Foundations · Year 1 · from Foundations
Case 1: Retinoblastoma (RB1 Tumor Suppressor Loss)
Clinical Image
Source: Wikipedia - Retinoblastoma - CC BY-SA 3.0
Case Presentation
The parents of an 18-month-old girl notice a white glow in their daughter's left pupil visible in flash photographs, which they initially attributed to the camera angle. They also observe that she seems to have a slight inward turn of the same eye. Ophthalmologic examination reveals leukocoria (white pupillary reflex instead of normal red reflex) and esotropia. Dilated fundoscopic examination shows a large creamy-white mass in the posterior chamber, and MRI confirms an intraocular tumor without optic nerve involvement. She is diagnosed with retinoblastoma. Given the young age and unilateral presentation, genetic testing is performed and reveals a germline mutation in RB1, indicating hereditary retinoblastoma despite the unilateral presentation. The geneticist explains Knudson's two-hit hypothesis: in hereditary retinoblastoma, the child inherits one mutated RB1 allele, requiring only one somatic mutation to lose the remaining functional copy. In sporadic cases, both hits must occur somatically in the same cell, making bilateral disease rare. The Rb protein normally prevents cell cycle progression by binding and inhibiting E2F transcription factors; when both RB1 alleles are lost, E2F is constitutively active, driving uncontrolled proliferation. She undergoes chemotherapy and focal laser therapy, preserving her eye. Lifelong surveillance for secondary tumors (particularly osteosarcoma) is required given her germline mutation.
Key Learning Points
- The Rb protein is the master regulator of the G1/S checkpoint; it binds and inhibits E2F transcription factors until phosphorylation by cyclin D-CDK4/6 releases E2F to activate S phase genes
- Retinoblastoma demonstrates Knudson's two-hit hypothesis: both alleles of a tumor suppressor must be inactivated for tumor development; hereditary cases inherit one hit and need only one somatic hit
- The Rb pathway (Rb, cyclin D, CDK4/6, p16) is functionally disrupted in the majority of human cancers through various mechanisms, highlighting its central role in proliferation control