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Retinoblastoma

, MD and , MD.

Author Information
, MD
Institut für Humangenetik, Universitätsklinikum Essen
Universität Duisburg-Essen
Essen, Germany
, MD
Professor, University of Toronto
Head, Cancer Informatics
Ontario Cancer Institute/Princess Margaret Hospital
University Health Network
Toronto, Ontario, Canada

Initial Posting: ; Last Update: November 19, 2015.

Summary

Clinical Characteristics.

Retinoblastoma (Rb) is a malignant tumor of the developing retina that occurs in children, usually before age five years. Rb develops from cells that have cancer-predisposing variants in both copies of RB1. Rb may be unifocal or multifocal. About 60% of affected individuals have unilateral Rb with a mean age of diagnosis of 24 months; about 40% have bilateral Rb with a mean age of diagnosis of 15 months. Heritable retinoblastoma is an autosomal dominant susceptibility for Rb. Individuals with heritable retinoblastoma are also at increased risk of developing non-ocular tumors.

Diagnosis/testing.

The diagnosis of Rb is usually established by examination of the fundus of the eye using indirect ophthalmoscopy. Imaging studies can be used to support the diagnosis and stage the tumor. The diagnosis of heritable retinoblastoma is established in a proband with Rb or retinoma and a family history of Rb or by detection of a germline pathogenic variant in RB1.

Management.

Treatment of manifestations: Early diagnosis and treatment of Rb and non-ocular tumors can reduce morbidity and increase longevity; care is best provided by multidisciplinary teams of specialists including ophthalmology, pediatric oncology, pathology, and radiation oncology. Treatment options depend on tumor stage, number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, the potential for useful vision, the extent and kind of extraocular extension, and the resources available. Treatment options include enucleation; cryotherapy; laser, systemic, or local ocular chemotherapy including intra-arterial chemotherapy combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy.

Prevention of secondary manifestations: If possible, radiation (including x-ray, CT scan, and external beam radiation) should be avoided in individuals with heritable Rb to minimize the lifetime risk of developing late-onset second cancers.

Surveillance: In children known to have an RB1 germline pathogenic variant: eye examination under anesthesia every three to four weeks until age six months, then less frequently until age three years. Clinical examinations with cooperative children are performed every three to six months until age seven years, then annually and eventually biannually for life. Individuals who have unilateral Rb without an identified heterozygous germline RB1 pathogenic variant are at risk for low-level mosaicism and should have regular clinical examination of the eyes, including clinical ultrasound. Individuals with retinomas are followed with retinal examinations and imaging every one to two years. To detect second non-ocular tumors in individuals with retinoblastoma, physicians and parents should promptly evaluate complaints of bone pain or lumps because of the high risk for sarcomas and other cancers; however, effective screening protocols have not yet been developed.

Agents/circumstances to avoid: Limiting exposures to DNA-damaging agents (radiation, tobacco, and UV light) may reduce the excess cancer risks in survivors of heritable retinoblastoma.

Evaluation of relatives at risk: Molecular genetic testing for early identification of asymptomatic at-risk children in a family reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant.

Genetic counseling.

Heritable retinoblastoma is inherited in an autosomal dominant manner. Individuals with heritable retinoblastoma have a heterozygous de novo or inherited germline RB1 pathogenic variant. Offspring of affected individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the RB1 pathogenic variant has been identified in an affected family member.

Diagnosis

Guidelines for diagnosis and care of children and families affected by retinoblastoma have been published [Canadian Retinoblastoma Society 2009] (full text).

Suggestive Findings

Retinoblastoma should be suspected in individuals with:

  • Leukocoria (white pupil)
  • Strabismus
  • Change in eye appearance
  • Reduced visual acuity

Heritable retinoblastoma should be suspected in individuals with the following clinical and family history:

  • Any individual with a diagnosis of retinoblastoma, including unilateral (unifocal and multifocal) and bilateral involvement
  • An individual with a retinoma
  • An individual with a family history of retinoblastoma

Establishing the Diagnosis

The diagnosis of retinoblastoma is established in a proband by retinal examination with full pupillary dilation by an ophthalmologist or optometrist. Confirmation of the diagnosis and determination of the disease extent is accomplished by examination under anesthesia. Ocular imaging can help confirm the diagnosis. Pathology is not required. Note: Biopsy can cause the tumor to spread beyond the eye, endangering the life of the individual.

