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Review Article

Genetics of Retinoblastoma

Mallipatna, Ashwin MD; Marino, Meghan MS; Singh, Arun D. MD

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Asia-Pacific Journal of Ophthalmology: July/August 2016 - Volume 5 - Issue 4 - p 260-264
doi: 10.1097/APO.0000000000000219
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Retinoblastoma is a malignant retinal tumor that affects young children.1,2 Mutations in the RB1 gene cause retinoblastoma.3–5 Mutations in both RB1 alleles within the precursor retinal cell are essential, with one mutation that may be germline or somatic and the second one that is always somatic. Identification of the RB1 germline status of a patient allows differentiation between nonheritable (somatic) and heritable retinoblastoma variants. Application of this knowledge is crucial for assessing short-term (risk of additional tumors in the same eye and other eye) and long-term (risk of nonocular malignant tumors) prognosis and offering cost-effective surveillance strategies.6

Genetic testing and genetic counseling are therefore essential components of care for all children diagnosed with retinoblastoma. The American Joint Committee on Cancer has acknowledged the importance of detecting this heritable trait and has introduced the letter “H” to denote a heritable trait of all cancers, starting with retinoblastoma (in publication). In this article, we discuss the clinically relevant aspects of genetic testing and genetic counseling for a child with retinoblastoma.


Retinoblastoma is inherited in an autosomal dominant pattern. Each child born to a person with a germline RB1 mutation has a 50% risk of inheriting the mutation, as is characteristic of dominant inheritance. Although 90% of persons with a germline RB1 mutation will develop retinoblastoma (60% multifocal, 30% unifocal), the remaining 10% will not develop tumors and remain as unaffected carriers.1 Only 10% of children with unilateral or bilateral retinoblastoma have a positive family history, implying that most children with heritable retinoblastoma have a de novo mutation. Approximately 30% of probands with a negative family history will have bilateral disease, and 60% of probands with a negative family history will have unilateral retinoblastoma.7 Of children with unilateral disease, a germline RB1 mutation is present in 15%.1

Knudson8 first proposed the “2-hit” hypothesis whereby 2 complementary mutational events are required for the development of retinoblastoma. In heritable retinoblastoma, the first “hit,” or mutation (M1), is a germline mutation present in all cells of the affected child. The second mutation (M2) usually occurs in multiple retinal progenitor cells, resulting in multifocal or bilateral retinoblastoma. In nonheritable retinoblastoma, there is no germline mutation and both mutations occur somatically in a single retinal progenitor cell causing unifocal (unilateral) retinoblastoma. The presence of additional mutations (M3 to Mn) within the retinoblastoma genome is critical for tumor progression rather than tumor initiation.9


The age of diagnosis is earlier in heritable retinoblastoma, at an average age of 15 months, whereas nonheritable cases usually present later at an average age of 24 months.2 It is assumed that all children with bilateral involvement of retinoblastoma have a germline mutation, even if genetic testing is unable to identify the mutation (which occurs in approximately 5% of cases).

The most common signs of presentation are a white pupil (leukocoria) and strabismus.2 Clinical signs of advanced intraocular disease include secondary neovascular glaucoma or massive tumor necrosis and intraocular hemorrhage.10 More advanced tumors could undergo extensive intraocular necrosis, leading to an aseptic orbital cellulitis. The tumor appears as a white-yellow lesion arising from the retina. Calcification is a pathognomonic feature of larger tumors and is of diagnostic value when detected by ultrasonography or radiological imaging. In each affected eye, tumors can occur as a single lesion or in multiples (multifocal), with the latter being suggestive of the presence of heritable retinoblastoma.11 Each lesion can produce “seeds” that disseminate into the vitreous or subretinal spaces. An exudative retinal detachment allows the tumor to seed into the subretinal space. The morphology of seeds in the vitreous can be described as dust, clouds, or pearl-like spheres.12,13 These could extend into the anterior chamber.

An invasive tumor may invade the predominantly vascular choroid, potentially allowing tumor cells to metastasize via a hematogenous route.14 Alternatively, the tumor might spread via the lamina cribrosa into the optic nerve, allowing the tumor to access cerebrospinal fluid and the central nervous system. Anterior tumor invasion of the sclera can lead to metastasis through the lymphatic system.

With timely detection, more than 95% of those affected can survive if a multidisciplinary team provides coordinated and collaborative treatment at specialized centers with appropriate expertise, up-to-date protocols, and modern equipment.15 The treatments may involve surgery (enucleation), chemotherapy (intravenous, intra-arterial, periocular, or intraocular), focal therapies (laser and cryotherapy), and radiation (brachytherapy, external beam radiation).16 Treatment is first prioritized toward ensuring patient survival and then at preserving the eyeball and optimizing visual function.17


A retinoma is a rare, benign variant of retinoblastoma also caused by mutations in the RB1 gene.18 Studies have shown that retinoma is a precursor of retinoblastoma. On occasion (4%), retinoma may undergo malignant transformation, and therefore adults and children with these lesions should be followed closely.19


Children with germline mutations usually present with multifocal or bilateral retinoblastoma. All affected children with a positive family history of retinoblastoma are considered to have heritable retinoblastoma.

