A 42-year-old Indian woman presents with a 3-month history of progressive vision loss and a painless palpable mass in her right eye. On examination, she has leukocoria (white pupil reflex) and intraocular pressure of 28 mmHg. Fundoscopy reveals a large retinal mass with vitreous seeding. Genetic testing shows a heterozygous germline mutation in the RB1 gene. Her 8-year-old son is asymptomatic but genetic screening is positive for the same mutation. What is the most likely diagnosis in the son?

Explanation

## Clinical Context The mother has a germline RB1 mutation causing unilateral retinoblastoma. Her son has inherited the same mutation, making him a carrier of a hereditary form of retinoblastoma. ## Key Pathophysiology of RB1 Mutations **Key Point:** RB1 is a tumor suppressor gene encoding the retinoblastoma protein, which regulates G1/S cell cycle transition. Germline mutations confer a predisposition to retinoblastoma, but penetrance is incomplete (~90%) and expressivity is variable. **High-Yield:** Germline RB1 mutations follow autosomal dominant inheritance with: - Penetrance: ~90% (not 100%) - Bilateral disease in ~65% of hereditary cases - Unilateral disease in ~35% of hereditary cases - Age of onset: typically before age 5 years ## Distinction: Hereditary vs. Sporadic Retinoblastoma | Feature | Hereditary (Germline RB1) | Sporadic (Somatic RB1) | |---------|---------------------------|------------------------| | **Inheritance** | Autosomal dominant | De novo somatic mutation | | **Bilateral disease** | ~65% | <1% | | **Age of onset** | Earlier (mean 18 months) | Later (mean 24 months) | | **Penetrance** | ~90% | N/A | | **Family history** | Positive in ~40% | Absent | | **Risk to offspring** | 50% (if parent affected) | <1% | ## Why Option 2 is Correct The son is an asymptomatic carrier of a germline RB1 mutation. He has a **90% penetrance risk** of developing retinoblastoma (typically bilateral in ~65% of cases), but he is currently asymptomatic. The correct answer acknowledges that: 1. He is a documented carrier (positive genetic screening) 2. He requires surveillance (ophthalmology screening every 2–4 weeks until age 5) 3. He may never develop disease (10% incomplete penetrance) 4. If disease develops, it will likely be bilateral **Clinical Pearl:** Asymptomatic carriers with germline RB1 mutations require intensive ophthalmologic surveillance from birth. Early detection via regular fundoscopy can identify tumors at a stage amenable to globe-sparing therapy (chemotherapy, external beam radiation, or laser/cryotherapy). ## Mechanism: Two-Hit Hypothesis Retinoblastoma follows Knudson's two-hit hypothesis: 1. **First hit:** Inherited germline RB1 mutation (present in all cells) 2. **Second hit:** Acquired somatic mutation in retinal cell (loss of heterozygosity) The son has the first hit but has not yet acquired the second hit in any retinal cell, hence he is asymptomatic. **Mnemonic: "RB1 = Retinal Blastoma 1"** — Remember: germline RB1 = predisposition, not destiny. Penetrance is ~90%, not 100%.