What is Marfan syndrome?

What is Marfan Syndrome

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene that primarily threatens life through progressive aortic root dilatation leading to dissection or rupture, with additional manifestations in the skeletal and ocular systems. 1

Genetic Basis and Inheritance

• Marfan syndrome results from mutations in the FBN1 gene on chromosome 15q21, which encodes fibrillin-1, a glycoprotein essential for extracellular matrix integrity. 1
• Over 1000 unique mutations have been identified, with most being family-specific, and only 12% occurring in multiple unrelated individuals. 1
• Approximately 25-30% of cases represent new spontaneous mutations without family history, making family history absence insufficient to exclude the diagnosis. 1, 2
• The disorder follows autosomal dominant inheritance with high penetrance but highly variable expression, meaning affected individuals have a 50% chance of passing the mutation to offspring, but severity varies dramatically even within families. 1, 2
• Genetic testing detects FBN1 mutations in only 90-95% of clinically definite cases, so molecular testing cannot replace clinical diagnosis. 3

Prevalence and Demographics

• The prevalence is 2-3 per 10,000 individuals in the general population. 1

Cardinal Clinical Features

The diagnosis prioritizes two cardinal features: aortic root aneurysm/dissection and ectopia lentis (lens dislocation). 1, 3

Cardiovascular Manifestations (Life-Threatening)

• Aortic root dilatation occurs in 60-80% of patients and represents the primary determinant of survival. 1
• Progressive aortic dilatation leads to dissection or rupture, which are the major causes of death, with mean survival of only 40 years in untreated patients. 1
• Virtually every patient develops aortic disease at some point during their lifetime. 1
• Mitral valve prolapse and regurgitation are common additional cardiovascular manifestations. 1
• Aortic regurgitation can result from distortion of valve cusps by the enlarged aortic root. 1
• Type A dissection risk increases with aortic diameter, but dissection can occur even with mild dilatation in 15% of cases at sizes less than 5.0 cm. 1

Ocular Manifestations

• Ectopia lentis (lens dislocation) is both sensitive and fairly specific for Marfan syndrome and serves as a major diagnostic criterion. 1, 3
• When ectopia lentis combines with aortic root dilatation, the diagnosis is established even without other features. 3

Skeletal Manifestations

• Skeletal features reflect overgrowth of long bones and include: 1
  • Arachnodactyly (long, thin fingers)
  • Dolichostenomelia (disproportionately long limbs)
  • Pectus deformities (carinatum or excavatum)
  • Kyphoscoliosis
  • Dolichocephaly (elongated skull)
  • Joint laxity
  • Reduced elbow extension
  • Pes planus (flat feet) with medial malleolus displacement
  • Protrusio acetabuli (hip socket abnormality)

Other Systemic Manifestations

• Connective tissue abnormalities manifest as recurrent or incisional hernias, striae atrophica (stretch marks), and dural ectasia (spinal dura expansion). 1
• Pulmonary, skin, and dura mater abnormalities may be present to variable degrees. 1

Diagnostic Approach

• Diagnosis is fundamentally clinical and requires meeting revised Ghent nosology criteria, which prioritize aortic root dilatation and ectopia lentis as cardinal features. 3
• A definite diagnosis requires a major manifestation in two different organ systems plus involvement of a third organ system. 1
• Early identification is critical because prophylactic surgery can prevent aortic dissection and rupture. 1
• A multidisciplinary team is essential for correct diagnosis, including cardiology, ophthalmology, genetics, and orthopedics. 1

Differential Diagnoses

Marfan syndrome can be confused with other heritable connective tissue disorders due to considerable clinical overlap, including: 1

• Loeys-Dietz syndrome
• Familial thoracic aortic aneurysm
• Bicuspid aortic valve with aortic dilation
• Familial ectopia lentis
• MASS phenotype
• Ehlers-Danlos syndrome

The presence of ectopia lentis is particularly useful to differentiate Marfan syndrome from Loeys-Dietz syndrome. 1

Prognosis and Natural History

• Untreated mean survival is 40 years, with aortic dissection or rupture as the primary causes of death. 1
• The rate of aortic dilatation is heterogeneous and unpredictable among affected individuals. 1
• Patients with dilated aorta are usually asymptomatic until catastrophic complications occur. 1
• With modern medical and surgical treatment, life expectancy has improved substantially to 60-70 years. 4