Version July 2025
INTRODUCTION —
Loss of functional retinoblastoma (Rb1) protein predisposes to retinoblastoma in the developing retina. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis".)
Genetic variants in the RB1 gene can be somatically acquired or carried in the germline. Testing deoxyribonucleic acid (DNA) from peripheral blood lymphocytes (and including tumor tissue when available) is performed in all children with retinoblastoma.
This monograph summarizes the interpretation of germline RB1 analysis. It does not discuss indications for testing. This and other considerations such as somatic RB1 mutations in cancer are discussed separately [1]. (See 'Resources' below.)
OVERVIEW
How to read the report — The tables summarize genetic testing caveats (table 1) and provide a glossary of selected terms (table 2).
Pathogenicity is classified into five categories, from pathogenic to benign. The classification reflects the confidence that the variant is associated with disease, not disease likelihood or severity.
Caveats specific to RB1 testing include:
●Likelihood of germline variant – Children with bilateral retinoblastoma are presumed to have a germline pathogenic variant in RB1. Children with unilateral retinoblastoma have a 15 percent chance of carrying a germline RB1 variant.
●RB1 gene versus chromosomal region – RB1 function can be disrupted by a variant within the gene or loss of a large chromosome 13 segment that includes RB1, such as 13q deletion syndrome.
Other types of testing besides DNA sequencing should be considered, such as (table 3):
•Fluorescence in situ hybridization (FISH) for RB1
•Quantitative DNA analysis of coding exons of RB1
•Whole genome chromosomal microarray
Each method may miss specific types of variants, especially if germline mosaicism is present. Review with a genetics expert or ocular oncologist is important to ensure appropriate and complete testing.
●De novo versus inherited – Most germline RB1 variants arise de novo (new in the affected individual) rather than being inherited from a parent. A negative family history cannot be used to exclude a germline variant.
●Mosaic variants – Germline variants are typically present in all cells of the body. Rarely, a mutation occurs later in development and is only present in a portion of cells, termed a mosaic variant. Mosaicism is a de novo mechanism; parents and siblings do not require testing. However, the variant may be passed on to the individual's offspring.
RB1 genetics — RB1 was the first tumor suppressor to be molecularly defined [2]. The pRB protein is a target of cyclin-dependent kinases that regulate the G1 to S cell cycle transition and protect cells from replicating DNA prematurely.
RB1 can be inactivated by single nucleotide variants, small insertions or deletions (in/dels), intragenic deletions or duplications, or whole gene deletions involving RB1 or a larger region of chromosome 13 (13q deletion). Promoter hypermethylation can also occur.
Inactivation of both RB1 alleles (one from each parent) is generally required for tumorigenesis.
●Individuals with heritable retinoblastoma (germline disease) are born with one RB1 variant in all or many of their cells; somatic inactivation of the second allele in developing retinal tissue (a "second hit") leads to retinoblastoma, which can be unilateral, bilateral, or trilateral (bilateral retinoblastoma plus an intracranial tumor of similar histology) [2].
●In sporadic retinoblastoma, both hits occur in the retina only (somatic disease), and the alteration causes a single tumor. The RB1 variant cannot cause other tumors nor be passed to the individual's future offspring since the alteration is not in the germline.
●Biallelic germline RB1 inactivation is incompatible with life.
Of patients with retinoblastoma and germline RB1 loss, approximately 10 percent also have a positive family history (referred to as familial retinoblastoma). Another 30 percent have a sporadic (de novo) germline variant, which is heritable. Another 60 percent of patients have inactivation of both RB1 alleles only in somatic tumor cells that is not heritable and cannot be transmitted to their children.
Heritable retinoblastoma — Individuals with heritable retinoblastoma are at risk for ocular and extraocular tumors. Retinomas (benign tumors that spontaneously regress) are extremely rare. Malignant tumors (eg, melanoma, several types of sarcoma) can develop later. (See 'Extraocular tumors' below.)
Retinoblastoma — Retinoblastoma is a malignant tumor of the developing retina. Untreated, it can destroy the eye, invade the orbit and nasal cavity, and metastasize to the lung, bone, liver, or brain. Survival is >95 percent with treatment if the tumor is confined to the eye; eye preservation depends on the disease stage. Prognosis decreases dramatically with extraocular disease. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Natural history'.)