The diagnosis of heritable retinoblastoma is established in a proband with retinoblastoma (Rb) or retinoma and a family history of Rb. The majority of individuals with Rb do not have a family history of the disorder. Therefore identification of a heterozygous germline RB1 pathogenic variant on molecular genetic testing (see Table 1) is necessary to determine if the Rb is heritable in index cases and to allow for early diagnosis and screening for relatives at risk of Rb.

Molecular testing approaches to identify individuals with heritable retinoblastoma can include single-gene testing and use of a multi-gene panel.

Single-gene testing

  • Individuals with bilateral, unilateral familial, or unilateral multifocal Rb. Sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on peripheral blood DNA. Note: Targeted analysis for pathogenic variants at methylated CpG dinucleotides may be offered by some laboratories.
  • Individuals with unilateral unifocal Rb and a negative family history
    • If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on peripheral blood DNA.
    • If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of RB1 are performed on tumor DNA. If pathogenic variants are identified, DNA from blood is tested for the presence of these variants. If no pathogenic variants are identified, methylation analysis of the RB1 promoter CpG island is performed to identify epigenetic inactivation of RB1 due to hypermethylation of the RB1 promoter. If no hypermethylation is identified at the promoter, DNA from tumor is tested for the presence of amplification of MYCN, which is the cause of Rb in the absence of RB1 pathogenic variants in about 1.5% of individuals with isolated unilateral retinoblastoma.

A multi-gene panel that includes RB1 may also be considered. However, as no locus heterogeneity is known for heritable retinoblastoma, evaluation of the analytic data is confined to variants that alter RB1.

Table 1.

Molecular Genetic Testing Used in Heritable Retinoblastoma

Gene 1Test MethodSampleProportion of Probands with a Germline Pathogenic Variant 2 Detectable by This Method
RB1Sequence analysis 3Germline, tumor70%-75%
Gene-targeted deletion/duplication analysis 4Germline, tumor8%-16% 5
Targeted analysis for pathogenic variantsGermline, tumor25% 6
Methylation analysisTumorSee footnote 7
MYCNGene-targeted deletion/duplication analysis 4TumorSee footnote 8
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

Testing for loss of heterozygosity in tumors. Comparative genotyping of polymorphic loci within and flanking RB1 in DNA from peripheral blood and tumor can reveal that loss of the normal allele (hemizygosity) with or without duplication (homozygosity) of the mutated allele constitutes the somatic pathogenic variant.

6.

Pathogenic variants that result in premature termination due to CpG-transitions account for 25% of pathogenic variants [Rushlow et al 2009].

7.

Hypermethylation of RB1 promoter (which silences gene expression) is observed in 10%-12% of tumors from individuals with sporadic, unilateral retinoblastoma [Zeschnigk et al 2004]. In these individuals, analysis of the promoter methylation status in DNA from tumor is needed to identify the two inactive RB1 alleles that triggered tumor development.

8.

About 1.5% of children with sporadic unilateral Rb have high-level MYCN amplification on tumor tissue testing but no pathogenic variants leading to inactivation of RB1 [Rushlow et al 2013].

Table 2.

Probability of a Germline Pathogenic Variant Being Present in a Proband with Retinoblastoma Based on Family History and Tumor Presentation

Family HistoryRb PresentationProbability that an RB1 Germline Pathogenic Variant is Present
UnilateralBilateral
MultifocalUnifocal
Positive 1+100%
+100%
+100%
Negative 2+Close to 100% 3
+14%-95%
+~14%
1.

Positive = more than one affected family member (10% of retinoblastoma)

2.

Negative = only one affected individual in the family (90% of retinoblastoma)

3.

RB1 pathogenic variants are identified by conventional molecular testing in 90%-97% of simplex cases with bilateral involvement; the remaining 5% may have translocations, deep intronic splice variants, or low-level mosaic pathogenic variants which may or may not be in the germline.

