Hereditary Retinoblastoma Syndrome

Hereditary retinoblastoma is caused by a germline RB1 variant, with bilateral or multifocal retinoblastoma in infancy and a lifelong increased risk of second cancers. It accounts for all bilateral and some unilateral cases.

Pathophysiology. RB1 encodes a tumour suppressor that blocks cell cycle entry. A germline variant plus a second somatic hit in a retinal cell gives tumours, usually before 3 years of age.

Most affected children have no family history because the variant is de novo. Penetrance is high, so most carriers develop retinoblastoma.

Survivors face sarcomas, melanoma and other cancers, especially after radiotherapy.

• Leukocoria (white pupillary reflex) as the commonest sign
• Strabismus, a red painful eye, poor vision or glaucoma
• Bilateral or multifocal tumours
• Trilateral retinoblastoma: a pineal or suprasellar midline tumour
• Second cancers: osteosarcoma, soft tissue sarcoma, melanoma, and others
• Rarely intellectual disability and dysmorphism with a 13q deletion
• Family history of childhood eye cancer

• Dilated fundus examination by an ophthalmologist, under anaesthesia for infants, with imaging by ultrasound and, when needed, MRI of the orbit and brain.
• Staging: MRI of the brain and orbits, with systemic evaluation (bone marrow and lumbar puncture) in advanced disease.
• Genetic testing of RB1 on blood, and on tumour tissue if available, with deletion and duplication analysis.
• Family testing: parents and siblings, and prenatal or early postnatal testing in at risk families.
• Screening schedule for babies at risk: serial examination (first examination in the first weeks of life, then at intervals that lengthen with age).

Differential diagnosis.

• Persistent foetal vasculature
• Coats disease
• Toxocariasis and other causes of uveitis
• Retinopathy of prematurity
• Congenital cataract
• Retinal astrocytic hamartoma (tuberous sclerosis)

• Screening of at risk infants: the first dilated examination within days to weeks of birth, then at about 2 to 4 week intervals in the early months, lengthening to every 3 months by 1 year and every 6 months until age 5 or more. Delivery at 36 to 38 weeks may allow earlier treatment when the risk is known.
• Local therapy for small tumours: laser photocoagulation, cryotherapy or transpupillary thermotherapy.
• Chemotherapy (reduction or adjuvant): systemic vincristine 0.05 mg/kg (1.5 mg/m2 in older children), carboplatin 18.6 mg/kg (560 mg/m2) and etoposide 5 mg/kg (150 mg/m2) intravenously, in cycles every 3 to 4 weeks, for 6 cycles, with doses reduced in infants under 3 years. Intra-arterial or intravitreal melphalan are used in selected eyes in expert centres.
• Plaque brachytherapy for solitary residual tumours.
• Enucleation for advanced disease with no hope of useful vision, or glaucoma. Examine the specimen for high risk features (post-laminar optic nerve invasion, massive choroidal invasion, scleral or anterior chamber spread) and give adjuvant chemotherapy when present.
• Avoid external beam radiotherapy because it raises second cancer risk in the field.
• Trilateral disease and metastasis: high dose chemotherapy with stem cell rescue in specialist care.
• Lifelong follow up: education about new lumps and bone pain, and avoidance of ultraviolet and tobacco.
• Genetic counselling: 50% risk for each child of a carrier, with prenatal or early testing options.

Special groups.

• Unilateral disease with a negative blood test: low risk of germline disease, but mosaicism is possible, so tumour analysis is useful.

Monitoring. Eye examination every 3 months in the first year and every 6 months afterwards until at least 5 to 7 years. Review for second cancers yearly, with MRI of the brain at intervals in the first years when trilateral disease is a concern.

Referral and escalation. Urgent same week referral to a retinoblastoma service for leukocoria or squint in an infant. Emergency for orbital swelling, neurological signs or bone pain.