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Marfan disease

Monday 17 November 2003

The Marfan syndrome is an autosomal dominant connective tissue disorder with a prevalence of 2-3 per 10,000 individuals and symptoms ranging from skeletal overgrowth, cutaneous striae to ectopia lentis and aortic dilatation leading to dissection.

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.




- 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.


- skeletal anomalies

  • tall
  • long extremities
  • long, tapering fingers and toes

- hyperlaxity
- dolichocephaly (long-headed)
- frontal bossing
- prominent supraorbital ridges
- kyphosis
- scoliosis
- rotation or slipping of the dorsal or lumbar vertebrae
- chest deformeions

- ocular anomalies

  • bilateral lens subluxation
  • ectopia lentis (bilateral lens dislocation, usually outward and upward)

- cardiovascular anomalies

  • mitral valve prolapse
  • cystic medial degeneration of the aorta
  • 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

- cardiac failure

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.


- 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.


- 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


- 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

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