Is Retinoblastoma Hereditary? RB1 Testing, Family Screening and Lifelong Care

"Is retinoblastoma hereditary?" is one of the first questions parents ask after the diagnosis — for the sake of their other children, and later for the child's own future family. The answer is: sometimes. About 4 in 10 children have a heritable form, and knowing which form your child has changes how brothers and sisters are screened, how the eye cancer is treated and how your child's health is followed for life.

Is retinoblastoma hereditary?

The RB1 gene, on chromosome 13, makes a protein that stops cells from dividing when they should not. Everyone has two copies, and retinoblastoma develops when both stop working in a developing retinal cell. What matters for the family is where the first change happens:

• Heritable retinoblastoma. The first change — a germline variant — is present in every cell of the body, either inherited from a parent or, far more often, arising new in the egg, the sperm or very early in development. Only one more change is then needed in a retinal cell, so tumors often appear in both eyes and at a younger age.
• Non-heritable retinoblastoma. Both changes happen by chance in a single retinal cell, so there is usually one tumor in one eye, and it cannot be passed on.

The American Cancer Society puts the heritable share at about 4 in 10 children (other sources give 25–40%). It includes every child with tumors in both eyes and about 15% of children with one eye affected, and about 9 in 10 of these children have no family history.

A few situations are less straightforward. In mosaicism, the change arose after conception and is present in only some cells; it is found in about 5.5% of children with bilateral and 3.8% with unilateral retinoblastoma. A 13q deletion removes a piece of chromosome 13 including RB1, often with developmental delay. In about 1.5% of children with a single tumor in one eye, the tumor is driven by the MYCN gene with normal RB1 — a non-heritable form. A retinoma is a benign, non-growing form that still involves RB1 and has the same implications for testing.

How does RB1 genetic testing work?

Testing starts with the affected child, usually from a blood sample. Sequencing finds about 80% of disease-causing variants, and tests for missing or duplicated pieces of the gene find most of the rest; together, standard methods identify the variant in more than 90% of children with the heritable form. If an eye has been removed, testing the tumor itself shows which two RB1 changes caused it, so the laboratory can then look for them in the blood — especially helpful in unilateral disease and for detecting mosaicism. Testing tumor DNA in a tiny sample of fluid from the front of the eye (an aqueous humor "liquid biopsy") is a promising research approach, not yet routine.

The result sets the H category in retinoblastoma staging — H1 when a germline variant is present, H0 when high-sensitivity testing finds normal RB1 — and allows cascade testing: parents, brothers and sisters can be tested for the child's specific change. A negative blood test in unilateral retinoblastoma lowers the chance of the heritable form considerably but does not remove it entirely, so the other eye is still examined.

What is the risk for brothers, sisters and future children?

When a germline RB1 variant is present, each child of the carrier has a 50% chance of inheriting it, and for most variant types more than 99% of those who inherit it develop retinoblastoma. Fewer than 10% of families carry "low-penetrance" variants, which cause fewer tumors; some carriers never develop one.

For a family with no previous history, before genetic results are available, the U.S. National Cancer Institute gives these estimates:

GeneReviews gives similar figures of about 1–2% for brothers and sisters. If a parent has had retinoblastoma or carries the family variant, each brother or sister has a 50% chance of inheriting it. After testing, relatives shown not to carry the family variant generally no longer need retinoblastoma screening; your genetics team will confirm what applies to your family.

How are brothers, sisters and babies screened?

Small children cannot report poor vision, so at-risk children are examined before any sign appears. The first dilated eye examination takes place within the first month of life, sometimes under anesthesia. For children who carry a germline RB1 variant, GeneReviews recommends:

Until testing shows that a brother, sister or newborn does not carry the family variant, they are usually examined on a similar schedule; anesthesia is used when the retina cannot be fully seen awake or a tumor is suspected. Schedules vary between centers. Children with the heritable form also have about a 5% risk of trilateral retinoblastoma, a related tumor in the midline of the brain, most often between about 20 and 36 months of age; some centers perform brain MRI every 6 months for up to 5 years.

Planning a family. Adults who had retinoblastoma, especially the heritable form, benefit from genetic counseling before planning children. Once the family variant is known, options may include early screening of the newborn, prenatal testing and preimplantation genetic testing with in-vitro fertilization; availability and regulations differ between countries.

Why does the heritable form raise the risk of other cancers?

Because every cell carries one non-working copy of RB1, people with heritable retinoblastoma have a higher lifelong risk of second primary cancers — most often bone cancer (osteosarcoma), soft-tissue sarcomas, melanoma and brain tumors — sometimes decades later. In high-income countries these, together with trilateral retinoblastoma, have replaced metastasis as the main causes of death among survivors. The American Academy of Ophthalmology cites a risk of about 25% within 50 years for heritable survivors even without radiotherapy.

External beam radiotherapy more than triples the risk, especially before age 1. This is why modern care relies on intra-arterial and intravitreal chemotherapy, laser, freezing and, where needed, removal of the eye, and why MRI is used instead of CT. Survivors should avoid radiation that is not medically necessary — an essential X-ray or CT scan should not be refused — and tell every doctor about their diagnosis.

What does lifelong survivorship care involve?

• Eye care: frequent examinations in early childhood, regular checks for life, and care of an artificial eye if one was removed (see enucleation and prosthesis).
• Effects of treatment: hearing tests after carboplatin, kidney tests, checks for nerve damage after vincristine and fertility counseling where relevant.
• Second cancers: prompt review of persistent bone pain or a new lump. Many survivorship programs also advise skin checks, not smoking and sun protection.
• A written treatment summary — diagnosis, genetic result, drugs, doses and any radiation — for every future doctor. Children's Oncology Group survivorship guidelines are widely used to plan these checks, and a U.S. National Cancer Institute study of more than 2,000 survivors continues to refine the advice.

Why is genetic counseling important?

Mosaicism, low-penetrance variants and negative results in unilateral cases need careful interpretation. A genetic counselor from the medical genetics team explains what the result means for the whole family, organizes testing of relatives and discusses family-planning options.

Prof. Türkoğlu reviews genetic results together with the eye findings — including when families send records for a second opinion — and uses them to plan examinations and treatment. See also our main retinoblastoma page and our guide to a white pupil in photos, the most common first sign.