Retinoblastoma

Actionability Pediatric Summary Report

Gene: RB1 (HGNC:9884)
Mode(s) of Inheritance:Autosomal Dominant
Literature Search: 04/30/2018
Curation Status: Released (1.3.4)
Release History
Related Reports
Adult Summary Report: (1.0.2)

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
RB1 retinoblastoma (0008380) 180200 Strong Actionability

Actionability Assertion Rationale

  • All experts agreed with the assertion computed according to the rubric. The actionability is well established, but the assertion does not meet the criteria for definitive due to lack of data from an unselected population.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
Morbidity or mortality from retinoblastoma / Surveillance 2 3C 3B 2 10CB
Morbidity or mortality from second extra-ocular malignant neoplasms / Surveillance 2 2C 2N 3 9CN
View scoring key
Domain of Actionability Scoring Metric State of the Knowledgebase
Severity: What is the nature of the threat to health to an individual? 3 = Sudden death as a reasonably possible outcome
2 = Reasonable possibility of death or major morbidity
1 = Modest morbidity
0 = Minimal or no morbidity 		N/A
Likelihood: What is the chance that the outcome will occur? 3 = >40% chance
2 = 5%-39% chance
1 = 1%-4% chance
0 = <1% chance 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Effectiveness: What is the effectiveness of a specific intervention in preventing or diminishing the risk of harm? 3 = Highly effective
2 = Moderately effective
1 = Minimally effective
0 = Controversial or unknown effectiveness
IN = Ineffective/No interventiona 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Nature of intervention: How risky, medically burdensome, or intensive is the intervention? 3 = Low risk, or medically acceptable and low intensity
2 = Moderate risk, moderately acceptable or intensive
1 = Greater risk, less acceptable and substantial intensity
0 = High risk, poorly acceptable or intensive 		N/A
a Do not score the remaining categories

Prevalence of the Genetic Condition

Retinoblastoma (Rb) is the most common intraocular tumor in children and is estimated to occur in 1 of 15,000 –20,000 live births.
View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, de Graaf P, et al. (2012) PMID: 21850471, Lohmann D, et al. (2011) PMID: 21150892, Skalet AH, et al. (2018) PMID: 29056300, DR Lohmann, et al. (2000) NCBI: NBK1452, Aerts I, et al. (2006) PMID: 16934146

Clinical Features (Signs / symptoms)

Rb is a is life- and vision-threatening childhood cancer. Roughly 60% of affected individuals have a unilateral Rb (if one eye is affected), which is usually unifocal. Roughly 40% have bilateral Rb (if both eyes are affected). Some cases are trilateral where bilateral Rb (or rarely unilateral) and a pinealoblastoma co-occur. The most common Rb presenting sign is a white pupillary reflex (leukocoria). Strabismus is the second most common Rb presenting sign and may accompany or precede leukocoria. Rb patients can also present with both exotropia (eye turned outward, temporal) and esotropia (eye turned inward, nasal). Unusual Rb presenting signs include glaucoma, orbital cellulitis, uveitis, hyphema, or vitreous hemorrhage. Atypical manifestations are more frequent in older children. There is an increased risk for other specific extraocular primary neoplasms (collectively called second primary tumors) typically osteosarcomas, soft tissue sarcomas, or melanomas.
View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, de Graaf P, et al. (2012) PMID: 21850471, DR Lohmann, et al. (2000) NCBI: NBK1452, Aerts I, et al. (2006) PMID: 16934146

Natural History (Important subgroups & survival / recovery)