Note: (1) If neither RB1 pathogenic variant identified in tumor tissue is found in the DNA of non-tumor cells (constitutional DNA), the affected individual has a low probability of having an RB1 germline pathogenic variant. (2) Because blood mosaicism as low as 20% can usually be detected by conventional molecular analysis such as sequencing, the failure to detect an RB1 pathogenic variant in constitutional DNA reduces but cannot eliminate the probability that the individual has an RB1 pathogenic variant in his/her germline.

Clinical Characteristics

Clinical Description

Retinoblastoma (Rb). The most common presenting sign is a white pupillary reflex (leukocoria). Strabismus is the second most common presenting sign and may accompany or precede leukocoria [Abramson et al 2003]. Unusual presenting signs include glaucoma, orbital cellulitis, uveitis, hyphema, or vitreous hemorrhage. Most affected children are diagnosed before age five years. Atypical manifestations are more frequent in older children.

Probands with Rb usually present in one of the following clinical settings:

  • Negative family history and unilateral Rb (60% of probands)
  • Negative family history and bilateral Rb (30% of probands)
  • Positive family history and unilateral or bilateral Rb (~10% of probands). 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.
  • Chromosome deletion involving band 13q14. Up to 5% of all index cases with unifocal Rb and 7.5% of all index cases with multifocal Rb have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [Mitter et al 2011, Castéra et al 2013].

Retinoblastoma is:

  • Unilateral if only one eye is affected by Rb. About 60% of affected individuals have a unilateral Rb with a mean age at diagnosis of 24 months. Usually, in individuals with unilateral Rb the tumor is also unifocal, i.e., only a single tumor is present. Some individuals have multifocal tumors in one eye (unilateral multifocal Rb). Intraocular seeding may mimic true multifocal tumor growth. In most persons with unilateral Rb without a family history, the tumor is large and it is not possible to determine if a single tumor is present.
  • Bilateral if both eyes are affected by Rb. About 40% of affected individuals have bilateral Rb with a mean age at diagnosis of 15 months. In most children with bilateral tumors, both eyes are affected at the time of initial diagnosis. In individuals with bilateral Rb both eyes may show multiple tumors. Some children who are initially diagnosed with unilateral Rb later develop a tumor in the contralateral unaffected eye.
  • Trilateral if bilateral (or, rarely, unilateral) Rb and a pinealoblastoma co-occur.

Retinoma and associated eye lesions. Benign retinal tumors (called retinoma) that have undergone spontaneous growth arrest may present within retinal scars [Dimaras et al 2008]. Calcified phthisic eyes may result from spontaneous regression of Rb associated with vascular occlusion [Valverde et al 2002].

Pinealoblastomas occur in "retina-like" tissue in the pineal gland of the brain. Co-occurrence of pinealoblastomas or primitive neuroectodermal tumors and Rb is referred to as trilateral Rb. Pinealoblastoma is rare and usually fatal, unlike Rb of the eye, which is generally curable [de Jong et al 2014].

Other tumors. There is an increased risk for other specific extraocular primary neoplasms (collectively called second primary tumors). Most of the second primary tumors are osteosarcomas, soft tissue sarcomas (mostly leiomyosarcomas and rhabdomyosarcomas), or melanomas [Kleinerman et al 2007, Marees et al 2008, Kleinerman et al 2012]. These tumors usually manifest in adolescence or adulthood. The incidence of second primary tumors is increased to more than 50% in individuals with Rb who have received external beam radiation therapy [Wong et al 1997]. Survivors of heritable retinoblastoma who are not exposed to high-dose radiotherapy have a high lifetime risk of developing a late-onset cancer [Fletcher et al 2004, Kleinerman et al 2012, Dommering et al 2012b, Temming et al 2015].

Genotype-Phenotype Correlations

In the majority of families with heritable retinoblastoma, all members who have inherited the germline pathogenic variant develop multiple tumors in both eyes. It is not unusual to find, however, that the founder (i.e., the first person in the family to have Rb) has only unilateral Rb. Most of these families segregate RB1 null alleles that are altered by frameshift or nonsense variants. With few specific exceptions, RB1 null alleles show nearly complete penetrance (>99%) [Lohmann et al 1996, Sippel et al 1998].

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%). This low penetrance phenotype is usually associated with mutated RB1 alleles showing in-frame or missense changes, distinct splice site variants, certain indel variants in exon 1, or pathogenic variants in the promoter region.

