retinoblastoma

Retinoblastoma is caused by mutation/deletion of the RB1 gene on chromosome 13q14, which encodes the retinoblastoma protein (pRb), a key regulator of the cell cycle G1-to-S checkpoint. Normally, pRb binds and inhibits E2F transcription factors; when RB1 is lost, E2F is unregulated, leading to uncontrolled cell cycle progression. Knudson's two-hit hypothesis explains the pattern: hereditary cases involve one germline mutation (first hit) plus a somatic mutation in the other allele (second hit), leading to earlier onset, often bilateral disease, and increased risk of secondary malignancies (e.g., osteosarcoma, pinealoma - 'trilateral retinoblastoma'). Sporadic cases require two somatic mutations in the same cell, making them typically unilateral and presenting slightly later. Clinical presentation includes leukocoria (most common sign, absent red reflex), strabismus, and sometimes decreased vision or a red, painful eye if the tumor causes secondary glaucoma. Diagnosis is via fundoscopic exam, ultrasound, and MRI (avoid CT due to radiation risk in this population with RB1 mutations, which predisposes to radiation-induced sarcomas). Histology shows small round blue cells with Homer-Wright or Flexner-Wintersteiner rosettes. Treatment depends on staging and may include enucleation, chemotherapy, laser therapy, cryotherapy, or radiation therapy for advanced/bilateral disease. Genetic counseling is essential for hereditary cases given autosomal dominant inheritance with high penetrance and risk to offspring. RB1 loss is also implicated in other cancers (osteosarcoma, small cell lung cancer), reinforcing its role as a critical tumor suppressor gene studied extensively in cancer biology.