Pediatric Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening P Current Version Rule-Out Dashboard Release History Status (Pediatric): Passed (Consensus scoring is Complete) Curation Status (Pediatric): Released

Condition: Retinoblastoma
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
RB10008380 (retinoblastoma; rb1)
Assertion Pending
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: RB10008380
Morbidity or mortality from retinoblastoma / Surveillance
Morbidity or mortality from second extra-ocular malignant neoplasms / Surveillance
2N 1
1. Extrapolated based on evidence from Li-Fraumeni syndrome.
a. To see the scoring key, please go to :

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Retinoblastoma (Rb) is the most common intraocular tumor in children and is estimated to occur in 1 of 15,000 –20,000 live births.
1 2 3 4 5 6
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.
1 2 5 6
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).
1 2 5 6
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
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)
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)
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)
1 4
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)
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)
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.
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)
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)
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)
1 2 5 12
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)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
1 3 5 13
Prevalence of Genetic Mutations
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)
2 3 5 6
(Include any high risk racial or ethnic subgroups)
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)
1 3 5 6
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)
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)
Relative Risk
(Include any high risk racial or ethnic subgroups)
No information exists on relative risk or odds ratio of Rb development in individuals with pathogenic RB1 variants. (Tier 3)
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)
4. What is the Nature of the Intervention?
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.
1 4 5
WBRMI surveillance for osteosarcoma among retinoblastoma survivors may result in psychological distress for patients and their families.
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.
1 5 6 14
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
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. (Tier 2)
1 4
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 Disease Associations
Disease Associations
Primary MONDO Identifier
Additional MONDO Identifiers
OMIM Identifier
Reference List
1. National Retinoblastoma Strategy Canadian Guidelines for Care: Strategie therapeutique du retinoblastome guide clinique canadien. Can J Ophthalmol. (2009) 44 Suppl 2:S1-88.
2. de Graaf P, Goricke S, Rodjan F, Galluzzi P, Maeder P, Castelijns JA, Brisse HJ. Guidelines for imaging retinoblastoma: imaging principles and MRI standardization. Pediatr Radiol. (2012) 42(1):2-14.
3. Lohmann D, Gallie B, Dommering C, Gauthier-Villars M. Clinical utility gene card for: retinoblastoma. Eur J Hum Genet. (2011) 19(3).
4. Skalet AH, Gombos DS, Gallie BL, Kim JW, Shields CL, Marr BP, Plon SE, Chevez-Barrios P. Screening Children at Risk for Retinoblastoma: Consensus Report from the American Association of Ophthalmic Oncologists and Pathologists. Ophthalmology. (2018) 125(3):453-458.
5. DR Lohmann, BL Gallie. Retinoblastoma. 2000 Jul 18 [Updated 2015 Nov 19]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from:
6. Aerts I, Lumbroso-Le Rouic L, Gauthier-Villars M, Brisse H, Doz F, Desjardins L. Retinoblastoma. Orphanet J Rare Dis. (2006) 1:31.
7. Yu CL, Tucker MA, Abramson DH, Furukawa K, Seddon JM, Stovall M, Fraumeni JF Jr, Kleinerman RA. Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst. (2009) 101(8):581-91.
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. Retinoblastoma and Neuroblastoma Predisposition and Surveillance. Clin Cancer Res. (2017) 23(13):e98-e106.
9. Friedman DN, Lis E, Sklar CA, Oeffinger KC, Reppucci M, Fleischut MH, Francis JH, Marr B, Abramson DH, Dunkel IJ. Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a pilot study. Pediatr Blood Cancer. (2014) 61(8):1440-4.
10. 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. Baseline Surveillance in Li-Fraumeni Syndrome Using Whole-Body Magnetic Resonance Imaging: A Meta-analysis. JAMA Oncol. (2017) 3(12):1634-1639.
11. 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. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. (2016) 17(9):1295-305.
12. Gallie BL, Budning A, DeBoer G, Thiessen JJ, Koren G, Verjee Z, Ling V, Chan HS. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol. (1996) 114(11):1321-8.
13. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. RETINOBLASTOMA; RB1. MIM: 180200: 2016 Aug 04. World Wide Web URL:
14. The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma. Brachytherapy. (2014) 13(1):1-14.
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