Summary

Retinoblastoma is an intraocular malignancy of neuroectodermal origin that arises in the retina. It primarily affects young children, and overall is the most common intraocular malignancy in children. Retinoblastoma typically presents with leukocoria (a white pupillary reflex) or strabismus (a squint). Treatment is very effective, curing 98% of children with retinoblastoma.

Epidemiology

Retinoblastoma typically affects young children, and is most common in children under 4 years old. About 40 cases of retinoblastoma are diagnosed each year in the UK (approximately 1:17,000 births).

Genetics

It has long been known that there is a genetic predisposition to some forms of retinoblastoma due to familial cases. Knudson’s “two-hit” hypothesis for tumourigenesis describes that mutations in both active copies of a gene are required for the development of retinoblastoma. The first “hit” (mutation) can occur in somatic or germline cells; and the second “hit” occurs in somatic cells in the developing retina.

The retinoblastoma gene (RB1), a tumour suppressor gene on chromosome 13q14 (the long arm of chromosome 13), was identified by Friend in 1986. As a tumour suppressor gene, RB1 restricts uncontrolled progress through the cell cycle (compared to oncogenes, which promote cell growth). Both alleles of a tumour suppressor gene must be inactivated for tumour development.

There are two forms of retinoblastoma, depending on whether the first “hit” (mutation) is genetic or somatic.

1. Familial (germline) cases (40% of retinoblastoma cases) - all cells in the body carry one mutated copy of RB1, and the second mutation is somatic. These patients tend to have bilateral and multifocal tumours. They have a significantly increased risk of secondary tumours, including primitive neuroectodermal tumours in the brain - termed “trilateral retinoblastoma”. There is a 45% chance that offspring will develop retinoblastoma (because the trait is inherited in an autosomal dominant fashion with 〜90% penetrance).
2. Sporadic cases (60%) - two RB1 mutations occur in a somatic cell of the developing retina. This form is not heritable. Patients present with unilateral disease.

Table summarising the key differences between familial and sporadic retinoblastoma.

Clinical features

As mentioned, 40% of retinoblastoma cases are bilateral and 60% are unilateral.

Physical examination

Typical clinical signs on physical examination include:

• Leukocoria (whitening of the red reflex) - this is the most common sign of retinoblastoma, and indicates that the pupil is not reflecting light. It is often picked up on flash photography, with the child’s affected eye appearing white in the photograph
• Strabismus (squint)
• Deterioration of vision