●In a child with a germline pathogenic variant in RB1 (regardless of whether the variant is familial or a new sporadic germline variant), the likelihood of developing retinoblastoma is 95 to 100 percent. The risk of ipsilateral and contralateral tumors is high. Tumors develop in infancy or early childhood, often before one year and nearly always before seven years [3-5].
●Knowing whether germline disease is present is paramount for risk assessment, surveillance, and screening of relatives. (See 'Relatives and reproductive counseling' below.)
•All children with retinoblastoma with a positive family history and/or bilateral (or trilateral) disease will have a germline pathogenic variant in RB1. Trilateral disease refers to bilateral retinoblastoma plus an intracranial tumor of similar histology).
•Up to 15 percent of children with unilateral disease also have a germline RB1 variant. The common and devastating misperception that these individuals cannot harbor a germline variant is incorrect and leads to poor follow-up and lack of surveillance for relatives and future offspring.
We perform genetic testing in all individuals with retinoblastoma, although some insurance policies will only cover testing in children with unilateral disease.
Extraocular tumors — The risk of extraocular tumors in heritable retinoblastoma is approximately 0.5 to 1 percent per year (20 percent risk by age 20 years) [4]. These include:
●Pineoblastoma (a pineal gland tumor), sometimes called "trilateral" retinoblastoma
●Sarcomas
•Osteosarcoma
•Rhabdomyosarcoma
•Leiomyosarcoma
•Angiosarcoma
•Fibrosarcoma of soft tissue
•Liposarcoma
●Melanoma
●Breast, skin, and lung cancer
Pineoblastoma may be diagnosed concurrently or within a few years of retinoblastoma. Other tumors generally occur later; risk may be further increased by exposure to ionizing radiation or ultraviolet light.
CANCER TREATMENT —
The following general principles may apply; individual decisions are made by an ocular oncologist and a multidisciplinary team who can fully evaluate the patient and determine the best treatment [5,6]:
●Retinoblastoma
•Early detection is essential; retinoblastoma that has spread outside the globe has a much worse prognosis than disease confined to the intraocular space [4]. (See "Retinoblastoma: Treatment and outcome".)
•Multidisciplinary involvement is used for planning and coordination of care, evaluation of extent of disease, and optimal therapy.
•Treatment that optimizes long-term patient survival is paramount. Saving the eye and preserving vision are secondary and tertiary priorities.
•Radiation therapy is avoided if possible as it increases the risk of secondary tumors. Radiation is generally reserved for relapsed disease in the remaining eye and is now infrequently used.
•For heritable retinoblastoma, lifelong follow-up is required to assess for complications of therapy, ensure adequate surveillance for other cancers, and provide appropriate genetic counseling and psychosocial care. (See 'Cancer surveillance' below.)
●Extraocular tumors – Management should be coordinated by an expert in the specific tumor type (eg, sarcoma or melanoma expert). Specialists should be informed that the individual has a germline pathogenic variant in RB1.
●Additional testing – When indicated, testing of the tumor or other tissues is sent by the specialist managing the patient.
•Tumor testing – Clinical guidelines specify genetic testing of the tumor when an eye has been removed (enucleated) as part of treatment. This is seldom possible since most patients are treated with a globe-sparing approach.
•Liquid biopsy – Advances in molecular diagnostics have facilitated the detection of circulating tumor DNA in other fluids such as blood or aqueous humor [7-9]. Laboratories certified by the College of American Pathologists (CAP) or Clinical Laboratory Improvement Amendments (CLIA) are beginning to use these tests.
Use of aqueous humor to identify tumor-derived RB1 variants increases the sensitivity and specificity of blood-based testing.
When tumor tissue or tumor DNA from a liquid biopsy source is available, genetic testing can identify biallelic inactivating variants in RB1 if present, including a possible germline variant. Negative germline testing when the tumor variant(s) are uncharacterized must be interpreted with caution due to a small risk (<1 percent) of a false negative test.
CANCER SURVEILLANCE
Individuals with a germline pathogenic variant — The approach to cancer surveillance depends on the level of risk, which is based on the specific variant and phenotype in the family. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Screening children at risk'.)
All at-risk individuals should undergo ophthalmic surveillance for retinoblastoma and imaging for pineoblastoma during early childhood, as summarized in the table (table 4). This is often best done by a multisubspecialty team with expertise in retinoblastoma management.