13q Deletion Syndrome

It is estimated that 5% to 6% of all children with retinoblastoma have an interstitial chromosome deletion or translocation of region 13q14.20 Such children may demonstrate dysmorphic features, developmental delay, and psychomotor retardation. The degree of severity correlates with the size of the chromosomal deletion and involvement of contiguous genes. Some of the characteristic facial features associated with this syndrome include thickened and anteverted ear lobes, high and broad forehead, prominent philtrum, short nose, and thick everted lower lip.21 Testing for chromosome deletions and translocations is typically performed using karyotype and/or chromosomal microarray.

Trilateral Retinoblastoma

The occurrence of a midline central nervous system embryonal tumor (or a pineoblastoma) in the setting of heritable retinoblastoma has been termed as “trilateral” retinoblastoma.22,23 These tumors may be located in the pineal gland or suprasellar/parasellar region. The chance of developing trilateral retinoblastoma is approximately 5% to 13%.24 Screening recommendations for intracranial malignancies include gadolinium-enhanced magnetic resonance imaging every 6 months until the age of 5 years in children with heritable retinoblastoma.25

Second Malignant Neoplasms

The risk of other (nonocular) malignancies in individuals with heritable retinoblastoma significantly increases over their lifespan. The most common second cancers include osteosarcoma, soft tissue sarcoma, melanoma, and epithelial cancers. Some studies suggest those with familial retinoblastoma have a greater risk for second cancers compared with those with a de novo RB1 mutation.26 Individuals with heritable disease who received external beam radiation therapy have a further increased risk of developing malignancies, especially in the radiation field.

Low Penetrance Retinoblastoma

Most RB1 germline mutations are highly penetrant. The penetrance, or chance to develop retinoblastoma with a typical “null” germline mutation, is 90% or higher. However, in a few families, the penetrance is much lower than 90%, with a high proportion of unilateral retinoblastoma (reduced expressivity) or carriers (no tumors at all, incomplete penetrance).27 Mutations associated with low penetrance are typically missense mutations or mutations in the promoter region that produce a low level of Rb protein rather than total absence of protein.28


The RB1 gene is a tumor suppressor gene that regulates cell cycle. Located on the long arm of chromosome 13, the gene consists of 27 exons dispersed over 185 kilobase of genomic DNA.29 The RB protein regulates the cell cycle by acting as a transcriptional repressor by targeting the E2F transcription factors. Dividing cells are therefore prevented from entering the S phase of mitosis and proceed to unregulated cycles of mitosis. Some functions of pRB in the genome such as stability, apoptosis, and differentiation are E2F-independent.30


Mutations in the RB1 gene result in a loss of function that inactivates the RB1 protein. The retinoblastoma protein is frequently inactivated by deletions and nonsense mutations.28 To date, many RB1 gene mutations have been identified that cause heritable retinoblastoma.3,5,28,31 Although suspected hotspots have been identified, they account for only 40% of the mutations. The rest of the mutations are scattered throughout the entire gene, most frequently in exons 9, 10, 14, 17, 18, 20, and 23.


A rare and genetically unique form of retinoblastoma was discovered in which both alleles of the RB1 gene are normal, and instead the MYCN gene shows copy number amplification at the DNA level.32 This form of tumor is clinically indistinguishable from RB1 mutated tumors. It has been exclusively discovered in 1% to 3% of children with unilateral retinoblastoma, especially in those younger than 12 months. Histopathology of these tumors seems to demonstrate undifferentiated cells with large, prominent, multiple nucleoli and necrosis, apoptosis, and little calcification. The histopathology features of this form of retinoblastoma resemble that of other MYCN amplified tumors such as neuroblastoma. The characteristics of this type of tumor strongly suggest nonhereditary disease, without risk for retinoblastoma in the other eye, risk of familial transmission, or other malignant cancers throughout life.


A meticulous and comprehensive approach can detect approximately 95% of the RB1 mutations (Table 1).11 Identification of the RB1 mutation reduces overall health care expenditures by identifying those children who are at risk for additional intraocular tumors (ipsilateral or contralateral eye), trilateral retinoblastoma, or second malignant tumors, thereby sparing relatives who test negative for the RB1 germline mutation from unnecessary screening evaluations.5 It is recommended that genetic testing be conducted in a certified laboratory with demonstrated sensitivity [% of all tested samples in which the mutation(s) are found, resulting in a useful report] and turnaround time to identify RB1 mutations.15 The One RB World Web site ( aims to list all genetic testing laboratories that perform retinoblastoma testing, including their contact information, test sensitivity, and relevant information about their processes.

