Retinoblastoma (RB) is an embryonic malignant neoplasm of retinal origin. It almost always presents in early childhood and is often bilateral. Spontaneous regression ('cure') occurs in some cases. The retinoblastoma gene (RB1) was the first tumor suppressor gene ... Retinoblastoma (RB) is an embryonic malignant neoplasm of retinal origin. It almost always presents in early childhood and is often bilateral. Spontaneous regression ('cure') occurs in some cases. The retinoblastoma gene (RB1) was the first tumor suppressor gene cloned. It is a negative regulator of the cell cycle through its ability to bind the transcription factor E2F (189971) and repress transcription of genes required for S phase (Hanahan and Weinberg, 2000).
Ophthalmoscopic examination typically shows a white 'cat's eye' reflex and a retinal tumor in one or both eyes, usually by age 3 years.
Sparkes et al. (1979, 1980) suggested that ... - Diagnosis and Counseling Ophthalmoscopic examination typically shows a white 'cat's eye' reflex and a retinal tumor in one or both eyes, usually by age 3 years. Sparkes et al. (1979, 1980) suggested that if linkage between retinoblastoma and esterase D were found, this would provide a means of genetic counseling and early diagnosis, including prenatal diagnosis. Turleau et al. (1983) added a fourth family to those with retinoblastoma due to deletion of the critical portion of 13q in the offspring of a parent with a balanced insertional translocation (Riccardi et al., 1979; Rivera et al., 1981; Strong et al., 1981). They pointed out that without karyotyping the recurrence risk after the birth of 1 case from normal parents might be thought to be virtually nil whereas in fact it is 25% if one of the normal parents is a carrier of an insertional translocation. The same risk, 25%, applies to occurrence of a trisomic offspring. Cavenee et al. (1985) showed that the chromosome 13 remaining in tumors from 2 hereditary retinoblastoma cases was derived from the affected parents. The ability to identify which chromosome of an affected parent carries the mutation predisposing to retinoblastoma would have obvious usefulness in genetic counseling. Cavenee et al. (1986) demonstrated the usefulness of multiple RFLP and isozymic markers flanking the RB1 locus in prenatal and postnatal prediction of susceptibility to retinoblastoma. Wiggs et al. (1988) used cloned fragments of a 'retinoblastoma gene' that detected RFLPs and tested the usefulness of these RFLPs in predicting cancer in 20 families with hereditary retinoblastoma. Predictions were possible in 19 of the 20 families; in 18 of the 19, the marker RFLPs showed a consistent association with the mutation predisposing to retinoblastoma. In the 19th kindred, there was a lack of cosegregation, which, however, may have been due to inaccuracy of the clinical diagnosis of the retinal lesion in the key member of the kindred. Greger et al. (1988) demonstrated the usefulness of linkage analysis with DNA markers in genetic counseling of families with hereditary retinoblastoma. Maat-Kievit et al. (1993) detected an enormous retinoblastoma at 21 weeks of gestation by means of ultrasound. Since about 75% of cases of retinoblastoma due to constitutional mutations represent new mutations, Janson and Nordenskjold (1994) recognized a need for methods to identify carriers of such germline mutations so that informed genetic counseling can be offered. Using pulsed field gel electrophoresis in a screening of 20 unrelated cases with bilateral retinoblastoma, 1 constitutional mutation was detected and found to be caused by a balanced translocation t(4;13), with the breakpoint within intron 17 of the retinoblastoma gene. Timely molecular diagnosis of RB1 mutations has many benefits: it enables earlier treatment, lower risk, and better health outcomes for patients with retinoblastoma; empowers families to make informed family-planning decisions; and costs less than conventional surveillance. However, complexity hinders its clinical implementation. Most RB1 mutations are unique and distributed throughout the RB1 gene, with no real hotspots. Richter et al. (2003) devised a sensitive and efficient strategy to identify RB1 mutations that combined quantitative