- Author: Prashanth Inna, MBBS, MS, DNB; Chief Editor: Jeffrey D Thomson, MD more...
Marfan syndrome (MFS) is a spectrum of disorders caused by a heritable genetic defect of connective tissue that has an autosomal dominant mode of transmission.[1, 2, 3, 4] The defect itself has been isolated to the FBN1 gene on chromosome 15, which codes for the connective tissue protein fibrillin.[1, 5, 6] Abnormalities in this protein cause a myriad of distinct clinical problems, of which the musculoskeletal, cardiac, and ocular system problems predominate.[2, 7, 8]
The most severe of these clinical problems include aortic root dilatation and dissection, which have historically been the causative factors in early patient demise. Skeletal deformities such as thoracolumbar scoliosis, thoracic lordosis, and pectus excavatum, may lead to pulmonary difficulties that include restrictive airway disease and cor pulmonale if the deformities are progressive and untreated. Finally, blindness may result from unrecognized and untreated glaucoma, retinal detachment, and cataracts.
The skeleton of patients with MFS typically displays multiple deformities including arachnodactyly (ie, abnormally long and thin digits), dolichostenomelia (ie, long limbs relative to trunk length), pectus deformities (ie, pectus excavatum and pectus carinatum), and thoracolumbar scoliosis.[10, 11]
In the cardiovascular system, aortic dilatation, aortic regurgitation, and aneurysms are the most worrisome clinical findings.[1, 3, 4] Mitral valve prolapse that requires valve replacement can occur as well. Ocular findings include myopia, cataracts, retinal detachment, and superior dislocation of the lens.
Antonin Bernard Jean Marfan, whose name this syndrome bears, was born in Castelnaudary, Aude, France on June 23, 1858. In 1892, he was appointed assistant professor of pediatrics in the Paris faculty. Marfan described the disease that still bears his name at a meeting of the Medical Society of Paris in 1896. He presented the case of a 5-year-old girl named Gabrielle, who had disproportionately long limbs.
In later studies, further anomalies were documented, including arachnodactyly (long digits), cardiovascular abnormalities, and dislocation of the ocular lens. A common and often lethal complication of MFS is dissection of the aorta, and the genetic inheritance is now known to be autosomal. Marfan gained an international reputation and was widely recognized as a pioneer of pediatric medicine in France. This was very much the case in Britain, too, where he received an honorary fellowship of the Royal Society of Medicine in 1934.
Pathophysiology and Etiology
Over many years, several investigators have studied various molecules found in the extracellular matrix in attempts to elucidate the cause of MFS.[14, 15] These molecules have included collagen, elastin, hyaluronic acid, and, more recently, fibrillin. Sakai et al identified fibrillin, a 350-kd protein, by using monoclonal antibodies raised against myofibrils. Immunofluorescence studies were then used to compare the reactivity in both healthy subjects and those with MFS. During this period, similar technology was used to construct a genetic exclusion map that led to the localization of the defect to chromosome 15 (bands q15-q23).
Several point mutations have now been identified in the fibrillin gene, most of which affect cysteine residues within the microfibril. Thus, these mutations are thought to cause defective fibrillin to be produced. Fibrillin's structure and function are altered by abnormal protein folding due to the alteration of bonding between cysteine residues, which in turn causes defective microfibril production.
Mutations in the FBN1 locus of the fibrillin gene on chromosome 15 have been linked to MFS and other distinct clinical entities with similar findings.
The estimated incidence of MFS ranges from 1 in 5000 to 2-3 in 10,000 persons. The mutation in the fibrillin gene causes pleiotropic effects; thus, a wide range of phenotypic features is derived from a single gene mutation. Several other diseases have presentations similar to MFS, making it exceedingly difficult to determine the exact incidence.
Advances in the management of the cardiovascular manifestations of MFS have led to a significant decrease in the morbidity and mortality that are associated with this condition. Before the advent of pharmacologic and surgical therapy for aortic root and valvular disease, the life expectancy for patients with MFS was about two thirds that of the healthy population. Aortic dissection and congestive heart failure due to aortic and mitral valvular anomalies accounted for over 90% of the known causes of death.
Patient longevity now approaches that of persons without MFS, although cardiovascular compromise is still the most common cause of patient death, likely due to sudden death in the previously undiagnosed patient and a new diagnosis in those whose disease process has progressed beyond the scope of medical or surgical cure.
Ammash NM, Sundt TM, Connolly HM. Marfan syndrome-diagnosis and management. Curr Probl Cardiol. 2008 Jan. 33(1):7-39. [Medline].
Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991 Jul 25. 352(6333):337-9. [Medline].
Tachdjian MO. Marfan's syndrome. Herring JA, ed. Tachdjian's Pediatric Orthopaedics. 3rd ed. Philadelphia, Pa: WB Saunders; 1990. 829-37.
Judge DP, Dietz HC. Therapy of Marfan syndrome. Annu Rev Med. 2008 Feb 18. 59:43-59. [Medline].
