Clinical characteristics: Retinoblastoma is a malignant tumor of the developing retina that occurs in children, usually before age five years. Retinoblastoma develops from cells that have cancer-predisposing variants in both copies of RB1. Retinoblastoma may be unifocal or multifocal. About 60% of affected individuals have unilateral retinoblastoma with a mean age of diagnosis of 24 months; about 40% have bilateral retinoblastoma with a mean age of diagnosis of 15 months. Heritable retinoblastoma is an autosomal dominant susceptibility for retinoblastoma. Individuals with heritable retinoblastoma are also at increased risk of developing non-ocular tumors.
Diagnosis/testing: The diagnosis of retinoblastoma is usually established by examination of the fundus of the eye using indirect ophthalmoscopy. Imaging studies can be used to support the diagnosis and stage the tumor. The diagnosis of heritable retinoblastoma is established in a proband with retinoblastoma or retinoma and a family history of retinoblastoma or by identification of a heterozygous germline pathogenic variant in RB1. The following staging has been recommended for individuals with retinoblastoma and/or risk of heritable retinoblastoma to include "H" to describe the genetic risk for an individual to have a germline pathogenic variant in RB1:
Management: Treatment of manifestations: Early diagnosis and treatment of retinoblastoma and non-ocular tumors can reduce morbidity and increase longevity; care is best provided by multidisciplinary teams of specialists including ophthalmology, pediatric oncology, pathology, and radiation oncology. Treatment options depend on tumor stage, number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, the potential for useful vision, the extent and kind of extraocular extension, and the resources available. Treatment options include enucleation; cryotherapy; laser, systemic, or local ocular chemotherapy including intra-arterial chemotherapy, combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy. Prevention of secondary manifestations: If possible, radiation (including x-ray, CT scan, and external beam radiation) should be avoided in H1 individuals with heritable retinoblastoma to minimize the lifetime risk of developing late-onset second cancers. Surveillance: Children known to have an RB1 germline pathogenic variant (H1) have eye examination under anesthesia every three to four weeks until age six months, then less frequently until age three years, in order to identify retinoblastoma tumors as early and small as possible. Clinical examinations with cooperative children are performed every three to six months until age seven years, then annually and eventually biennially for life. Individuals who have unilateral retinoblastoma without an identified heterozygous germline RB1 pathogenic variant (H0*) are still at risk for low-level mosaicism and should have regular clinical examination of the eyes, including clinical ultrasound. Individuals with retinomas are followed with retinal examinations and imaging every one to two years. To detect second non-ocular tumors in H1 individuals with retinoblastoma, physicians and parents should promptly evaluate complaints of bone pain or lumps because of the high risk for sarcomas and other cancers; however, effective screening protocols have not yet been developed. Agents/circumstances to avoid: Limiting exposure to DNA-damaging agents (radiation, tobacco, and UV light) may reduce the excess cancer risks in H1 survivors of heritable retinoblastoma. Evaluation of relatives at risk: Molecular genetic testing for early identification of asymptomatic at-risk children in a family reduces the need for costly screening procedures in those family members who have not inherited the pathogenic variant (i.e., H0).
Genetic counseling: Heritable retinoblastoma is inherited in an autosomal dominant manner. Individuals with heritable retinoblastoma (H1) have a heterozygous de novo or inherited germline RB1 pathogenic variant. Offspring of H1 individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the RB1 pathogenic variant has been identified in an affected family member.
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