A third category of families shows differential penetrance depending on the parental origin of the pathogenic allele (parent-of-origin effect) [Klutz et al 2002].

Cytogenetically visible deletions involving 13q14 that also result in deletions of additional genes in the same chromosome region as RB1 may cause developmental delay [Castéra et al 2013] and mild-to-moderate facial dysmorphism. As sizeable deletions of 13q14 show reduced expressivity, a considerable proportion of individuals with such deletions show unilateral Rb only; some of these children develop no tumors at all [Mitter et al 2011]. Contiguous loss of MED4, which is located centromeric to RB1, explains reduced expressivity in individuals with large deletions that include both RB1 and MED4 [Dehainault et al 2014].

Nomenclature

Glioma retinae is a historical name for retinoblastoma.

Prevalence

The incidence of Rb is estimated at between 1:15,000 and 1:20,000 live births [Moll et al 1997, Seregard et al 2004].

Differential Diagnosis

Several ocular conditions of childhood can clinically simulate retinoblastoma:

Management

Guidelines for retinoblastoma (Rb) care have been developed [Canadian Retinoblastoma Society 2009] (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Rb, the following evaluations are recommended:

  • Prior to the planning of therapy, the extent of the tumor within and outside the eye should be determined. Each affected eye is assigned a classification, depending on the extent of disease and the risk that the cancer has spread outside the eye. Extent of the tumor is estimated by clinical examination under anesthetic and ultrasound or MRI, particularly focusing on the tumor-optic nerve relationship. Head MRI is also useful to evaluate for a pinealoblastoma, indicating trilateral retinoblastoma.
  • For very large tumors with risk factors for extraocular disease, bone marrow aspiration and examination of cerebrospinal fluid (CSF) may also be performed at diagnosis, or performed when pathologic examination of the enucleated eye reveals optic nerve invasion or significant risks for extraocular extension.
  • If Rb has spread outside the eye, the stage of cancer will need to be evaluated to determine the most appropriate care of the child.
  • In those individuals with a family history of Rb, and in uncommon circumstances in which the child presents with strabismus or poor vision, the retinal tumors may be small and detected on clinical examination under anesthesia.
  • Consultation with a medical geneticist and/or genetic counselor is indicated.

Treatment of Manifestations

Goals of treatment are first preservation of life, and then of sight. As optimal treatment may be complex, specialists skilled in the treatment of Rb from various fields including ophthalmology, pediatric oncology, pathology and radiation oncology collaborate to deliver optimized care.

In addition to eye classification and tumor stage, choice of treatment depends on many factors, including the number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, the potential for useful vision, the extent and kind of extraocular extension, and the resources available.

Treatment options for the eye include enucleation; cryotherapy; laser, systemic, or local ocular chemotherapy including intra-arterial chemotherapy combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy.

Prevention of Secondary Complications

If possible, any radiation (including x-ray, CT scan, and external beam radiation) should be avoided to minimize the lifetime risk of developing late-onset second cancers. Such tests should only be used if absolutely necessary in essential health care.

Surveillance

Further information regarding medical surveillance for those who have had or are at risk of developing Rb is available in the guidelines for retinoblastoma care.

Detection of subsequent Rb after initial diagnosis. Following successful treatment, children require frequent follow-up examination for early detection of newly arising intraocular tumors:

  • It is recommended that children known to have an RB1 germline pathogenic variant have an eye examination under anesthesia every three to four weeks until age six months, then less frequently until age three years. Clinical examinations with cooperative children are performed every three to six months until age seven years, then annually and eventually biannually for life.
  • Individuals who have unilateral Rb without an identified heterozygous germline RB1 pathogenic variant are at risk for low-level mosaicism and can develop a tumor in the other eye [Rushlow et al 2009, Temming et al 2013]. This risk is small enough that examination under anesthesia may be replaced with regular clinical examination of the eyes, including clinical ultrasound (a simple, noninvasive procedure).
  • Individuals with retinomas (premalignant retinal lesions associated with Rb) are followed with retinal examinations and imaging every one to two years, to detect any change early.

Detection of second non-ocular tumors in individuals with retinoblastoma. Because of the high risk for second cancers, including sarcomas, melanoma, and specific other cancers, prompt investigation of any signs or symptoms is indicated. Total body MRI at regular intervals is under investigation to determine when the technology will be specific and sensitive enough for screening for second cancers in persons with a heterozygous germline RB1 pathogenic variant.

