Learning Objective: Describe the genetic basis, pathophysiology, and key clinical features of Marfan syndrome and recognize life-threatening cardiovascular complications in a Step 1-style clinical context.
Overview
Marfan syndrome is an autosomal dominant connective tissue disorder that affects the skeleton, eyes, and cardiovascular system. It is an example of pleiotropy—a single gene defect leading to multiple system manifestations.
Genetic and Molecular Basis
| Feature |
Detail |
| Gene involved |
FBN1 (Fibrillin-1 gene) |
| Chromosome location |
Chromosome 15 |
| Inheritance pattern |
Autosomal dominant (variable expression) |
| Pathogenesis |
Mutation → defective fibrillin-1 → abnormal microfibril formation → weakened connective tissue and increased TGF-β signaling |
| Mechanism |
Fibrillin normally forms a sheath around elastin and sequesters TGF-β. Mutation leads to excess TGF-β activity, damaging connective tissues (especially in the aorta and ligaments). |
Systemic Manifestations
| System |
Clinical Features |
USMLE Tips |
| Skeletal |
Tall, thin habitus; long limbs; arachnodactyly (spider-like fingers); pectus excavatum/carinatum; hypermobile joints |
Mimics homocystinuria but no intellectual disability |
| Ocular |
Lens subluxation (ectopia lentis)—usually upward and temporal |
Compare: Homocystinuria = downward and medial lens dislocation |
| Cardiovascular |
Cystic medial necrosis of the aorta → aortic root dilation, aneurysm, dissection (most common cause of death); mitral valve prolapse; risk of spontaneous pneumothorax |
Sudden death in a young athlete → think aortic dissection |
Clinical Insight
- The most life-threatening complication of Marfan syndrome is aortic root aneurysm rupture or dissection due to cystic medial degeneration. Screening and β-blockers are essential to slow aortic dilation.
Key Differentiating Features
| Feature |
Marfan Syndrome |
Homocystinuria |
| Inheritance |
Autosomal dominant |
Autosomal recessive |
| Lens dislocation |
Upward |
Downward |
| Intellectual disability |
Absent |
Present |
| Cardiac involvement |
Aortic root dilation, MVP |
Thromboembolism |
Key Points
- FBN1 mutation → defective fibrillin-1 → abnormal connective tissue elasticity
- Autosomal dominant inheritance with variable expression (pleiotropy)
- Upward lens dislocation and aortic root aneurysm are hallmark findings
- Aortic dissection is the most common cause of death
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