Retinoblastoma Syndrome

Timothy A. Damron

Retinoblastoma syndrome encompasses familial retinoblastoma and a number of secondary malignancies that may develop as a result of a “second hit” at the site of the RB1 gene, where a somatic mutation added to the germline RB1 mutation inactivates the tumor suppressor gene function. The synonym “retinoblastoma/osteogenic sarcoma syndrome” reflects the fact that osteosarcoma is the most common secondary tumor in these patients. Retinoblastoma is a malignancy of the embryonic neural retina.

Pathogenesis

Etiology

Prototypical example of “two-hit” theory for genetic predisposition to cancer
- First hit: germline (familial form) or somatic (nonfamilial form) mutation of RB1 gene at 13q14.1
- Second hit: somatic mutation in all cases at RB1 locus
  - Radiation increases the risk in a dose-dependent fashion above 5 Gy.
  - Resultant inactivation of RB1 tumor suppressor gene function is associated with retinoblastoma, post-retinoblastoma osteosarcomas, and other sarcomas (Box 7.4-1), and in some sarcomas not associated with retinoblastoma syndrome (breast and non–small-cell lung carcinoma).
Inheritance: autosomal dominant (AD) with almost full penetrance in familial form

Epidemiology

Retinoblastoma
- Frequency: 1/3,500 to 1/25,000 (Fig. 7.4-1)
- Male:female equal
Secondary sarcoma
- Relative risk compared to normal population: 30
- Cumulative incidence over 50 years
  - Hereditary retinoblastoma: 51%
  - Nonhereditary retinoblastoma: 5%