Marfan syndrome (MFS) is caused by FBN1 (fibrillin-1) mutation. The primary pathogenic mechanism of cardiovascular and skeletal manifestations in MFS, beyond structural weakness, is:

• A Decreased collagen cross-linking due to lysyl oxidase deficiency
• B Excess TGF-β signaling due to impaired sequestration of latent TGF-β in the extracellular matrix by mutant fibrillin-1 ✓
• C Upregulation of matrix metalloproteinases (MMP-9) due to elastin fragmentation
• D Activation of RAAS via angiotensin II type 1 receptor signaling in aortic smooth muscle

Explanation

Fibrillin-1 normally sequesters latent TGF-β (as part of the large latent complex) in the extracellular matrix, keeping TGF-β inactive. Mutant fibrillin-1 cannot properly sequester latent TGF-β, resulting in constitutive TGF-β release and receptor activation. Excess TGF-β signaling drives smooth muscle cell apoptosis, extracellular matrix degradation (upregulating MMPs), and impaired elastic fiber homeostasis in the aortic wall, predisposing to aneurysm and dissection. This mechanism explains why losartan (AT1R blocker, which reduces TGF-β signaling) is being evaluated in MFS — it works partially through reducing TGF-β bioavailability. Lysyl oxidase deficiency causes cutis laxa; MMP-9 upregulation is downstream of TGF-β excess.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.