Agents/Circumstances to Avoid

It has been suggested by Fletcher et al [2004] that cancer risks in survivors of heritable retinoblastoma may be reduced by limiting exposure to DNA-damaging agents (radiotherapy, tobacco, and UV light). It is plausible that cancer risks in these individuals may be reduced by limiting exposure to chemotherapy.

Evaluation of Relatives at Risk

The American Society of Clinical Oncologists identifies heritable retinoblastoma as a Group 1 disorder, i.e., a hereditary syndrome for which genetic testing is considered part of the standard management for at-risk family members [American Society of Clinical Oncology 2003]. It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from eye examination by an experienced ophthalmologist and allow for early identification of a retinoblastoma.

Evaluations can include:

  • Molecular genetic testing if the pathogenic variant in the family is known, which reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant [Noorani et al 1996, Richter et al 2003];
  • Eye examinations by an ophthalmologist experienced in the treatment of retinoblastoma starting directly after birth as described above (see Surveillance, Detection of subsequent Rb after initial diagnosis. Young or uncooperative children may require examination under anesthesia.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There are not many clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Heritable retinoblastoma is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband.

  • Some individuals diagnosed with heritable retinoblastoma have an affected parent.
  • A proband with heritable retinoblastoma may have the disorder as the result of a de novo germline RB1 pathogenic variant. The majority of individuals with heritable retinoblastoma and no family history of retinoblastoma have the disorder as the result of a de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband. The incidence of mosaicism is approximately 6%. Mosaicism may be detected by sensitive methods such as allele-specific PCR [Rushlow et al 2009] or next-generation sequencing [Chen et al 2014].
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant. If the RB1 pathogenic variant in the proband is not known, recommendations for the evaluation of parents of a proband include examination by an ophthalmologist knowledgeable about retinoblastoma (Rb), retinoma, and retinoblastoma-associated eye lesions.
  • The family history of some individuals diagnosed with heritable retinoblastoma may appear to be negative because of failure to recognize the disorder in family members (retinoma), low-level mosaicism, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing have been performed on the parents of the proband. In approximately 10% of individuals with a heterozygous germline RB1 pathogenic variant who represent simplex cases, one of the proband’s unaffected parents also has the pathogenic variant. In most cases this is a mosaic or heterozygous “reduced penetrance” pathogenic variant, such as a missense variant [Rushlow et al 2009].
  • If the proband with Rb has the disorder as the result of a mosaic RB1 pathogenic variant, the parents do not have the pathogenic variant.
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and have fewer (unilateral) or no retinoblastomas.

Sibs of a proband

  • The risk to sibs of a proband depends on the phenotype and the genetic status of the parents.
  • If a parent of the proband and the proband have bilateral Rb, the risk to the sibs is almost 50%. In rare families with "familial low-penetrance Rb" the risk for tumor development in a sib with the germline pathogenic variant is reduced.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (i.e.,1%-2%; see Table 3).
  • The sibs of a proband with clinically unaffected parents are still at increased risk for heritable retinoblastoma because of the possibility of reduced penetrance in a parent.
  • If the RB1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. Thus, it is recommended that each sib be tested for the RB1 pathogenic variant identified in the proband.
  • If the proband clearly shows mosaicism for an RB1 cancer-predisposing variant in non-cancer cells such as leukocyte DNA, it is assumed that the pathogenic variant arose as a post-zygotic event and that neither parent has an RB1 germline pathogenic variant. The risk to the sibs is not increased and thus the testing of sibs for the RB1 pathogenic variant identified in the proband is not warranted.
  • If molecular genetic testing is not available or is uninformative, empiric risks based on tumor presentation (i.e., unifocal or multifocal) and family history can be used (Table 3). The low, but not negligible, risk to sibs of a proband with a negative family history presumably reflects the presence of either a germline RB1 pathogenic variant with reduced penetrance in one parent or somatic mosaicism (that includes the germline) for an RB1 pathogenic variant in one parent.
  • If a parent has a cytogenetically detectable balanced chromosome 13 translocation or rearrangement, the sibs are at increased risk of inheriting an unbalanced chromosome rearrangement.

