A 28-year-old Indian male presents to the cardiology clinic with a family history of sudden cardiac death. On examination, the structure marked **A** (arachnodactyly with positive thumb sign) is noted, along with tall stature and arm span exceeding height. Echocardiography reveals aortic root dilatation (Z-score 2.5). Which of the following best explains the pathophysiology underlying this patient's clinical presentation?
A. Mutation in COL3A1 gene encoding type III collagen, resulting in vascular fragility and spontaneous rupture
B. Deficiency of homocysteine metabolism causing cross-linking abnormalities in collagen and elastin
C. Deficiency of vitamin C-dependent hydroxylation of proline and lysine residues in collagen synthesis
D. Mutation in FBN1 gene on chromosome 15q21.1 encoding fibrillin-1, leading to loss of extracellular microfibril scaffold and abnormal TGF-β signaling
Explanation
Why option 1 is correct
Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene on chromosome 15q21.1, which encodes fibrillin-1, a major glycoprotein component of extracellular microfibrils. Loss of fibrillin-1 compromises the structural scaffold for elastin deposition and, critically, releases sequestered TGF-β, leading to pathologic vascular and skeletal remodeling. The presence of arachnodactyly with positive thumb sign (structure A), tall stature with increased arm span, and aortic root dilatation are cardinal features of Marfan syndrome that fit the Revised Ghent Nosology 2010 diagnostic criteria. The combination of aortic root dilatation (Z-score ≥2) plus systemic features (arachnodactyly scoring 3 points on the systemic score) establishes the diagnosis and directly reflects FBN1 pathology.
Why each distractor is wrong
Option 2 (Homocysteine deficiency): This is the pathophysiology of homocystinuria, which presents with ectopia lentis (characteristically INFEROMEDIAL/downward dislocation, contrasting with the SUPEROTEMPORAL dislocation in Marfan syndrome), intellectual disability, thrombosis, and lens dislocation. While homocystinuria can mimic Marfan syndrome clinically, the biochemical defect and inheritance pattern differ fundamentally.
Option 3 (COL3A1 mutation): Mutations in COL3A1 encoding type III collagen cause Ehlers-Danlos syndrome type IV (vascular EDS), characterized by spontaneous arterial rupture, thin translucent skin, and easy bruising—not the skeletal features or progressive aortic root dilatation typical of Marfan syndrome.
Option 4 (Vitamin C deficiency): Vitamin C deficiency causes scurvy, characterized by defective hydroxylation of proline and lysine in collagen synthesis, leading to bleeding, poor wound healing, and bone fragility—not the connective tissue architecture defect or TGF-β dysregulation seen in Marfan syndrome.
