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Internal Medicine

Marfan syndrome (MFS)

Marfan syndrome is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, due to mutations in the FBN1 gene encoding fibrillin 1.

Marfan syndrome is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, due to mutations in the FBN1 gene encoding fibrillin 1.

History

Marfan syndrome is named after Antoine Marfan, the French paediatrician who first described the condition in 1896 after noticing striking features in a five-year-old girl. The term ‘Marfan’s syndrome’ was first being used by Henricus Jacobus Marie Weve (1888–1962) of Utrecht in 1931. Today, it is thought that the patient was affected by congenital contractural arachnodactyly, and not Marfan’s syndrome.

The gene linked to the disease was first identified by Francesco Ramirez at the Mount Sinai Medical Center in New York City in 1991.

Antoine Marfan (1858-1942) was a French pediatrician | Portrait by Henry Bataille (1872-1922)

Pathophysiology

Fibrillin 1 (28-66% cases have fibrillin 1 mutation):

Extracellular matrix protein that forms major component of microfibrils of extracellular matrix of both elastic and non-elastic connective tissues, essential for normal elastic fibrillogenesis

Histopathology:

  • Widespread fragmentation of the elastin component
  • Thin elastin fibres
  • Mitral valve findings:
    • Annular dilation
      Fibromyxomatous changes to the leaflets and chordae
    • Elongation and rupture of chordae and deposition of calcium
Micrograph of myxomatous degeneration of the aortic valve. Surgical specimen. Movat’s stain (Black = nuclei, elastic fibres. Yellow = collagen, reticular fibers. Blue = ground substance, mucin. Bright red = Fibrin. Red = muscle.) In myxomatous degeneration, the ventricularis layer (composed primarily of elastic tissue) is thinned and the spongiosa layer (composed of loose connective tissue) is thickened. On the image, the fibrosa layer (composed of collagen) is on the top, the thickened spongiosa layer below it and the ventricularis layer (made of elastic tissue) at the bottom. The ventricularis layer, as the name may suggest, is closest to the (left) ventricle. The fibrosa layer is closest to the sinus of valsalva. Marfan’s syndrome is a condition, due to a defect in fibrillin (an essential component of elastic fibers), in which myxomatous degeneration is common. | Nephron – CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5938626

Presentation

Ocular manifestations:

  • Axial myopia (M/C symptom)
  • Ectopia lentis (60% cases): Supratemporal dislocation of lens
  • Megalocornea
  • Cornea plana
  • Hypoplasia of dilator pupillae muscle
  • Lattice degeneration of retina
  • Increased risk for: Retinal detachment, glaucoma, and early cataracts

Skeletal system manifestations:

  • Bone overgrowth and joint laxity
    • Arachnodactyly (abnormally long, slender or spidery fingers and toes)
    • Tall stature
    • Dolichostenomelia (disproportionately long extremities for the size of the trunk)
  • Overgrowth of ribs that push the sternum in (pectus excavatum) or out (pectus carinatum)
  • Scoliosis (mild to severe and progressive)

Cardiovascular system manifestations:

Major cause of morbidity and early mortality
  • Primary CVS lesions:
    • Aortic root dilatation (at the level of the sinuses of Valsalva) (60% cases)
      • Predisposing toAortic dilation, aneurysm and dissection
    • Mitral valve prolapse with/without regurgitation (91% cases)
      • Aortic regurgitation (23% cases)
    • Severe and prolonged regurgitation of the mitral and/or aortic valve:
      • Left ventricular dysfunction and occasionally heart failure
  • Other CVS lesions:
    • Coarctation of aorta (CoA), atrial septal defect (ASD), patent ductus arteriosus (PDA), pulmonary artery stenosis, persistent left superior vena cava, etc
  • Tricuspid valve prolapse
  • Proximal pulmonary artery enlargement

Pregnant cases:

  • Acute aortic dissection (esp. under conditions of aortic root dilation and fetal death)
    • Cesarean section is preferred in women with aortic dilation

Diagnosis

Diagnostic criteria:

2010 Revised Ghent Nosology for Marfan syndrome
Ghent nosology (revised diagnostic criteria): Major and minor diagnostic findings | Yuan, S.-M., & Jing, H. (2010). Marfan’s syndrome: an overview . Sao Paulo Medical Journal . scielo .

Imaging:

Main diagnostic work-up for Marfan’s syndrome
Main diagnostic work-up for Marfan’s syndrome | Yuan, S.-M., & Jing, H. (2010). Marfan’s syndrome: an overview . Sao Paulo Medical Journal . scielo .

Aortogram:

Echocardiography showing aortic root dilation to 67 mm in diameter on a long-axis view, in a 34-year-old male patient with Marfan’s syndrome. | Yuan, S.-M., & Jing, H. (2010). Marfan’s syndrome: an overview . Sao Paulo Medical Journal . scielo .

Echocardiography:

Differential diagnosis:

  • Homocystinuria
  • Familial mitral valve prolapse syndrome
  • Familial annuloaortic ectasia
  • Isolated ectopia lentis
  • Ehlers-Danlos syndrome (types II and III)
  • Stickler syndrome (hereditary arthro-ophthalmopathy)
  • Klinefelter syndrome
Differential diagnoses for Marfan’s syndrome | Yuan, S.-M., & Jing, H. (2010). Marfan’s syndrome: an overview . Sao Paulo Medical Journal . scielo .

Management

There is no known cure.

Supportive management:

  • Blood pressure control
  • Restrictions on physical activities
  • Regular surveillance:
    • Cardiovascular (echocardiography)
    • Ocular (slit-lamp examination)
    • Skeletal surveillance (MRI

Medical management:

  • Prophylactic β-blockers (prevent progressive dilation of the aorta)

Surgical management:

  • Prophylactic aortic surgery (when dilated aortic root has a tendency to rupture)
    • Prophylactic aortic root replacement with composite graft

Summary

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