Offspring of a proband. Each child of an individual with heritable retinoblastoma has a 50% chance of inheriting the RB1 pathogenic variant.

  • If the proband has bilateral Rb and no family history of Rb, the presence of a germline RB1 cancer-predisposing variant is assumed and the risk to each offspring of inheriting the pathogenic variant is 50%. Predictive DNA testing in offspring is possible if the cancer-predisposing RB1 variant has been identified in the proband.
  • If the proband has had unilateral multifocal Rb and no family history of Rb, recurrence risk to offspring is lower [Sippel et al 1998, Rushlow et al 2009].
  • The risk to offspring of a proband with unilateral unifocal disease and a negative family history is 6%, reflecting the possibility that the proband has mosaicism for a pathogenic variant or a germline RB1 pathogenic variant associated with milder phenotypic expression. In families with "familial low-penetrance Rb" the risk for tumor development in persons with the low-penetrance RB1 allele is lower than the 95% observed with highly penetrant RB1 “null” alleles.
  • If the RB1 pathogenic variants that have been detected in tumor tissue are not detected in DNA from leukocytes of the proband, there is an estimated 1.2% chance that the proband has germline mosaicism for one of the pathogenic variants identified in the tumor tissue. The offspring of the proband are at a 0.6% risk of inheriting a germline pathogenic variant [Richter et al 2003]. Molecular genetic testing in offspring must check for both of the pathogenic variants identified in the tumor of the proband.
  • If one of the pathogenic variants identified in the tumor is mosaic in DNA from leukocytes of the proband, the level of germline involvement is uncertain. All offspring should be checked for the pathogenic variant identified in leukocyte DNA.

Table 3.

Empiric Risks for Development of Retinoblastoma in Sibs and Offspring of a Proband when an RB1 Germline Pathogenic Variant Has Not Been Identified

Tumor Presentation in Index CaseFamily HistoryRisk to Sibs of an Index CaseRisk to Offspring of an Index Case
BilateralUnilateral
MultifocalUnifocal
XNegative2% 150%
XNegative1%-2% 16%-50%
XNegative~1%6%
XPositiveVariable 2Variable 2
XPositive50%50%
1.

If there is no unaffected sib [Draper et al 1992]

2.

In families with unilateral Rb, penetrance varies widely.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the RB1 pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with heritable retinoblastoma has the pathogenic variant or clinical evidence of the disorder, the RB1 pathogenic variant is likely de novo. However, other possible non-medical explanations that could be explored include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk [Dommering et al 2012a].

DNA banking is the storage of DNA for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. If possible, DNA extracted from white blood cells and DNA extracted from tumor should be stored.

Prenatal Testing

When there is a family history of Rb, various options are available to optimize management of an at-risk pregnancy [Canadian Retinoblastoma Society 2009]

  • If the RB1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.
  • If an RB1 pathogenic variant is identified in the fetus, ultrasound examination may be used to identify medium-sized intraocular tumors. If tumors are present, preterm delivery to enable early treatment may be considered [Sahgal et al 2006]. Even if no tumors are visible on obstetric ultrasound, delivery of the fetus at 36 weeks’ gestation may be recommended, as 30% of babies with an RB1 pathogenic variant will have a tiny vision-threatening tumor [Authors, unpublished data].
  • If the RB1 pathogenic variant has not been identified in an affected family member, prenatal ultrasound or MRI may reveal a moderately large Rb in the eye of an affected fetus; however, these tests are not sensitive enough to detect small Rb tumors.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the RB1 pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • A Parent's Guide to Understanding Retinoblastoma
    Adobe Acrobat Reader required
    IRIS Medical
  • Childhood Eye Cancer Trust (CHECT)
    The Royal London Hospital
    Whitechapel Road
    London E1 1BB
    United Kingdom
    Phone: +44 020 7377 5578
    Fax: +44 020 7377 0740
    Email: info@chect.org.uk
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • National Retinoblastoma Parents Group
    PO Box 317
    Watertown MA 02471
    Phone: 800-562-6265
    Fax: 617-972-7444
    Email: napvi@perkins.pvt.k12.ma.us
  • NCBI Genes and Disease
  • World Eye Cancer Hope (WE C Hope)
  • American Childhood Cancer Organization (ACCO)
    PO Box 498
    Kensington MD 20895-0498
    Phone: 800-366-2223 (toll-free); 301-962-3520
    Fax: 301-962-3521
    Email: staff@acco.org
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-4-CANCER
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jernigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Retinoblastoma: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Retinoblastoma (View All in OMIM)

180200RETINOBLASTOMA; RB1
614041RB1 GENE; RB1

Molecular Genetic Pathogenesis

With very rare exceptions, tumor development starts from cells that do not have a normal RB1 allele [Rushlow et al 2013]. See Figure 1.