Individuals with unilateral and bilateral Rb have a mean diagnosis ages of 24 and 15 months, respectively. The majority of Rb cases are detected before 5 years. If left untreated, Rb is fatal. With timely screening, diagnosis, referral, treatment, and follow-up delivered in a systematic way by a multidisciplinary team, 95 – 98% of children with Rb are cured, many with useful vision. Ocular survival rate is significantly lower when the presenting sign is leukocoria (8.5% over 5 years), rather than strabismus (17% over 5 years). Prognosis of trilateral Rb remains poor, with most patients dying from progressive disease within 2 years of diagnosis.Second primary tumors usually manifest in adolescence or adulthood and are associated with a cumulative mortality rate of 17% and cumulative incidence of 28% within 40 years in survivors of hereditary Rb. The incidence is increased to more than 50% in individuals with Rb who have received external beam radiation therapy (EBRT).
View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, de Graaf P, et al. (2012) PMID: 21850471, DR Lohmann, et al. (2000) NCBI: NBK1452, Aerts I, et al. (2006) PMID: 16934146

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Mode of Inheritance

Autosomal Dominant
View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, Lohmann D, et al. (2011) PMID: 21150892, DR Lohmann, et al. (2000) NCBI: NBK1452, Online Medelian Inheritance in Man. (2016) OMIM: 180200

Prevalence of Genetic Variants

< 1-2 in 100000
The incidence of retinoblastoma is 1 in 15,000–20,000 live births. In 60% of cases Rb is unilateral and of these, 15% are caused by RB1 pathogenic variants. In 40% of cases, Rb is bilateral and all of these cases are attributable to RB1 pathogenic variants. Therefore, the population prevalence of unilateral and bilateral retinoblastoma attributable to RB1 pathogenic variants is 3/500,000 – 9/2,000,000 and 4/150,000 – 2/100,000, respectively.
Tier 3 View Citations

de Graaf P, et al. (2012) PMID: 21850471, Lohmann D, et al. (2011) PMID: 21150892, DR Lohmann, et al. (2000) NCBI: NBK1452, Aerts I, et al. (2006) PMID: 16934146

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %
Germinal RB1 mutations with a high penetrance rate (> 90%) concern all patients with bilateral retinoblastoma as well as 15% of patients with the unilateral form.
Tier 3 View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, Lohmann D, et al. (2011) PMID: 21150892, DR Lohmann, et al. (2000) NCBI: NBK1452, Aerts I, et al. (2006) PMID: 16934146

5-39 %
Fewer than 10% of families show a “low penetrance” phenotype with reduced expressivity (i.e., increased prevalence of unilateral Rb) and incomplete penetrance (i.e., ≤25%).
Tier 4 View Citations

DR Lohmann, et al. (2000) NCBI: NBK1452

>= 40 %
The risk of second malignant neoplasms is about 20% in individuals with Rb who have not received radiotherapy and substantially higher (40-50%) in those that have been irradiated.
Tier 3 View Citations

Kamihara J, et al. (2017) PMID: 28674118

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown
No information exists on relative risk or odds ratio of Rb development in individuals with pathogenic RB1 variants.
Tier 3 View Citations

Online Medelian Inheritance in Man. (2016) OMIM: 180200

Expressivity

There are 3 expression patterns of the RB1 gene: unilateral or bilateral retinoblastoma, retinoma, or no visible retinal pathology except for “normal degeneration” with age.
Tier 3 View Citations

Online Medelian Inheritance in Man. (2016) OMIM: 180200

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Patient Management

Specialized treatment centers with multidisciplinary teams of specialists including an RB specialist, ophthalmology, pediatric oncology, anesthetist, ocularist, pathology, radiation oncology, and social worker/psychosocial support are critical for the care of children and families with Rb, given the complex treatment required to deliver positive outcomes. With timely screening, diagnosis, referral, treatment, and follow-up delivered in a systematic way by a multidisciplinary team, 95 – 98% of children with Rb are cured, many with useful vision.
Tier 2 View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571

Subsequent malignant neoplasms are a major cause of premature death in survivors of hereditary retinoblastoma. A recent retrospective cohort study conducted in the United States found that cumulative mortality from subsequent malignant neoplasms at 50 years after retinoblastoma diagnosis was 25.5% (95% CI = 20.8% to 30.2%) for hereditary retinoblastoma survivors and 1.0% (95% CI = 0.2% to 1.8%) for nonhereditary retinoblastoma survivors.
Tier 5 View Citations

