Heritable Retinoblastoma

Heritable retinoblastoma is defined by the presence of a germline pathogenic variant of the RB1 gene. This germline pathogenic variant may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.

Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 variant (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4 polymorphisms.[1,2] All children with bilateral disease and approximately 15% of patients with unilateral disease are presumed to have the heritable form, even though only 25% have an affected parent. In a series of 482 patients with unilateral retinoblastoma, germline pathogenic variants were identified in 33% of infants younger than 12 months, 6% of children aged 12 to 24 months, and 7% of children aged 24 to 39 months. The highest incidence of germline retinoblastoma was in patients younger than 1 year compared with patients older than 1 year (odds ratio, 2.96).[3][Level of evidence C2]

Children with heritable retinoblastoma tend to be diagnosed at a younger age than children with the nonheritable form of the disease.[4]