A 28-year-old Indian man presents to cardiology clinic for evaluation of a family history of sudden cardiac death. On examination, he demonstrates the clinical features marked **A** in the diagram—tall stature with arm span exceeding height by 7%, long slender fingers with positive Steinberg and Walker-Murdoch signs, pectus excavatum, and generalized joint hypermobility. Echocardiography reveals aortic root dilatation at the sinuses of Valsalva. Genetic testing confirms a heterozygous mutation in the FBN1 gene on chromosome 15q21.1. Which of the following best explains the pathophysiologic mechanism linking the FBN1 mutation to aortic root dilatation in this patient?

Explanation

## Why "Defective fibrillin-1 impairs sequestration of latent TGF-β, leading to unopposed TGF-β signaling and aortic wall remodeling" is right Fibrillin-1 is the major structural component of extracellular microfibrils that serve a dual role: (1) scaffolding elastic fibers and (2) sequestering latent TGF-β complexes. FBN1 mutations cause both structural weakness of elastic tissues AND impaired TGF-β sequestration. The unopposed TGF-β signaling drives pathologic aortic wall remodeling, smooth muscle cell dysfunction, and progressive aortic root dilatation—the hallmark life-limiting feature of Marfan syndrome. This TGF-β mechanism is the rationale for losartan therapy (an ARB that suppresses TGF-β signaling), demonstrating that the TGF-β pathway is central to pathogenesis. (Harrison 21e Ch 411) ## Why each distractor is wrong - **Loss of type I collagen cross-linking in the aortic media causes direct structural weakness without inflammatory signaling**: This describes Ehlers-Danlos syndrome (particularly vascular type, caused by COL3A1 mutations), not Marfan syndrome. While Marfan does involve structural weakness, the TGF-β dysregulation is the critical pathogenic mechanism distinguishing it from pure collagen disorders. - **Deficiency of elastin synthesis in elastic fibers results in passive mechanical stretching of the aortic wall**: Although Marfan syndrome does involve elastic fiber dysfunction, the primary defect is in fibrillin-1 (not elastin synthesis per se), and the mechanism is not merely passive mechanical stretching but active TGF-β-driven remodeling. Elastin deficiency alone would not explain why losartan (which does not directly restore elastin) provides therapeutic benefit. - **Impaired angiotensin II receptor expression reduces vascular smooth muscle contractility and aortic wall tone**: This confuses the mechanism of losartan therapy with the underlying pathophysiology. Losartan suppresses TGF-β signaling (not angiotensin II signaling per se in this context), and the primary defect is fibrillin-1 dysfunction, not angiotensin receptor expression. **High-Yield:** Marfan = fibrillin-1 defect → impaired TGF-β sequestration → unopposed TGF-β signaling → aortic root dilatation; losartan suppresses TGF-β, not angiotensin II, in this context. [cite: Harrison 21e Ch 411 (Inherited Disorders of Connective Tissue)]