. Atlas of Genetic Diagnosis and Counseling. Totowa, New Jersey: Humana Press; 2006. 619-629.
Dagoneau N, Benoist-Lasselin C, Huber C, et al. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet. 2004 Nov. 75(5):801-6. [Medline].
Demetracopoulos CA, Sponseller PD. Spinal deformities in Marfan syndrome. Orthop Clin North Am. 2007 Oct. 38(4):563-72, vii. [Medline].
Gelb BD. Marfan's syndrome and related disorders--more tightly connected than we thought. N Engl J Med. 2006 Aug 24. 355(8):841-4. [Medline].
Ha HI, Seo JB, Lee SH, Kang JW, Goo HW, Lim TH, et al. Imaging of Marfan syndrome: multisystemic manifestations. Radiographics. 2007 Jul-Aug. 27(4):989-1004. [Medline].
Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006 Apr 7. 312(5770):117-21. [Medline].
Habermann CR, Weiss F, Schoder V, et al. MR evaluation of dural ectasia in Marfan syndrome: reassessment of the established criteria in children, adolescents, and young adults. Radiology. 2005 Feb. 234(2):535-41. [Medline].
Lacro RV, Dietz HC, Wruck LM, et al. 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. Am Heart J. 2007 Oct. 154(4):624-31. [Medline].
Ladouceur M, Fermanian C, Lupoglazoff JM, et al. Effect of beta-blockade on ascending aortic dilatation in children with the Marfan syndrome. Am J Cardiol. 2007 Feb 1. 99(3):406-9. [Medline].
Marfan AB. Un cas de deformation congenitale des quatre membres plus prononcee aux extremites caracterisee par l'allongement des os avec un certain degre d'amincissement. Bull Mem Soc Med Hop Paris (ser 3). 1896. 13:220-6.
Mizuguchi T, Collod-Beroud G, Akiyama T, et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet. 2004 Aug. 36(8):855-60. [Medline].
Mohamed SA, Aherrahrou Z, Liptau H, et al. Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve. Biochem Biophys Res Commun. 2006 Jul 14. 345(4):1460-5. [Medline].
Nemet AY, Assia EI, Apple DJ, Barequet IS. Current concepts of ocular manifestations in Marfan syndrome. Surv Ophthalmol. 2006 Nov-Dec. 51(6):561-75. [Medline].
Nollen GJ, Mulder BJ. What is new in the Marfan syndrome?. Int J Cardiol. 2004 Dec. 97 Suppl 1:103-8. [Medline].
Pearson GD, Devereux R, Loeys B, et al. Report of the National Heart, Lung, and Blood Institute and National Marfan Foundation Working Group on research in Marfan syndrome and related disorders. Circulation. 2008 Aug 12. 118(7):785-91. [Medline].
Ramirez F, Dietz HC. Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr Opin Genet Dev. 2007 Apr 26. [Medline].
Robinson PN, Arteaga-Solis E, Baldock C, et al. The molecular genetics of Marfan syndrome and related disorders. J Med Genet. 2006 Oct. 43(10):769-87. [Medline].
Spits C, De Rycke M, Van Ranst N, et al. Preimplantation genetic diagnosis for cancer predisposition syndromes. Prenat Diagn. 2007 May. 27(5):447-56. [Medline].
Stuart AG, Williams A. Marfan's syndrome and the heart. Arch Dis Child. 2007 Apr. 92(4):351-6. [Medline].
Summers KM, West JA, Peterson MM, et al. Challenges in the diagnosis of Marfan syndrome. Med J Aust. 2006 Jun 19. 184(12):627-31. [Medline].
Weigang E, Ghanem N, Chang XC, et al. Evaluation of three different measurement methods for dural ectasia in Marfan syndrome. Clin Radiol. 2006 Nov. 61(11):971-8. [Medline].