Q. A very tall man presents with visual problems and is found to have ectopia lentis on ophthalmological evaluation. Which gene is most likely defective in this patient?

Explanation

## Correct Answer: A. FBN1 ✅(chromosome 15) The combination of tall stature and ectopia lentis is pathognomonic for **Marfan syndrome**, caused by mutations in the **FBN1 gene** on chromosome 15. FBN1 encodes fibrillin-1, a crucial structural protein in the extracellular matrix that provides mechanical support and regulates TGF-β signaling. Defective fibrillin-1 leads to weakening of connective tissues throughout the body. In the eye, fibrillin-1 is a key component of the zonular fibers (suspensory ligaments) that anchor the lens. Loss of fibrillin-1 integrity causes these zonules to stretch and rupture, resulting in ectopia lentis—typically bilateral and often superior displacement. The tall stature reflects skeletal manifestations: increased long bone growth due to altered TGF-β regulation and abnormal endochondral ossification. Other cardinal features include arachnodactyly, pectus deformities, and cardiovascular complications (aortic root dilatation, dissection). Marfan syndrome follows autosomal dominant inheritance with high penetrance. In Indian clinical practice, this diagnosis is critical because untreated aortic root dilatation carries risk of sudden cardiac death in young patients, necessitating regular echocardiographic surveillance and β-blocker or ARB therapy per guidelines. ## Why the other options are wrong **B. FGFR3** — FGFR3 mutations cause **achondroplasia** (most common skeletal dysplasia), which presents with short stature, not tall stature. Achondroplasia features rhizomelic dwarfism, bowing of legs, and normal lens position. This is an NBE trap pairing a skeletal dysplasia with ectopia lentis, but the height direction is opposite to the clinical presentation. **C. PAX6** — PAX6 mutations cause **aniridia** (congenital absence of iris) and other anterior segment dysgenesis, not ectopia lentis. While PAX6 is involved in ocular development, it does not regulate zonular fiber formation or connective tissue integrity. This option exploits confusion between different genetic eye disorders. **D. COL1A1** — COL1A1 mutations cause **Ehlers-Danlos syndrome (EDS) type I/III**, characterized by skin hyperextensibility, joint hypermobility, and tissue fragility—not tall stature or ectopia lentis. While EDS shares connective tissue pathology with Marfan syndrome, the clinical phenotype and ocular manifestations are distinct. This is a common confusion trap in connective tissue disorders. ## High-Yield Facts - **Marfan syndrome** = FBN1 mutation on chromosome 15; autosomal dominant inheritance with high penetrance. - **Ectopia lentis** in Marfan is typically bilateral and superior (upward displacement), caused by zonular fiber weakness. - **Tall stature + arachnodactyly + ectopia lentis + aortic root dilatation** = classic tetrad of Marfan syndrome. - **Fibrillin-1** is essential for both structural support and TGF-β sequestration; defects cause skeletal overgrowth and connective tissue weakness. - **Aortic root dilatation** is the life-threatening complication; β-blockers or ARBs are first-line preventive therapy in Indian clinical practice. ## Mnemonics **MARFAN = Fibrillin-1 (FBN1)** **M**usculoskeletal (tall, arachnodactyly) + **A**ortic (root dilatation) + **R**etinal (ectopia lentis) + **F**ibrillin defect (FBN1) + **A**utosomal dominant + **N**eed cardiac screening. Use this when you see tall + lens dislocation. **Ectopia Lentis Genes (Quick Recall)** **Marfan** = FBN1 (tall, superior lens); **Homocystinuria** = CBS (short, inferior lens); **Ectopia Lentis et Pupillae** = ADAMTSL4. Remember: Marfan goes UP (tall + upward lens), homocystinuria goes DOWN (short + downward lens). ## NBE Trap NBE pairs "tall stature" with skeletal dysplasia genes (FGFR3 = achondroplasia) to trap students who conflate all skeletal overgrowth disorders. The key discriminator is that FGFR3 causes SHORT stature, not tall stature, and does not cause ectopia lentis. ## Clinical Pearl In Indian tertiary care, young patients presenting with tall stature and visual complaints should trigger immediate ophthalmological referral for slit-lamp examination to detect ectopia lentis, followed by echocardiography to assess aortic root diameter. Early diagnosis and β-blocker initiation can prevent sudden cardiac death—a leading cause of mortality in undiagnosed Marfan syndrome in India. _Reference: Robbins Ch. 5 (Genetic Disorders); Harrison Ch. 387 (Marfan Syndrome); KD Tripathi Ch. 12 (Connective Tissue Disorders)_