Definition: Marfan syndrome is a disorder of the connective tissues of the body, manifested principally by changes in the skeleton, eyes, and cardiovascular system. Its prevalence is estimated to be 1 in 5000. Approximately 70% to 85% of cases are familial and transmitted by autosomal dominant inheritance. The remainder are sporadic and arise from new mutations.
Pathogenesis
Marfan syndrome results from an inherited defect in an extracellular glycoprotein called fibrillin-1.
Fibrillin is the major component of microfibrils found in the extracellular matrix. These fibrils form a scaffolding on which tropoelastin is deposited to form elastic fibers. Although microfibrils are widely distributed in the body, they are particularly abundant in the aorta, ligaments, and ciliary zonules of the lens, where they support the lens; these tissues are prominently affected in Marfan syndrome.
Fibrillin occurs in two homologous forms, fibrillin-1 and fibrillin-2, encoded by two separate genes, FBN1 and FBN2, mapped to chromosomes 15q21 and 5q3, respectively.
Synopsis
skeletal anomalies
hyperlaxity
dolichocephaly (long-headed)
frontal bossing
prominent supraorbital ridges
kyphosis
scoliosis
rotation or slipping of the dorsal or lumbar vertebrae
chest deformeions
- pectus excavatum (deeply depressed sternum)
- pigeon-breast deformity
ocular anomalies
- bilateral lens subluxation
- ectopia lentis (bilateral lens dislocation, usually outward and upward)
cardiovascular anomalies
- mitral valve prolapse
- dilation of the ascending aorta
- cystic medionecrosis
- progressive dilation of the aortic valve ring and the root of the aorta
- aortic incompetence
- aortic dilation
- intramural hematoma
- aortic dissection (30%-45%)
- aortic aneurysm
- fragmentation of elastic fibers
- cystic medial change
- medial fibrosis
- medial necrosis
- atherosclerosis
- periaortic fibrosis
- thickening of the vasa vasorum
- elastic fragmentation
mitral floppy valve
valvular lesions
- lengthening of the chordae tendineae
- mitral regurgitation
- tricuspid
- aortic valve
Nota bene: Cystic medial change is inversely correlated with increasing age of patients, especially in the group of patients without clinical evidence of Marfan’s syndrome.
Marked changes of these types in many younger patients without Marfan’s syndrome could reflect a "tissue insufficiency" in early life that causes the aortic wall to weaken and dilate.
Medial necrosis, fibrosis, and atherosclerosis were directly correlated with age.
Hemodynamic events are considered to initiate injury and repair within the aortic wall. Dissection was more frequently seen with medial abnormalities than with atherosclerosis.
Etiology
mutations in the fibrillin-1 gene
- A significant group of disease-causing FBN1 mutations are cysteine substitutions within EGF domains that are predicted to cause misfolding by removal of disulphide bonds that stabilize the native domain fold.
Reviews
Robinson PN, Booms P. The molecular pathogenesis of the Marfan syndrome. Cell Mol Life Sci. 2001 Oct;58(11):1698-707. PMID: 11706995
Dietz HC, Pyeritz RE. Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet. 1995 ;4 Spec No:1799-809. PMID : 8541880
References
Faivre L, Collod-Beroud G, Loeys BL, Child A, Binquet C, Gautier E, Callewaert B, Arbustini E, Mayer K, Arslan-Kirchner M, Kiotsekoglou A, Comeglio P, Marziliano N, Dietz HC, Halliday D, Beroud C, Bonithon-Kopp C, Claustres M, Muti C, Plauchu H, Robinson PN, Ades LC, Biggin A, Benetts B, Brett M, Holman KJ, De Backer J, Coucke P, Francke U, De Paepe A, Jondeau G, Boileau C. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet. 2007 Sep;81(3):454-66. PMID: 17701892
The morphology of ascending aortic aneurysms. Klima T, Spjut HJ, Coelho A, Gray AG, Wukasch DC, Reul GJ Jr, Cooley DA. Hum Pathol. 1983 Sep;14(9):810-7. PMID: 6885038
Molecular pathology in inherited disorders of collagen metabolism. Byers PH, Barsh GS, Holbrook KA. Hum Pathol. 1982 Feb;13(2):89-95. PMID: 7042525