A child has normal intellectual development, tall stature, hyperextensible joints, aortic root dilatation, and lens subluxation superiorly and temporally. FBN1 gene mutation is identified. What is the underlying molecular defect in Marfan syndrome?

• A Defective type I collagen causing connective tissue fragility and aortic dissection
• B Deficient elastin production from ELN gene mutation causing supravalvular aortic stenosis
• C Defective ADAMTS10 metalloprotease causing enhanced microfibril degradation
• D Defective fibrillin-1 leading to impaired elastic fiber assembly and excess free TGF-beta signaling ✓

Explanation

Marfan syndrome results from mutations in FBN1 encoding fibrillin-1, a glycoprotein essential for microfibril assembly. Defective fibrillin-1 impairs sequestration of TGF-beta by microfibrils, leading to excess active TGF-beta signaling that drives aortic wall remodeling, extracellular matrix degradation, and mitral valve prolapse. Notably, lens subluxation in Marfan is superiorly and temporally (vs homocystinuria where it is inferiorly and nasally). Losartan (TGF-beta inhibitor) is used therapeutically based on this mechanism.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.