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

• 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

• 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%)

 mitral floppy valve
 valvular lesions

• lengthening of the chordae tendineae
• mitral regurgitation
• tricuspid
• aortic valve

 cardiac failure

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.

Reference

 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#