Yu CL, et al. (2009) PMID: 19351917

Surveillance

Clinical screening, including examination by an ophthalmologist with experience in Rb, begins at birth and is lifelong. Screening is initiated with examination by an ophthalmologist with experience in Rb beginning at birth and going to 5 years of age, by way of the red reflex test and the Hirschberg test. If these tests yield abnormal results, it is recommended that a pediatric anesthetist provide frequent examinations under anesthesia (EUAs). Early diagnosis, when tumors are small, maximizes survival and vision outcomes and reduces the need for chemotherapy, enucleation, and radiotherapy. A retrospective study compared outcomes of 18 probands with Rb and 26 nonproband family members who underwent screening due to increased risk and reported that probands compared to nonprobands were diagnosed later (17 months vs 8 months, respectively), were less likely to have an early intraocular stage (group A or B) at diagnosis (3% vs 58%, respectively), were more likely to have one eye enucleated (100% vs 20%, respectively), more likely to have affected eyes radiated (32% vs 9%, respectively), less likely to have visual acuity more than 0.5 (26% vs 50%, respectively), and less likely to salvage the eye (45% vs 80%, respectively), indicating that screening in nonprobands led to earlier diagnosis and better outcomes.
Tier 2 View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, Skalet AH, et al. (2018) PMID: 29056300

No established screening protocols exist for early detection of second primary tumors in hereditary Rb. However, given the increased risks for bone and soft-tissue sarcomas, one guideline recommends an annual physical exam, potentially through a long-term survivor clinic, as well as education about signs and symptoms. Annual whole-body MRI (WBMRI) could be considered, which (if done) would be most appropriate after age 8 to 10 when the child is able to tolerate the study without the risks of general anesthesia. This should be performed in the context of a prospective study when feasible, as further data are needed to understand the value of this modality in surveillance among Rb survivors.
Tier 2 View Citations

Kamihara J, et al. (2017) PMID: 28674118

A pilot study evaluated WBMRI for detection of osteosarcoma among 25 Rb survivors. WBMRI detected new osseous abnormalities suspicious for malignancy in 5 patients, with 2 diagnosed with osteosarcoma and one diagnosed with osteosarcoma 3 months after a normal scan. Among a total of 41 WBMRI screening tests performed, the sensitivity of detecting a secondary neoplasm was 66.7% with a specificity of 92.1%. The positive predictive value was 0.4 and the negative predictive value was 0.97.
Tier 5 View Citations

Friedman DN, et al. (2014) PMID: 24402721

NB: We are providing the following information to show that the source is not directly related to the gene-disease pair in question. The following editorial comments explain evidence, not contained in the sources below. Evidence for effectiveness of WBMRI for detection of second primary tumors is not available. LFS patients have some tumor type overlap with pediatric retinoblastoma secondary neoplasms. The penetrance of secondary neoplasms in retinoblastoma is not known but is likely to be lower than in LFS. Therefore, we reviewed studies that were related to WBMRI in LFS.
View Citations

A meta-analysis evaluated WBMRI among 578 individuals with Li Fraumeni syndrome (mean age=33.2 years, SD=17.1 years) across 13 prospective cohorts where a WBMRI was administered as part of a baseline assessment with all participants asymptomatic at the time of the baseline scan and not required to be newly diagnosed. Cancer was identified in 7% of the sample, with 83% of cancers being localized and able to treat with curative intent.
Tier 5 View Citations

Ballinger ML, et al. (2017) PMID: 28772291

In addition, an 11-year prospective observational study reported outcomes of a clinical surveillance protocol using physical examination and frequent biochemical and imaging studies, including WBMRI among children and adults with Li Fraumeni syndrome, where 40 chose to undergo surveillance and 40 declined surveillance (19 crossed over to the surveillance group for a total of 59 undergoing surveillance). The 5-year overall survival was 88.8% (95% CI: 78.7–100) in the surveillance group and 59.6% (95% CI: 47.2–75.2) in the non-surveillance group (p=0.0132).
Tier 5 View Citations

