Handbook of Genetic Counseling/Retinoblastoma
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What is Retinoblastoma? 
- a rare, malignant tumor of the retina (nerve-rich, light-sensitive layer that enables us to see) of one or both eyes that occurs in children, usually before 3 years of age
- affects 1 in every 15,000 to 20,000 live births
- represents about 2% of all childhood malignancies
- approximately 350 new cases are diagnosed in the U.S. each year
- affects both sexes in all races
Types of Retinoblastoma 
- Unilateral - when the tumors are present in one eye
- 50-70% of cases
- mean age of diagnosis is 24 months
- Bilateral - when the tumors occur in both eyes
- 30-50% of cases
- mean age of diagnosis is 15 months
- "Trilateral" - the occurrence of bilateral RB plus a pinealoma
- Unifocal - when a single RB tumor is present
- Multifocal - when more than one tumor is present in one eye
Mode of Inheritance 
- 90% of patients have no family history of retinoblastoma
- most cases arise spontaneously for no apparent reason (sporadic)
- 20% of cases are transmitted as an autosomal dominant trait
- patients heterozygous for a cancer-predisposing mutation in one RB1 allele are said to have a germline mutation & have a hereditary predisposition to RB
- a combo. of clinical presentation, family history, and mutation analysis is used to determine if a proband has a germline (heritable) mutation or 2 somatic mutations
- occurs in cells that have cancer-predisposing mutations in both copies of the gene
- "Two hit model" - if a child inherits a gene predisposing it to get Retinoblastoma, a second event must take place to change the other gene, causing Retinoblastoma to occur. The nature of the 2nd event is unknown, but research is trying to determine which factors can precipitate the onset of this disorder.
Risks to family members 
- Parents of a proband -
- Cytogenetically detectable chromosome 13 deletion or rearrangement. Recommendation: Parental cytogenetic studies to determine if either parent carries a balanced chromosome translocation or rearrangement
- Positive family history (i.e., the parent had retinoblastoma or a close relative of one parent had retinoblastoma). Conclusion: The parent has an RB1 cancer-predisposing germline mutation
- Negative family history. Recommendation: Examination of apparently unaffected parents by an ophthalmologist knowledgeable about retinoblastoma, retinoma, and retinoblastoma-associated eye lesions. If such a lesion is detected, the parent has an RB1 cancer-predisposing germline mutation
- Presence of a germline RB1 cancer-predisposing mutation. Recommendation: Molecular genetic testing of a blood sample of both parents.
- If a germline mutation is identified in either parent, the parent is at risk of developing non-ocular second primary tumors and is at-risk to transmit the mutation to other offspring.
- If a germline RB1 mutation is not identified in either parent, two possibilities exist: 1) the index case has a de novo RB1 germline mutation (90-94% chance); or 2) one parent has mosaicism (which includes the germline) for the RB1 cancer-predisposing mutation (6-10% chance).
- Mosaicism for an RB1 cancer-predisposing mutation. Recommendation: Molecular genetic testing of the parents is not necessary.
- Sibs of a proband - The risk to sibs of an index case depends on the genetic status of the parents of the index case.
- If a parent is determined to have a germline RB1 cancer-predisposing mutation either by positive family history, by an eye examination that reveals a retinoblastoma-associated eye lesion, or by molecular genetic testing that reveals the presence of a cancer-predisposing RB1 mutation, the risk to each sib of the index case is 50% (or lower if the carrier parent is a mutational mosaic) of inheriting the cancer-predisposing RB1 mutation. Given the approximately 99% penetrance of most RB1 cancer-predisposing mutations, the actual risk for retinoblastoma in these individuals is about 50% (or lower if the carrier parent is a mutational mosaic). (Note: In rare families with "familial-low penetrance retinoblastoma," the risk of tumor development is less than 40%)
- If neither parent has the cancer-predisposing RB1 mutation that was identified in the index case, germline mosaicism in one parent is possible and the risk to each sib of having retinoblastoma is 3-5%
- If the index case has mosaicism for an RB1 cancer-predisposing mutation, it is assumed that the mutation arose as a post-zygotic event and that neither parent has an RB1 germline mutation. The risk to the sibs is not increased.
- 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. The low, but not negligible, risk to sibs of an index case with a negative family history presumably reflects the presence of either a germline RB1 mutation with reduced penetrance in one parent or somatic mosaicism (that includes the germline) for an RB1 mutation in one parent.
- Offspring of a proband -
- If the index case has sporadic bilateral RB, a germline RB1 cancer-predisposing mutation has to be assumed and the risk to each offspring is close to 50%.
- If the index case has had sporadic unilateral multifocal RB, recurrence risk for offspring is lower. (Note: In rare families with "familial-low penetrance retinoblastoma," the risk of tumor development is less than 40%).