Methods for Detecting or Tracking Mutations in the RB1 Gene


A clinical diagnosis of retinoblastoma in a child whose germline RB1 status is not already known is an indication for testing. Children with bilateral disease, with trilateral retinoblastoma, and those with a family history almost certainly carry a germline RB1 gene mutation, making them at risk for developing second malignant neoplasms. Children with unilateral disease without any family history require genetic testing to determine their risk for additional intraocular tumors (ipsilateral or contralateral eye), trilateral retinoblastoma, or second malignant tumors. Genetic testing for both bilateral and unilateral cases may also detect at-risk members of the family who may harbor the RB1 mutation, including the possibility of prenatal testing for the parents.


High-quality DNA is required from the affected proband to detect mutations in the RB1 gene. Testing for the germline RB1 mutation usually requires a peripheral blood sample or saliva collected using a specifically designed kit. It is important to preserve tumor tissue so that high-quality DNA can be obtained for subsequent genetic studies. Tumor tissue can be obtained fresh in the operating room (after an enucleation) or in the pathology laboratory before formalin fixation. Although fresh tumor extraction and flash freezing yields sufficient good-quality tissue for analysis, it needs to be done very carefully using minimally disruptive techniques that will least affect histopathological analysis of an enucleated eye. Two RB1 mutations should be detected in tumor DNA. For the most conclusive test, and especially for unilateral patients, it is ideal to analyze the tumor DNA first. Then any mutations identified can be sought in the leukocyte DNA. If one of these mutations is detected in the blood or saliva sample, the child has the germline (heritable) form of retinoblastoma. If neither mutation is identified in germline DNA, the chance for heritable retinoblastoma is low but cannot be ruled out due to the chance of low-level mosaicism (the presence of 2 or more genotypically different cell populations in an individual). The incidence of mosaicism is approximately 6% and may be detected by sensitive methods such as allele-specific polymerase chain reaction.31 Experienced laboratories should be able to detect mosaicism in as low as 1% to 20% of sampled leukocytes. Blood and tissue extraction methods, storage methods, and transportation to the testing laboratory are unique to each laboratory and it is necessary to discuss them in detail before sample collection.

Analysis for copy number variations of the MYCN gene should be pursued if no germline mutations are detected in the RB1 gene, especially in unilateral cases. As mentioned earlier, approximately 1% to 3% of children with sporadic unilateral Rb have high-level MYCN amplification on tumor tissue testing but no pathogenic variants leading to inactivation of RB1.27


The purpose of genetic counseling is to educate the family (and when older, the patients themselves) about the heritability of retinoblastoma, genetic testing, risks of future malignancies, recurrence risks for relatives, and reproductive options. All families of children with a diagnosis of retinoblastoma should be referred for a consultation with a genetic counselor or other qualified professional. Genetic counseling should occur soon after the initial diagnosis and again when a survivor enters reproductive age or before planning a family.

Initial Consultation

An initial consultation with the family in a genetics clinic will help provide a basic overview of retinoblastoma, especially its genetic intricacies. The family members at risk can be identified when a family history has been obtained and a detailed pedigree drawn. The discussions would include the purposes of testing and likely outcomes of the test, test sensitivity, and residual risks. Genetic testing is then offered to the families, with their consent. Appropriate pretest counseling also helps the parents understand the cost of testing and assesses for any psychosocial needs.

A second counseling session should be arranged to report and interpret the results. Once the results are reported, the family is advised to contact the relatives at risk so that they can be referred for counseling and testing.

Genetic Testing Outcomes

RB1 analysis is recommended in all children where results will influence surveillance or clarify recurrence risks for family members. The probability of a germline mutation varies based on tumor laterality and family history.

In unilateral retinoblastoma, it is advisable that tumor DNA be analyzed first to detect the 2 RB1 mutations. Then, the proband’s leukocyte DNA is analyzed for the presence of those mutations. If neither mutation is identified, the likelihood for heritable retinoblastoma is very low but cannot be ruled out due to the possibility of low-level mosaicism. In such a scenario, the proband’s potential future children should be tested for the mutations detected in tumor DNA, but no other family members need genetic testing.

If a tumor sample is not available and no mutation is identified in leukocyte DNA, the chance for an undetected germline mutation is approximately 1% to 1.5%. In such cases, surveillance without anesthetic of the unaffected eye should occur until age 5. The offspring of such children may also receive surveillance without anesthetic.33

In children with bilateral retinoblastoma, the germline mutation can be identified using only blood DNA in 95% of cases. When a germline mutation is unable to be identified, tumor DNA analysis may aid in recurrence risk assessment. If both mutations are identified in the tumor, but not in blood, low-level mosaicism caused by a postzygotic mutation in the proband is assumed and only his/her future children would be at a low but definite risk to inherit the mutation.