Villani A, et al. (2016) PMID: 27501770

Circumstances to Avoid

Radiation should be avoided due to the increased risk of primary secondary tumors. Thus MRI of the head and orbits is preferred over CT scan to image Rb upon presentation due to increased image resolution and avoidance of radiation. Conservative treatment strategies that avoid radiotherapy can be successful in the early stages of retinoblastoma and in some patients with advanced intraocular disease. In a cohort of 963 patients with hereditary Rb, the risk of a subsequent cancer was elevated 3.1-fold (95% CI: 2-5.3) in those exposed to radiation (standardized incident ratio or SIR: 22, 95% CI: 19-24) compared to those not exposed to radiation (SIR: 6.9, 95% CI: 4.1-11). In addition, radiotherapy increased the cumulative probability of developing a second cancer to 38.2% (95% CI: 32.6-43.8%) at 50 years compared to 21.0% (95% CI: 9.4-35.6%) for nonirradiated patients.
Tier 2 View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, de Graaf P, et al. (2012) PMID: 21850471, DR Lohmann, et al. (2000) NCBI: NBK1452, Gallie BL, et al. (1996) PMID: 8906022

In addition to radiotherapy, patients should also limit exposure to other DNA-damaging agents (tobacco, UV light) due to the increased risk of primary secondary tumors.
Tier 3 View Citations

DR Lohmann, et al. (2000) NCBI: NBK1452

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Nature of Intervention

Surveillance by way of dedicated ophthalmic screening is recommended for all children at risk for retinoblastoma and is stratified on the basis of high, intermediate and low risk. Although surveillance is not invasive, examination schedules are frequent and life-long.
Context: Pediatric
View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, Skalet AH, et al. (2018) PMID: 29056300, DR Lohmann, et al. (2000) NCBI: NBK1452

WBRMI surveillance for osteosarcoma among retinoblastoma survivors may result in psychological distress for patients and their families.
Context: Pediatric
View Citations

Friedman DN, et al. (2014) PMID: 24402721

If possible, it is recommended to avoid radiotherapy, except in cases where other methods have failed, to avoid the increased risk of a second non-ocular cancer and serious adverse effects. Other treatments include transpupillary thermotherapy, laser photocoagulation and cryotherapy, chemotherapy and enucleation. Enucleation is used only in extreme intraocular cases but results in the complete loss of eyesight in the removed eye(s). Depending on the agent used, complications of chemotherapy can include ototoxicity, nephrotoxicity, secondary non-Rb cancer, and neuropathy.
Context: Pediatric
View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, DR Lohmann, et al. (2000) NCBI: NBK1452, Aerts I, et al. (2006) PMID: 16934146, American Brachytherapy Society - Ophthalmic Oncology Task Force. Electronic address: paulfinger@eyecancer.com, et al. (2014) PMID: 24373763

Chance to Escape Clinical Detection

Early diagnosis, when tumors are small, maximizes survival and vision outcomes and reduces the need for chemotherapy, enucleation and radiotherapy. For individuals with a positive family history who undergo clinical surveillance via serial retinal examinations, tumors are often identified in the first month of life.
Context: Pediatric
Tier 2 View Citations

Canadian Retinoblastoma Society, et al. (2009) PMID: 20237571, Skalet AH, et al. (2018) PMID: 29056300

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers
RB1 180200 0008380

References List

Aerts I, Lumbroso-Le Rouic L, Gauthier-Villars M, Brisse H, Doz F, Desjardins L. (2006) Retinoblastoma. Orphanet journal of rare diseases. 1(1750-1172):31.

American Brachytherapy Society - Ophthalmic Oncology Task Force. Electronic address: paulfinger@eyecancer.com, ABS – OOTF Committee. (2014) The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma. Brachytherapy. 13(1):1-14.

