A 15-year-old tall boy with long limbs presents to the OPD. On ocular examination, bilateral ectopia lentis is noted. Which gene is most likely affected in this inherited disorder?

Explanation

## Correct Answer: A. FBN1 (Fibrillin-1) The clinical presentation of a tall boy with long limbs and bilateral ectopia lentis is pathognomonic for **Marfan syndrome**, an autosomal dominant connective tissue disorder caused by mutations in the **FBN1 gene** on chromosome 15q21. Fibrillin-1 is a crucial component of extracellular microfibrils that provide structural integrity to connective tissue and regulate TGF-β signaling. The skeletal features (arachnodactyly, tall stature, long limbs) combined with ocular manifestations (bilateral ectopia lentis—lens displacement superiorly and temporally) are cardinal diagnostic criteria. In Indian populations, Marfan syndrome, though less common than in Western cohorts, presents with the same genetic basis and phenotype. The lens dislocation occurs because fibrillin-1 is essential for zonular fiber integrity; defective microfibrils weaken zonular support, leading to lens subluxation. This is the most common cause of ectopia lentis in children and adolescents presenting with systemic features. The diagnosis is confirmed by genetic testing for FBN1 mutations, and management includes ophthalmologic surveillance, cardiac screening (aortic root dilatation), and genetic counseling for family members. ## Why the other options are wrong **B. PAX6** — PAX6 mutations cause aniridia (iris hypoplasia) and congenital cataracts, not ectopia lentis. While PAX6 does affect ocular development, it does not produce the systemic skeletal features (tall stature, arachnodactyly) seen in this patient. This is an NBE trap pairing a gene with ocular manifestations to distract from the syndromic diagnosis. **C. COL5A** — COL5A mutations cause Ehlers-Danlos syndrome (EDS), which presents with skin hyperextensibility, joint hypermobility, and tissue fragility—not ectopia lentis. While EDS patients may be tall, they lack the characteristic lens dislocation and the specific skeletal habitus of Marfan syndrome. This option tests confusion between connective tissue disorders. **D. TGFβR2** — TGFβR2 mutations cause Loeys-Dietz syndrome, which shares aortic dilatation with Marfan syndrome but presents with distinctive features: bifid uvula, cleft palate, and arterial tortuosity. Ectopia lentis is not a cardinal feature of Loeys-Dietz syndrome. This option exploits overlap in connective tissue pathology but lacks the ocular hallmark. ## High-Yield Facts - **Ectopia lentis** (bilateral, superior-temporal displacement) is the most common ocular manifestation of Marfan syndrome and occurs in ~60% of patients. - **FBN1 gene** mutations disrupt fibrillin-1 microfibrils, weakening zonular fibers and causing lens subluxation; this is the pathophysiologic basis for ectopia lentis in Marfan syndrome. - **Marfan syndrome** diagnosis requires systemic involvement: skeletal (arachnodactyly, tall stature, pectus deformity), ocular (ectopia lentis, myopia, astigmatism), and cardiovascular (aortic root dilatation, aortic dissection risk). - **Revised Ghent nosology** (2010) uses FBN1 genetic testing as a major criterion; ectopia lentis + family history of Marfan syndrome = clinical diagnosis without genetic confirmation. - **Cardiovascular screening** (echocardiography for aortic root diameter) is mandatory in all Marfan syndrome patients; aortic dissection is the leading cause of premature death. ## Mnemonics **MARFAN = Skeletal + Ocular + Cardiac** **M**icrofibril (FBN1) defect → **A**rachnodactyly, **R**ib/chest deformity → **F**ibrillin weakness → **A**ortic dilatation → **N**eed lens dislocation (ectopia lentis). Use this when you see tall + long limbs + lens displacement. **Ectopia Lentis Differential** **Marfan** (FBN1) = superior-temporal; **Homocystinuria** (cystathionine β-synthase) = inferior; **Ehlers-Danlos** (COL5A) = no lens dislocation. In a tall boy with systemic features, think Marfan first. ## NBE Trap NBE pairs ocular findings (ectopia lentis) with multiple genes affecting eye development (PAX6) or other connective tissue disorders (EDS, Loeys-Dietz) to distract from recognizing the syndromic diagnosis. The key discriminator is the **combination of tall stature + arachnodactyly + bilateral ectopia lentis**, which is pathognomonic for Marfan syndrome.</trap> <parameter name="textbookRef">Robbins Ch. 5 (Genetic Disorders); Harrison Ch. 431 (Marfan Syndrome); OP Ghai Ch. 7 (Connective Tissue Disorders) ## Clinical Pearl In Indian pediatric practice, any adolescent presenting with tall stature, arachnodactyly, and lens dislocation should trigger immediate cardiac screening (echocardiography) and ophthalmology referral for zonular assessment. Aortic root dilatation and dissection risk necessitate beta-blocker or ARB therapy and activity restriction—early diagnosis prevents sudden cardiac death in young patients.