A 42-year-old woman from Delhi presents with a 3-month history of progressive vision loss and a painless mass in her right eye. Fundoscopy reveals a large intraocular tumor. Imaging confirms retinoblastoma. On detailed family history, her 6-year-old son was diagnosed with bilateral retinoblastoma 2 years ago. Genetic testing reveals a heterozygous germline mutation in the RB1 gene. Which of the following best explains the inheritance pattern and molecular basis of tumor development in this family?

Explanation

## Molecular Basis of Hereditary Retinoblastoma **Key Point:** Retinoblastoma follows the **two-hit hypothesis** (Knudson hypothesis). Individuals with germline RB1 mutations inherit one defective copy; tumors arise when the second allele is lost somatically in retinal cells. ### Inheritance Pattern - **Autosomal dominant** inheritance of the germline mutation - Heterozygous carriers (like the mother and son) have ~90% lifetime risk of developing retinoblastoma - Bilateral disease is pathognomonic for germline mutation ### Two-Hit Mechanism 1. **First hit:** Germline RB1 mutation (inherited from affected parent or de novo) 2. **Second hit:** Somatic loss of the normal allele in retinal cells via: - Somatic mutation - Deletion - Loss of heterozygosity (LOH) - Epigenetic silencing ### Clinical Correlation - The mother carries a germline RB1 mutation (evidenced by her own retinoblastoma) - Her son inherited the same mutation → bilateral retinoblastoma (earlier onset, ~50% bilateral) - The mother's tumor likely arose from LOH in a single retinal cell during development **High-Yield:** Bilateral retinoblastoma = germline RB1 mutation until proven otherwise. Unilateral disease can be either germline (10–15%) or sporadic (85–90%). **Clinical Pearl:** RB1 is a **negative regulator of G1/S transition**. Loss of RB protein → uncontrolled cell cycle progression → retinal cell proliferation and tumor formation. ### Why This Family Pattern? - The mother's germline mutation was inherited from her parent (not shown) or arose de novo - She transmitted the mutation to her son with 50% probability - Both developed tumors because the germline mutation predisposes to LOH in multiple retinal cells [cite:Robbins 10e Ch 7]