- The low (~1%), but not negligible, risk to the offspring of index cases with unifocal disease and a negative family history reflects the possibility of a germline RB1 mutation with low penetrance or mutational mosaicism.
Chromosome location 
- chromosome 13q14
- cytogenetic analysis (600-650 bands for at least 30 metaphases) detects deletions or rearrangements in approx. 5% of patients with unilateral RB and 7.5% of patients with bilateral RB -may also result in DD and facial dysmorphism
- with a normal cytogenetic study? 10% of cases have a positive family history and unilateral or bilateral RB; 30% of cases have a negative family history and multifocal RB; 60% of cases have a negative family history and unifocal RB
- mosaic aberrations are present in about 1% of patients
Molecular genetics 
- gene RB1
- Normal gene product: The RB1 gene 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. Upon phosphorylation, the binding activity of the pocket domain is lost, resulting in the release of cellular proteins
- 80% of patients have a point mutation in the coding regions of RB1 gene; 15% have a partial deletion in the RB1 gene; 5% are unknown (mo mutation found)
- recessive oncogene - gene that appears to prevent retinoblastoma
- Two kinds of oncogenes - can cause cancer either by their presence or their absence. Both are mutants/incomplete versions of ordinary genes that normally regulate cell growth. One is dominant and causes out-of-control cell growth (cancer). The other kind is recessive and normally limits or stops the growth of cells. When they are lost, cells can proliferate wildly, causing cancer.
- incomplete (90%; including all bilateral cases and about 15% of unilateral cases)
- up to 10% of gene carriers will not develop the tumor but may pass on the gene
- leukocoria (white pupil reflex or "cat's eye reflex") - distinctive white mass in the pupil area behind the lens
- eye may become red and painful
- unusual: glaucoma (increased pressure in the eyeball), orbital cellulites, uveitis, hyphema, vitreous hemorrhage
- some retinal tumors (retinocytoma, retinoma) may undergo spontaneous growth arrest, leading to retinal lesions and scars
- Diagnostic -
- clinical ophthalmoscopic examination of the fundus of the eye with dilated pupils
tumors appear as gray-yellow elevations on the retina ("tumor seeds" - the beginnings of tumors may be visible in the vitreous body of the eye)
- imaging studies may be used to support the diagnosis and stage the tumor
- ultrasound, CAT scan, or MRI may detect calcifications in the tumors
- probes may be used to identify newborns with a genetic predisposition in order to diagnose earlier
- imaging studies may be used to support the diagnosis and stage the tumor
- Molecular - used in patients with RB with normal cytogenetic studies for risk prediction in relatives
- mutation analysis of RB1 gene in white blood cell DNA and tumor cells
- 40% of patients have an abnormal RB1 gene
- can detect a germline mutation in 80% of the patients with hereditary RB
- Testing available at several labs, including Retinoblastoma Solutions, University of Pennsylvania, Vermont, etc.
- detection depends on whether the tumor is unifocal or multifocal, whether the family history is positive or negative, and the sensitivity of the methodology
- if a germline mutation is identified in the proband, RB1mutation analysis can be used to determine the status of at-risk siblings and offspring
- indirect testing using linkage analysis (microsatellite markers) can be used in some families
- Prenatal - RB1 mutations can be detected in utero through CVS or amnio if the RB1 mutation is known or if linkage was informative
- Screening - ASCO classifies RB as a Group 1 disorder (genetic testing is considered part of the standard management for at-risk family members). Therefore, asymptomatic at-risk children are tested for early identification to improve diagnostic certainty and also to reduce the need for costly screening procedures in those members who have not inherited the mutation.
- 9 of 10 children are treated successfully (goal is preservation of sight and life)
- enucleation - excision of the tumor and the eye, removal of some of the optic nerve
- bilateral? more involved eye is removed, other treated in another way
- systemic chemotherapy
- follow-up ophthalmological exams every 3 months
- radiologic surveys for bony metastases
- studies of spinal fluid & bone marrow for malignant cells
Future prognosis 
- early diagnosis and treatment can reduce morbidity and increase longevity
- patients with hereditary RB are at an increased risk of developing other (non-ocular) tumors, including pinealomas in the brain which are usually fatal
- may be at risk of developing osteosarcoma (rare form of bone cancer) - same gene involved in both disorders, soft tissue sarcomas, or melanomas
Differential diagnosis 
- sporadic congenital disorders such as persistent hyperplastic primary vitreous & Coat's disease
- hereditary disorders such as tuberous sclerosis, Norrie disease, incontinentia pigmenti, and familial exudative vitreoretinopathy
- ocular infestation by Toxocara canis
- Retinoblastoma Genetics
The information in this outline was last updated in 2001.