Ballinger ML, Best A, Mai PL, Khincha PP, Loud JT, Peters JA, Achatz MI, Chojniak R, Balieiro da Costa A, Santiago KM, Garber J, O'Neill AF, Eeles RA, Evans DG, Bleiker E, Sonke GS, Ruijs M, Loo C, Schiffman J, Naumer A, Kohlmann W, Strong LC, Bojadzieva J, Malkin D, Rednam SP, Stoffel EM, Koeppe E, Weitzel JN, Slavin TP, Nehoray B, Robson M, Walsh M, Manelli L, Villani A, Thomas DM, Savage SA. (2017) Baseline Surveillance in Li-Fraumeni Syndrome Using Whole-Body Magnetic Resonance Imaging: A Meta-analysis. JAMA oncology. 3(12):1634-1639.

Canadian Retinoblastoma Society. (2009) National Retinoblastoma Strategy Canadian Guidelines for Care: Strategie therapeutique du retinoblastome guide clinique canadien. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. 44 Suppl 2(1715-3360):S1-88.

de Graaf P, Goricke S, Rodjan F, Galluzzi P, Maeder P, Castelijns JA, Brisse HJ. (2012) Guidelines for imaging retinoblastoma: imaging principles and MRI standardization. Pediatric radiology. 42(1):2-14.

DR Lohmann, BL Gallie. Retinoblastoma. (2000) [Updated Nov 19 2015]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1452/

Friedman DN, Lis E, Sklar CA, Oeffinger KC, Reppucci M, Fleischut MH, Francis JH, Marr B, Abramson DH, Dunkel IJ. (2014) Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a pilot study. Pediatric blood & cancer. 61(8):1440-4.

Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, Ling V, Chan HS. (1996) Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Archives of ophthalmology (Chicago, Ill. : 1960). 114(11):1321-8.

Kamihara J, Bourdeaut F, Foulkes WD, Molenaar JJ, Mosse YP, Nakagawara A, Parareda A, Scollon SR, Schneider KW, Skalet AH, States LJ, Walsh MF, Diller LR, Brodeur GM. (2017) Retinoblastoma and Neuroblastoma Predisposition and Surveillance. Clinical cancer research : an official journal of the American Association for Cancer Research. 23(13):e98-e106.

Lohmann D, Gallie B, Dommering C, Gauthier-Villars M. (2011) Clinical utility gene card for: retinoblastoma. European journal of human genetics : EJHG. 19(3).

RETINOBLASTOMA; RB1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 180200, (2016) World Wide Web URL: http://omim.org/

Skalet AH, Gombos DS, Gallie BL, Kim JW, Shields CL, Marr BP, Plon SE, Chevez-Barrios P. (2018) Screening Children at Risk for Retinoblastoma: Consensus Report from the American Association of Ophthalmic Oncologists and Pathologists. Ophthalmology. 125(3):453-458.

Villani A, Shore A, Wasserman JD, Stephens D, Kim RH, Druker H, Gallinger B, Naumer A, Kohlmann W, Novokmet A, Tabori U, Tijerin M, Greer ML, Finlay JL, Schiffman JD, Malkin D. (2016) Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. The Lancet. Oncology. 17(9):1295-305.

Yu CL, Tucker MA, Abramson DH, Furukawa K, Seddon JM, Stovall M, Fraumeni JF Jr, Kleinerman RA. (2009) Cause-specific mortality in long-term survivors of retinoblastoma. Journal of the National Cancer Institute. 101(8):581-91.

Early Rule-Out Summary

This topic did not pass the early rule out stage due to insufficient evidence for actionability. However, the Actionability Working Group discussed and granted an exception to move this topic forward for a full evidence curation and summary report.

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is there an intervention that is initiated during childhood (<18 years of age) in an undiagnosed child with the genetic condition?
  4. Does the disease present outside of the neonatal period?
  5. Is this condition an important health problem?
  6. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?