What is the inheritance pattern and genetic/metabolic abnormality of Marfan syndrome?

Marfan Syndrome: Inheritance Pattern and Genetic Abnormality

Marfan syndrome is an autosomal dominant disorder caused by mutations in the FBN1 gene on chromosome 15q21, which encodes fibrillin-1, a glycoprotein in the extracellular matrix. 1

Inheritance Pattern

Marfan syndrome follows an autosomal dominant inheritance pattern with:

• High penetrance but variable expressivity
• 25-30% of cases representing new (de novo) mutations 1
• Estimated prevalence of 2-3 per 10,000 individuals 1

The autosomal dominant inheritance means:

• Each child of an affected individual has a 50% chance of inheriting the mutation
• Males and females are equally affected
• The condition can be transmitted from either parent
• Family history may be absent in approximately one-third of cases due to de novo mutations 1

Genetic and Metabolic Abnormality

Primary Genetic Defect

• Located on chromosome 15q21 in the FBN1 gene 1
• More than 1,000 different mutations have been identified in FBN1 1
• Almost all mutations are unique to an affected individual or family 1
• In approximately 10% of patients with a definite clinical diagnosis of Marfan syndrome, current testing methods cannot detect an FBN1 mutation 1

Molecular Pathophysiology

1. Fibrillin-1 Abnormality:

   • Fibrillin-1 is a major structural component of microfibrils in the extracellular matrix 1
   • These microfibrils provide support to connective tissues, particularly in:
     • Arteries
     • Pericondrium
     • Ocular structures 2

2. Pathogenic Mechanisms:

   • Deficiency of fibrillin leads to weakening of supportive tissues 1
   • Abnormal fibrillin-1 causes dysregulation of transforming growth factor-beta (TGF-β) signaling 1, 3
   • Loss of cell-matrix interactions occurs 3
   • These changes ultimately result in the various clinical manifestations of Marfan syndrome

Diagnostic Considerations

• Diagnosis is primarily clinical, based on the revised Ghent nosology criteria 1
• Genetic testing can confirm the diagnosis but is not always required 2
• The diagnosis requires occurrence of major manifestations in multiple organ systems 1

Clinical Implications of the Genetic Defect

The FBN1 mutations result in several key pathological processes:

• Progressive dilation of the aorta, leading to aortic dissection or rupture (the major cause of death) 1
• Ectopia lentis (dislocation of the ocular lens) 1
• Skeletal abnormalities characterized by overgrowth of long bones 2
• Dural ectasia and other connective tissue manifestations 1

Diagnostic Testing

When Marfan syndrome is suspected:

1. Clinical evaluation using Ghent criteria
2. Genetic testing for FBN1 mutations:
   • Particularly useful in equivocal cases
   • Can help distinguish Marfan syndrome from other heritable thoracic aortic diseases 2
   • Current testing detects mutations in 90-95% of unequivocal cases 1

Key Points for Clinical Practice

• The wide clinical variability in Marfan syndrome is partly explained by the large number of different mutations in the FBN1 gene 1
• Genetic heterogeneity exists, with some cases showing normal fibrillin metabolism 1
• Early identification and diagnosis are critical since prophylactic interventions can prevent life-threatening complications like aortic dissection 1
• Regular cardiovascular monitoring is essential due to the progressive nature of aortic disease 1