Gould RA, Sinha R, Aziz H, Rouf R, Dietz HC 3rd, Judge DP, et al. Multi-scale biomechanical remodeling in aging and genetic mutant murine mitral valve leaflets: insights into marfan syndrome. PLoS One. 2012. 7(9):e44639. [Medline]. [Full Text].
Matt P, Habashi J, Carrel T, et al. Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan?. J Thorac Cardiovasc Surg. 2008 Feb. 135(2):389-94. [Medline].
Demetracopoulos CA, Sponseller PD. Spinal deformities in Marfan syndrome. Orthop Clin North Am. 2007 Oct. 38(4):563-72, vii. [Medline].
Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med. 1972 Apr 13. 286(15):804-8. [Medline].
Robins PR, Moe JH, Winter RB. Scoliosis in Marfan's syndrome. Its characteristics and results of treatment in thirty-five patients. J Bone Joint Surg Am. 1975 Apr. 57(3):358-68. [Medline]. [Full Text].
Mommertz G, Sigala F, Langer S, et al. Thoracoabdominal aortic aneurysm repair in patients with Marfan syndrome. Eur J Vasc Endovasc Surg. 2008 Feb. 35(2):181-6. [Medline].
Cañadas V, Vilacosta I, Bruna I, Fuster V. Marfan syndrome. Part 1: pathophysiology and diagnosis. Nat Rev Cardiol. 2010 Mar 30. [Medline].
Iams HD. Diagnosis and management of Marfan syndrome. Curr Sports Med Rep. 2010 Mar-Apr. 9(2):93-8. [Medline].
Sponseller PD, Erkula G, Skolasky RL, Venuti KD, Dietz HC 3rd. Improving clinical recognition of Marfan syndrome. J Bone Joint Surg Am. 2010 Aug 4. 92 (9):1868-75. [Medline].
National Heart, Lung and Blood Institute. Marfan syndrome. Available at http://www.nhlbi.nih.gov/health/dci/Diseases/mar/mar_diagnosis.html. Accessed: February 15, 2008.
Porter RS, Kaplan JL, Homeier BP, Beers MH, eds. Diagnostic criteria for Marfan syndrome (Ghent nosology) [table]. The Merck Manuals Online Medical Library. Available at http://www.merck.com/media/mmpe/pdf/Table_284-1.pdf. Accessed: February 15, 2008.
Faivre L, Collod-Beroud G, Adès L, et al. The new Ghent criteria for Marfan syndrome: what do they change?. Clin Genet. 2012 May. 81 (5):433-42. [Medline].
Pepe G, Lapini I, Evangelisti L, et al. Is ectopia lentis in some cases a mild phenotypic expression of Marfan syndrome? Need for a long-term follow-up. Mol Vis. 2007. 13:2242-7. [Medline]. [Full Text].
Cipriano GF, Peres PA, Cipriano G Jr, Arena R, Carvalho AC. Safety and cardiovascular behavior during pulmonary function in patients with Marfan syndrome. Clin Genet. 2010 Mar 29. [Medline].
Wang R, Ma WG, Tian LX, Sun LZ, Chang Q. Valve-sparing operation for aortic root aneurysm in patients with marfan syndrome. Thorac Cardiovasc Surg. 2010 Mar. 58(2):76-80. [Medline].
Giacheti CM, Zanchetta S, Maranhe E, et al. A newly recognized syndrome of Marfanoid habitus; long face; hypotelorism; long, thin nose; long, thin hands and feet; and a specific pattern of language and learning disabilities. Am J Med Genet A. 2007 Dec 15. 143(24):3137-9. [Medline].
Mariucci EM, Lovato L, Rosati M, Palena LM, Bonvicini M, Fattori R. Dilation of peripheral vessels in Marfan syndrome: Importance of thoracoabdominal MR angiography. Int J Cardiol. 2012 Sep 3. [Medline].
Cañadas V, Vilacosta I, Bruna I, Fuster V. Marfan syndrome. Part 2: treatment and management of patients. Nat Rev Cardiol. 2010 Mar 30. [Medline].
Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan's syndrome. N Engl J Med. 1994 May 12. 330(19):1335-41. [Medline]. [Full Text].
Gjolaj JP, Sponseller PD, Shah SA, Newton PO, Flynn JM, Neubauer PR, et al. Spinal deformity correction in Marfan syndrome versus adolescent idiopathic scoliosis: learning from the differences. Spine (Phila Pa 1976). 2012 Aug 15. 37 (18):1558-65. [Medline].
Gott VL, Cameron DE, Pyeritz RE, et al. Composite graft repair of Marfan aneurysm of the ascending aorta: results in 150 patients. J Card Surg. 1994 Sep. 9(5):482-9. [Medline].
Levy BJ, Schulz JF, Fornari ED, Wollowick AL. Complications associated with surgical repair of syndromic scoliosis. Scoliosis. 2015. 10:14. [Medline].
Dietz HC, Loeys B, Carta L, Ramirez F. Recent progress towards a molecular understanding of Marfan syndrome. Am J Med Genet C Semin Med Genet. 2005 Nov 15. 139C(1):4-9. [Full Text].