●Physical examination – Dilated funduscopic examination is performed starting at birth, with intervals and need for examination under anesthesia based on risk category, which is based on a 2018 consensus report from the American Association of Ophthalmic Oncologists and Pathologists (AAOOP) [6]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Screening children at risk'.)
●Imaging – Brain magnetic resonance imaging (MRI), including pineal images in patients with a germline RB1 variant, is started at three months and continued every six months to age three to five years, depending on the center. MRI is preferred over computed tomography (CT) to avoid radiation exposure. Some centers (in Europe and other regions) omit brain MRI.
There are no routine imaging recommendations for older children and adults, for whom imaging confers risks and burdens and has not been shown to improve outcomes. However, regular examinations (including full skin assessments) are important. The clinician should have a low threshold to further evaluate symptoms or findings that are suggestive of a malignancy, such as unexplained pain or swelling. Ideally, follow-up should occur in a cancer survivorship clinic.
Individuals with a VUS — Individuals who have a germline variant of uncertain significance (VUS) in RB1 are evaluated based on their personal and family history. Variant interpretation should be re-evaluated periodically to determine if its significance has been clarified based on additional research.
Individuals with negative germline testing — Individuals with unilateral retinoblastoma who lack a germline RB1 variant can be spared additional surveillance for retinoblastoma in the contralateral eye and associated secondary tumors. These individuals do not require preconception counseling or testing of their children, with the caveats that, without tumor testing, there is a small (<1 percent) risk of a false negative test, and offspring should have ophthalmic screening.
CANCER RISK REDUCTION —
Strategies to reduce cancer risk include (table 4):
●Healthy diet
●Avoiding radiation exposure
●Avoiding DNA-damaging agents such as cigarette smoke and alcohol
RELATIVES AND REPRODUCTIVE COUNSELING
Testing in relatives — If a child has heritable retinoblastoma, first-degree relatives should be tested for that child's RB1 variant (algorithm 1). A heritable syndrome due to a germline pathogenic variant in RB1 may be seen in individuals with unilateral, bilateral, or trilateral retinoblastoma. (See 'Heritable retinoblastoma' above.)
The parents can be evaluated by an ophthalmologist for retinomas (benign retinal tumors) but should undergo genetic testing for the variant regardless of ophthalmic findings.
If a parent carries the same RB1 variant as the affected child, all the child's siblings should be tested. The parent's siblings should consider testing as well.
If a familial RB1 variant is known and a relative tests negative for that specific variant, they can be reassured that they are not at increased risk for familial retinoblastoma.
Reproductive counseling — For individuals with a germline RB1 variant, reproductive counseling is appropriate to review the risk that a future child will be affected and to discuss reproductive options such as:
●In vitro fertilization (IVF) with preimplantation genetic testing (PGT)
●Donor gametes (egg or sperm)
●Adoption
Individuals who do not use PGT or donor gametes may have prenatal testing (chorionic villus sampling or amniocentesis). Others may pursue genetic testing and ophthalmic surveillance once the child is born. This should be done promptly after birth because retinoblastoma can form in utero.
A child who tests positive for the familial variant is at risk for retinoblastoma; in some cases, tumors can develop before birth. Ophthalmic examination is recommended as soon as possible after birth, with prenatal and postnatal care coordinated among a high-risk obstetrician, geneticist, and ocular oncologist to determine the best surveillance approach. Some specialists suggest early delivery, whereas others believe the benefits may not outweigh the risks and burdens of preterm birth. (See 'Individuals with a germline pathogenic variant' above.)
RESOURCES
UpToDate topics and NCI information
●Retinoblastoma – (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis" and "Retinoblastoma: Treatment and outcome".)
●Chromosome 13q deletion – (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '13q14 deletion syndrome (Retinoblastoma syndrome)'.)
●Reproductive options:
•(See "Preimplantation genetic testing".)
•(See "Donor insemination".)
•(See "Adoption".)
●National Cancer Institute (NCI) Physician Data Query (PDQ) document for retinoblastoma [10]
Locating a specialist
•Genetic counselors – National Society of Genetic Counselors (NSGC)
•Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
•Retinoblastoma treatment centers – One retinoblastoma world database
