CHAPTER 19
Retinoblastoma
Retinoblastoma is the most common primary intraocular malignant tumor of childhood, second only to uveal melanoma as the most common primary intraocular malignant tumor in all age groups (Table 19-1). The frequency of retinoblastoma ranges from 1 in 14,000 to 1 in 20,000 live births, depending on the country. It is estimated that 250–300 new cases occur in the United States each year. There is no sexual predilection, and the tumor occurs bilaterally in 30%–40% of cases. Approximately 90% of cases are diagnosed in patients younger than 3 years. The mean age at diagnosis depends on family history and the laterality of the disease:
patients with a known family history of retinoblastoma—4 months patients with bilateral disease—12 months
patients with unilateral disease—24 months
Geographic variation in the incidence of the disease has been noted. In Mexico, 6.8 cases per million population have been reported compared to 4 cases per million in the United States. In Central America, there has been an increased incidence in recent years. The highest incidence of the disease has been noted in Africa and India.
Genetic Counseling
Retinoblastoma is caused by a mutation in the RB1 tumor suppressor gene located on the long arm of chromosome 13 at locus 14 (13q14). Both copies of the RB1 gene must be mutated in order for a tumor to form. If a patient has bilateral retinoblastoma, there is approximately a 98% chance that it represents a germline mutation. Only about 5% of retinoblastoma patients have a family history of retinoblastoma. The children of a retinoblastoma survivor who has the hereditary form of retinoblastoma have a 45% chance of being affected (50% chance of inheriting and 90% chance of penetrance). In these cases, the child inherits an abnormal gene from the affected parent. This abnormal gene coupled with somatic mutations in the remaining normal RB1 allele leads to the development of multiple tumors in 1 or both eyes.
Table 19-1
Sporadic cases constitute approximately 95% of all retinoblastomas. Of these, 60% of patients have unilateral disease with no germline mutations. The remaining patients have new germline mutations and will develop multiple tumors. It should be noted that approximately 15% of the sporadic unilateral patients are carriers of a germline RB1 mutation. Unless there are multiple tumors in the affected eye, these patients cannot be distinguished from children without a germline mutation. Children with unilateral retinoblastoma and a germline mutation, much like their counterparts with bilateral retinoblastoma, are more likely to present at an earlier age. Commercial laboratories are available to test the blood of all retinoblastoma patients for germline mutations. Methods of genetic testing used in retinoblastoma screening include gene sequencing via quantitative polymerase chain reaction (PCR), karyotyping, fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and RNA analysis. There is approximately a 95% chance of finding a new mutation if one exists.
Genetic counseling for retinoblastoma can be very complex (Fig 19-1). A bilateral retinoblastoma survivor has a 45% chance of having an affected child, whereas a unilateral survivor has a 7% chance of having an affected child. Normal parents of a child with bilateral involvement have less than a 5% risk of having another child with retinoblastoma. If 2 or more siblings are affected, the chance that another child will be affected increases to 45%. See also Chapter 11 in this volume and BCSC Section 6, Pediatric Ophthalmology and Strabismus.
Abramson DH, Mendelsohn ME, Servodidio CA, Tretter T, Gombos DS. Familial retinoblastoma: where and when? Acta Ophthalmol Scand. 1998;76(3):334–338.
Gallie BL, Dunn JM, Chan HS, Hamel PA, Phillips RA. The genetics of retinoblastoma: relevance to the patient. Pediatr Clin North Am. 1991;38(2):299–315.
Murphree AL. Molecular genetics of retinoblastoma. Ophthalmol Clin North Am. 1995;8: 155–166.