A 17-year-old boy presents to the cardiology clinic after a school screening detected a diastolic murmur. He is asymptomatic but has always been noted to be tall and thin. On examination, his arm span exceeds his height (ratio 1.08), and he has marked arachnodactyly with positive Steinberg and Walker-Murdoch signs. Ophthalmology reveals bilateral upward ectopia lentis. Echocardiography shows aortic root dilatation at the sinuses of Valsalva (Z-score +3.2) with mild aortic regurgitation. The clinical and imaging findings are consistent with the condition marked **B** in the diagram. Which of the following best explains the underlying pathophysiology of aortic root dilatation in this syndrome?

Question

Accepted Answer

B. FBN1 mutations cause loss of fibrillin-1 microfibrils, leading to liberation of latent TGF-β and aortic media degeneration. ## Why FBN1 mutations cause loss of fibrillin-1 microfibrils, leading to liberation of latent TGF-β and aortic media degeneration is right

The condition marked **B** is Marfan syndrome, an autosomal dominant connective-tissue disorder caused by mutations in the FBN1 gene (chromosome 15q21.1) encoding fibrillin-1. Fibrillin-1 is a critical glycoprotein that forms microfibrils in the extracellular matrix and crucially sequesters latent TGF-β. Loss-of-function FBN1 mutations disrupt this sequestration, liberating excessive TGF-β, which drives aortic media degeneration, smooth muscle cell apoptosis, and progressive aortic root dilatation—the cardinal cardiac feature in this patient. This mechanism is the pathophysiological basis for the aortic complications in Marfan syndrome (Ghent-2 2010 criteria; Pediatric Heart Network).

## Why each distractor is wrong

- **TGFBR1/2 mutations impair transforming growth factor-β receptor signaling with bifid uvula and arterial tortuosity**: This describes Loeys-Dietz syndrome, a related but distinct connective-tissue disorder. While both syndromes involve TGF-β dysregulation, Loeys-Dietz has TGFBR mutations (not FBN1), and the clinical phenotype includes bifid uvula or cleft palate, hypertelorism, and arterial tortuosity—features absent in this patient. The patient's upward ectopia lentis is cardinal for Marfan, not Loeys-Dietz.

- **Cystathionine β-synthase deficiency causes homocysteine accumulation and venous thrombosis with downward lens subluxation**: This is homocystinuria (marked **A** in the diagram), a metabolic disorder with a Marfan-like habitus but distinguished by DOWNWARD (not upward) ectopia lentis, intellectual disability, and venous thrombosis. The biochemical defect and clinical presentation are entirely different from Marfan syndrome.

- **Type IV collagen mutations result in thin translucent skin and spontaneous arterial rupture without skeletal features**: This describes Ehlers-Danlos syndrome, vascular type (marked **D** in the diagram), caused by COL3A1 mutations. The phenotype includes thin translucent skin, easy bruising, and life-threatening arterial rupture—not the tall stature, arachnodactyly, and upward lens subluxation seen in this patient.

**High-Yield:** Marfan syndrome = FBN1 mutation → loss of fibrillin-1 microfibrils → TGF-β liberation → aortic root dilatation + upward ectopia lentis. Losartan or beta-blockers slow progression; prophylactic aortic root replacement when diameter ≥5.0 cm.

[cite: Ghent-2 2010; Pediatric Heart Network]

Answer

A. Cystathionine β-synthase deficiency causes homocysteine accumulation and venous thrombosis with downward lens subluxation

Answer

C. TGFBR1/2 mutations impair transforming growth factor-β receptor signaling with bifid uvula and arterial tortuosity

Answer

D. Type IV collagen mutations result in thin translucent skin and spontaneous arterial rupture without skeletal features

Explanation

Why FBN1 mutations cause loss of fibrillin-1 microfibrils, leading to liberation of latent TGF-β and aortic media degeneration is right

Why each distractor is wrong

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