multiplex PCR, double-exon sequencing, and promoter-targeted methylation-sensitive PCR. Optimization of test order by stochastic dynamic programming and the development of allele-specific PCR for 4 recurrent point mutations decreased the estimated turnaround time to less than 3 weeks and decreased direct costs by one-third. Using this multistep method, Richter et al. (2003) detected 89% of mutations (199 of 224) in bilaterally affected probands and both mutant alleles in 84% (112 of 134) of tumors from unilaterally affected probands. By revealing those family members who did not carry the mutation found in the related proband, molecular analysis enabled 97 at-risk children from 20 representative families to avoid 313 surveillance examinations under anesthetic and 852 clinic visits. The average savings in direct costs from clinical examinations avoided by children in these families substantially exceeded the cost of molecular testing. Moreover, health care savings would continue to accrue, as children in succeeding generations would avoid unnecessary repeated anesthetics and examinations. Rushlow et al. (2009) found that the RB1 gene mutation detection rate in 1,020 retinoblastoma families was increased by the use of highly sensitive allele-specific PCR (AS-PCR) to detect low-level mosaicism for 11 recurrent RB1 nonsense mutations. Mosaicism was evident in 23 (5.5%) of 421 bilaterally affected probands and in 22 (3.8%) of 572 unilaterally affected probands, as well as in 1 unaffected mother of a unilateral proband. Noting that half of the mosaic mutations were detectable only by AS-PCR, Rushlow et al. (2009) suggested that significant numbers of low-level mosaics with other classes of RB1 mutations might remain unidentified by current technologies. In addition, since only 1 (0.7%) of 142 unaffected parents showed somatic mosaicism for the proband's mutation, in contrast to an overall 4.5% somatic mosaicism rate for retinoblastoma patients, Rushlow et al. (2009) suggested that mosaicism for an RB1 mutation is highly likely to manifest as retinoblastoma. - Screening Noorani et al. (1996) compared the direct health care costs of molecular and conventional screening of relatives of individuals affected with retinoblastoma. With variables set at the most likely values (baseline), the expected cost (in 1994 Canadian dollars) of conventional screening was $31,430 for a prototype family consisting of 7 at-risk relatives. The cost included 3 clinic examinations and 8 examinations under anesthetic over the first 3 years of life for each relative. Using baseline variables, the molecular strategy consisted of the screening of a prototype family of 1 proband and 7 at-risk relatives at a cost of $8,674, including identification of the RB1 mutation in the proband, subsequent testing of the relevant relatives for that mutation, and clinical follow-up similar to the conventional strategy for relatives with the mutation. Sensitivity analysis over the range of values for each variable revealed a significant saving of health care dollars by the molecular route, indicating the benefit of redirecting economic resources to molecular diagnosis in retinoblastoma. Zeschnigk et al. (1999) reported a PCR-based assay for the detection of methylation at the RB1 promoter. The assay gave results which were concordant with those achieved by Southern blot analysis in 40 samples. Tsai et al. (2004) reported the usefulness of protein truncation testing (PTT) for rapid detection and sequencing of germline mutations in the RB1 gene. Nineteen (70%) of 27 probands tested positive for germline mutations by PTT. In 1 kindred, the proband had negative PTT results but an additional affected relative had positive PTT results. Using a multitiered approach to genetic testing, 23 (85%) of the 27 kindreds had mutations identified, and those detected by PTT received a positive result in as few as 7 days. In control subjects, PTT produced no false-positive results. The authors concluded that when used as an initial screen, PTT can increase the yield of additional testing modalities, providing a timely and cost-effective approach for the diagnosis of heritable germline mutations in patients with retinoblastoma.