Other analyses to be considered when the germline mutation is not identified on sequence analysis include karyotyping to assess for chromosome translocations and RNA analysis to detect splicing variants. If 2 or more family members have retinoblastoma, linkage analysis may also be used to clarify the mutation status of at-risk family members. In some cases, loss of heterozygosity (loss of 1 parental copy of a chromosomal region) testing in the tumor may be used to determine whether siblings and offspring are at risk. If loss of heterozygosity is detected, the haplotype analysis can be used to determine which allele carries the undetectable germline mutation. Siblings and children of the proband with the mutant haplotype are at increased risk for developing retinoblastoma and should be followed appropriately.34

If genetic testing is not possible or is uninformative, empiric risk estimates can be used in genetic counseling. These risks are estimated from observational studies or calculated by multiplying the likelihood of a germline RB1 mutation in the proband by the degree of relationship to the proband and likelihood of a mutation or mosaicism in the proband’s parents.7


Children of the Proband

All future children of a proband with heritable retinoblastoma have a 50% chance of inheriting the RB1 mutation. Although most children with heritable retinoblastoma have a de novo mutation, single-site testing for parents is recommended to clarify recurrence risks for siblings and extended relatives. In approximately 10% of cases, a parent has mosaicism for the mutation or may harbor the mutation and be unaffected.35 The parent with a mosaic mutation is at elevated risk for second primary neoplasms and has up to a 50% chance of transmitting the mutation to other offspring. If a child is diagnosed with a cytogenetic mutation such as a deletion or translocation, parents should also have karyotype analyses to determine whether one carries a balanced translocation. It is recommended that children with heritable retinoblastoma and RB1 mutation carriers be monitored for new tumors with frequent examination under anesthesia or clinic visits until 5 years of age. Lifelong counseling for increased risk of other tumors is important.36

It should be noted that mosaicism cannot be inherited, and therefore all antecedent relatives are cleared of risk. Future offspring of a mosaic proband still require testing to determine if they have inherited the same RB1 mutant allele as their parent’s tumor.


Risks of retinoblastoma for the proband’s siblings depend on parental status. If a parent has a history of retinoblastoma, retinoma, or positive genetic testing results, future offspring have a 50% risk of retinoblastoma. The risk may be lower for offspring of parents with mosaicism; but for genetic counseling purposes, a risk of up to 50% should be presumed. If neither parent’s testing reveals the familial RB1 mutation, there is still a small chance that 1 parent has germline or gonadal mosaicism that blood testing did not identify and subsequent children have a 2% to 3% chance of inheriting the mutation. Therefore, all siblings of a child with heritable retinoblastoma should be tested for the germline mutation. If the mutation is not identified, the sibling has the same risk of developing retinoblastoma as a child in the general population and does not need surveillance.

Any unaffected child found to have a germline RB1 mutation should be examined under anesthesia every 3 to 4 weeks until the age of 1 and then every 3 to 4 months until the age of 5 years. Children with a known RB1 mutation who receive frequent screening are diagnosed with retinoblastoma at an earlier age and have a better outcome than those who do not receive regular surveillance.37


Studies have shown that the parents’ perceived risk of retinoblastoma in their offspring strongly influences their decision to have children in the future.38 When RB1 germline mutation is detected, options for testing an embryo or fetus including preimplantation genetic diagnosis and prenatal diagnosis should be discussed with parents of an affected child and adult survivors of retinoblastoma. Preimplantation genetic diagnosis is performed by testing an embryo for the presence of the RB1 mutation after in vitro fertilization (IVF).

It is important to note that de novo RB1 mutations have occurred in children conceived by IVF.39 Therefore, the small possibility of an unrelated RB1 mutation, along with unforeseen de novo mutations, occurring throughout the genome during IVF should be discussed. Prenatal diagnosis with chorionic villus sampling (at 10–12 weeks gestation) or amniocentesis (after 15 weeks gestation) may be used to determine whether a fetus is affected to either plan for surveillance or make decisions regarding continuing the pregnancy. These procedures are associated with a risk of miscarriage less than or equal to 2%. If the mutation is identified prenatally, ultrasound can be used to identify some large intraocular tumors. Preterm delivery may be considered to allow for early treatment of tumors or early ocular examination.33 If prenatal diagnosis is not performed, cord blood or an infant’s peripheral blood may be used for testing after delivery. When test results are not yet available, at-risk children should have ocular evaluation soon after delivery and be followed on a regular schedule, including examinations under anesthesia for the first 3 years.


Retinoblastoma is a genetic disease; therefore, genetic counseling and genetic testing are integral in providing optimal care.


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genetics; retinoblastoma

© 2016 by Asia Pacific Academy of Ophthalmology