Retinoblastoma

Retinoblastoma is a malignant embryonal tumour of the developing retina. The most common presenting signs are a white pupillary reflex (leukocoria) and strabismus, which may accompany or precede leukocoria. Less common presentations include glaucoma, orbital cellulitis, uveitis, hyphema, or vitreous haemorrhage. Most affected children are diagnosed before the age of five years. Approximately 60% of affected individuals have unilateral disease, with a mean age at diagnosis of 24 months, while about 40% present with bilateral disease at a mean age of 15 months. Intraocular retinoblastoma is generally curable with prompt multimodal treatment, whereas trilateral retinoblastoma (concurrent pinealoblastoma or primitive neuroectodermal tumour) is usually fatal. Survivors of heritable retinoblastoma carry a lifelong, markedly increased risk of subsequent malignant neoplasms, most commonly osteosarcoma, soft tissue sarcoma, and melanoma.

The estimated incidence is 1/15,000 to 1/20,000 live births.

Heritable retinoblastoma is caused by germline pathogenic variants in RB1 (13q14.2), which result in a loss-of-function. RB1 encodes a ubiquitously expressed nuclear tumour-suppressor protein regulating the G1-to-S cell-cycle transition. Tumour development begins when a developing retinal cell in the cone photoreceptor lineage loses both RB1 alleles. Conventional molecular testing identifies an RB1 pathogenic variant in 90-97% of simplex cases with bilateral involvement, while the rest of patients may have translocations, deep intronic splice variants, or low-level mosaic pathogenic variants. In patients with Retinoblastoma and a positive family history, pathogenic RB1 variants can be detected in close to 100% of cases.

Retinoblastoma is inherited in an autosomal dominant manner. Simplex cases with bilateral tumours present with a de novo RB1 pathogenic variant or carry a variant inherited from a mosaic or reduced-penetrance unaffected parent. Prenatal molecular testing is technically possible once a familial pathogenic variant has been identified.

The clinical diagnosis is established by retinal examination under full pupillary dilatation; ocular ultrasound and MRI support diagnosis and staging. The diagnosis of heritable retinoblastoma is established by identification of a pathogenic variant in RB1 by molecular genetic testing.

Other ophthalmic tumours or mass accumulations occur, among others, in association with:

• NDP-related persistent fetal vasculature, NDP-related Coats disease and Norrie disease; NDP
• ; TSC1
• ; VHL
• Toxocara canis infestation: posterior or peripheral granuloma with intraocular inflammation and supportive serology, lacking the calcification typical of retinoblastoma; non-heritable (parasitic aetiology)

• Establishing the molecular diagnosis enables precise classification of the condition and provides the genetic basis for individualised care.
• Identification of the causative variant supports specific and individualised surveillance and clinical management, including early ophthalmological examination for at-risk relatives and monitoring for subsequent malignant neoplasms; the choice and timing of measures are determined by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, predictive testing of at-risk relatives is technically possible and can inform reproductive decisions and family planning.

• Lohmann DR, Gallie BL. Retinoblastoma. 2000 Jul 18 [updated 2023 Sep 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301625.
• Yamanaka R, Hayano A, Takashima Y. Trilateral retinoblastoma: a systematic review of 211 cases. Neurosurg Rev. 2019;42(1):39-48. doi:10.1007/s10143-017-0890-4. PMID:.