Figure 1. . Schematic of the molecular genetic mechanisms that result in non-heritable and heritable retinoblastoma (Rb).

Figure 1.

Schematic of the molecular genetic mechanisms that result in non-heritable and heritable retinoblastoma (Rb). The development of Rb is initiated if both alleles of RB1 are mutated.

In non-heritable Rb, both pathogenic variants (first (more...)

Gene structure. Twenty-seven exons are transcribed and spliced into a 4.7-kb mRNA. There is no indication of functional alternative splicing. A frequently used reference sequence for the transcript is NM_000321.2. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. No frequent polymorphic sites within the 2.7-kb open reading frame are known, but there are intronic variants, two highly polymorphic microsatellites (Rb1.20, Rbi2), and one minisatellite (RBD).

Pathogenic allelic variants. More than 2500 nucleotide variants have been observed in white blood-cell DNA of individuals with retinoblastoma or in tumors; more than 1700 are archived (see Table A, Locus Specific). The majority of RB1 pathogenic variants result in a premature termination codon, usually through single base substitutions, frameshift variants, or out-of-frame exon skipping caused by splice site variants. Pathogenic variants have been found scattered throughout exon 1 to exon 25 of RB1 and its promoter region. In a single family, a possible pathogenic variant in exon 27 was identified [Mitter et al 2009]. Recurrent pathogenic variants are observed at methylated CpG dinucleotides that are part of CGA codons or the splice donor site of intron 12. Other important types of pathogenic variants are complex rearrangements and deletions [Albrecht et al 2005, Rushlow et al 2009, Castéra et al 2013].

Normal gene product. RB1 encodes a ubiquitously expressed nuclear protein that is involved in cell cycle regulation (G1 to S transition). The RB protein is phosphorylated by members of the cyclin-dependent kinase (cdk) system prior to the entry into S-phase. On phosphorylation, the binding activity of the pocket domain is lost, resulting in the release of cellular proteins. For a review see Dick & Rubin [2013] and Dimaras et al [2015].

Abnormal gene product. Pathogenic variants in RB1 lead to the expression of proteins that have lost cell cycle-regulating functions. Retention of partial activities has been observed in proteins resulting from pathogenic variants that are associated with low-penetrance retinoblastoma [Lohmann et al 1994, Bremner et al 1997, Otterson et al 1997].

References

Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online; registration or institutional access required. 2010. Accessed 2-10-16.
  2. American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. Available online. 2003. Accessed 2-10-16.
  3. Canadian Retinoblastoma Society. National Retinoblastoma Strategy Canadian Guidelines for Care: Stratégie thérapeutique du rétinoblastome guide clinique canadien. Available online. 2009. Accessed 2-10-16. [PubMed: 20237571]

Literature Cited

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Chapter Notes

Author History

Norbert Bornfeld, MD; University of Essen (2000-2004)
Brenda L Gallie, MD (2004-present)
Bernhard Horsthemke, PhD; University of Essen (2000-2004)
Dietmar R Lohmann, MD (2000-present)
Eberhard Passarge, MD; University of Essen (2000-2004)

Revision History

  • 19 November 2015 (me) Comprehensive update posted live
  • 28 March 2013 (me) Comprehensive update posted live
  • 10 June 2010 (me) Comprehensive update posted live
  • 7 May 2007 (me) Comprehensive update posted to live Web site
  • 21 January 2005 (dl) Revision: Risk to offspring of a proband
  • 28 December 2004 (me) Comprehensive update posted to live Web site
  • 21 January 2003 (me) Comprehensive update posted to live Web site
  • 18 July 2000 (me) Review posted to live Web site
  • 21 January 1999 (dl) Original submission
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