Connolly et al. (1983) reported a 4-generation family with 3 patterns of expression of the retinoblastoma gene: frank retinoblastoma, unilateral or bilateral; retinoma; and no visible retinal pathology except for 'normal degeneration' with age. ('Paving stone degeneration' of ... Connolly et al. (1983) reported a 4-generation family with 3 patterns of expression of the retinoblastoma gene: frank retinoblastoma, unilateral or bilateral; retinoma; and no visible retinal pathology except for 'normal degeneration' with age. ('Paving stone degeneration' of the type observed in 2 of 3 RB carriers, aged 49 and 59, is said by Duane (1980) to occur in about 20% of the adult population.) In a review, Balmer et al. (2006) noted that the most common presenting signs of retinoblastoma are leukocoria (a late sign) and strabismus (an early sign), but that many other ocular or general signs have been observed. Although the malignant tumor is curable with early treatment, there remains in the heritable form a major risk of second nonocular primary tumors. - Retinoma Gallie and Phillips (1982) described benign lesions in the retina in retinoblastoma patients. The distinctive characteristics of these lesions, referred to by the authors as retinomas, included a translucent, grayish retinal mass protruding into the vitreous, 'cottage-cheese' calcification in 75%, and retinal pigment epithelial migration and proliferation in 60%. They suggested that retinomas represent not the heterozygous state postulated by the Knudson 2-stage model of carcinogenesis but rather the homozygous state occurring in differentiated cell(s). Gallie et al. (1982) suggested that retinomas represent either spontaneous regression of a retinoblastoma or a benign manifestation of the RB gene. - Trilateral Retinoblastoma Brownstein et al. (1984) described 3 children with bilateral retinoblastoma and a morphologically similar neoplasm in the region of the pineal. They referred to this as trilateral retinoblastoma. The pineal gland has sometimes been referred to as 'the third eye.' Lueder et al. (1991) described a fourth case of pinealoma associated with bilateral retinoblastoma. The patient was one of 56 with heritable RB. Amoaku et al. (1996) reported 5 patients with trilateral retinoblastoma (including 2 previously reported), diagnosed among 146 consecutive patients with retinoblastoma in the West Midlands Health Authority Region in England between 1957 and 1994. This represented an incidence of 3%. There were 4 patients with pineoblastoma, only 1 of whom had a positive family history. The mean age at diagnosis of RB in the entire series was 6 months, whereas the patients with pineoblastoma were diagnosed at a mean age of 2 years. The tumors were not evident on the initial computed tomographic (CT) scans. One child presented with a calcified suprasellar mass 13 months before bilateral sporadic retinoblastoma was identified. Death occurred within 1 month of diagnosis of the intracranial tumor in 3 patients who received no treatment. In the other 2 patients, who were treated, death occurred at 15 months and 2 years, respectively, after diagnosis of intracranial tumor. Kivela (1999) performed a metaanalysis of trilateral retinoblastoma by reviewing the literature systematically and contacting authors to obtain missing information. Data from 106 children were used to determine frequency and Kaplan-Meier survival curves. No sex predilection was found. Median age at diagnosis of retinoblastoma was 5 months (range, 0 to 29 months); age at diagnosis was younger among 47 children (47%) with familial retinoblastoma compared with age at diagnosis among 52 children (53%) with sporadic retinoblastoma (2 vs 6.5 months; P less than 0.0001). Trilateral retinoblastoma usually affected the second or third generation with retinoblastoma. Median time from retinoblastoma to trilateral retinoblastoma was 21 months (range, 6 months before to 141 months after); time to trilateral retinoblastoma was longer for 78 (77%) pineal tumors compared with 23 (23%) suprasellar tumors (32 vs 6.5 months; P less than 0.0001). The size and prognosis of pineal and suprasellar tumors were similar. Screening by neuroimaging improved outcome. The cure rate was improved when the tumors were at or below 15 mm at the time of detection. Karatza et al. (2006) reported a pineal cyst simulating pineoblastoma in 11 children with retinoblastoma (2 familial and 9 sporadic). - Second Primary Tumors The risk of osteogenic sarcoma is increased 500-fold in bilateral retinoblastoma patients, the bone malignancy being at sites removed from those exposed to radiation treatment of the eye tumor (Abramson et al., 1976). Francois (1977) concluded that there is a special predisposition to osteogenic sarcoma, both radiogenic and nonradiogenic, in retinoblastoma patients and possibly in their relatives. Matsunaga (1980) estimated that the relative risk of development of nonradiogenic osteosarcoma in persons with the retinoblastoma gene is 230. That osteosarcoma is a direct effect of the genomic change that underlies retinoblastoma is indicated by the cases of osteosarcoma without retinoblastoma but with genomic changes like those of retinoblastoma. Chauveinc et al. (2001) reviewed retinoblastoma survivors who subsequently developed osteosarcoma. They found that osteosarcomas occurred 1.2 years earlier inside than outside the radiation field in patients who had undergone external beam irradiation. Also, the latency between radiotherapy and osteosarcoma was 1.3 years shorter inside than outside the radiation field. Bimodal distribution of latency periods was observed for osteosarcomas arising inside but not outside the radiation field: 40% occurred after a short latency, while the latency for the remaining 60% was comparable to that of osteosarcoma arising outside the radiation field. The authors suggested that different mechanisms may be involved in the radiocarcinogenesis. They hypothesized that a radiation-induced mutation of the second RB1 allele may be the cause of osteosarcomas occurring after a short delay, while other genes may be responsible for osteosarcomas occurring after a longer delay. To understand why the RB protein is specifically targeted in osteosarcoma, Thomas et al. (2001) studied its function in osteogenesis. Loss of RB but not p107 (116957) or p130 (180203) blocked late osteoblast differentiation. RB physically interacted with the osteoblast transcription factor, CBFA1 (600211), and associated with osteoblast-specific promoters in vivo in a CBFA1-dependent fashion. Association of RB with CBFA1 and promoter sequences resulted in synergistic transactivation of an osteoblast-specific reporter. This transactivation function was lost in tumor-derived RB mutants, underscoring a potential role in tumor suppression. Thus, RB functions as a direct transcriptional coactivator promoting osteoblast differentiation, which may contribute to the targeting of RB in osteosarcoma. Friend et al. (1987) found that the same DNA segment that they had isolated from 13q14 and showed to have attributes of the retinoblastoma gene is additionally the target of somatic mutations in mesenchymal tumors among patients having no apparent predisposition to retinoblastoma. Almost two-thirds of the secondary tumors arising in patients with retinoblastoma are mesenchymal in origin. Over 60% of the mesenchymal tumors are osteosarcomas; the soft tissue sarcomas include fibrosarcoma, leiomyosarcoma, liposarcoma, and others. Friend et al. (1987) specifically demonstrated homozygous deletions of the RB1 locus in sporadic cases of leiomyosarcoma, malignant fibrous histiocytoma, and undifferentiated sarcoma in the absence of any history of retinoblastoma. Friend et al. (1988) reviewed the subject of tumor-suppressing genes in retinoblastoma and other disorders. Henson et al. (1994) found loss of heterozygosity for the RB1 protein in 16 of 54 informative high-grade astrocytomas but not in 12 low-grade gliomas. Deletion mapping with ranking markers revealed that the retinoblastoma locus was preferentially targeted by the deletions. SSCP analysis and direct DNA sequencing demonstrated mutations in the remaining retinoblastoma allele. This evidence suggested to the authors that whereas mutation of the p53 tumor suppressor gene (191170) is an early event in the formation of many astrocytomas, mutation of the retinoblastoma gene is associated with progression of the astrocytoma into high-grade astrocytoma or glioblastoma multiforme. Previous work had demonstrated frequent loss of 9p, 10, 13q, 17p, 19q, and 22q in astrocytomas. Mutations in the RB1 gene were described. Cance et al. (1990) found that leiomyosarcomas and other soft tissue sarcomas in which expression of the RB gene product was decreased were more aggressive than tumors in which this protein was expressed by nearly all cells. Moll et al. (2001) evaluated the influence of age at external beam irradiation (EBRT) on the occurrence of second primary tumors (SPTs) inside and outside the irradiation field in 263 patients with hereditary retinoblastoma. They calculated cumulative incidences of SPT in 3 subgroups: irradiation before 12 months of age (early EBRT), irradiation after 12 months of age (late EBRT), and no irradiation. They found that hereditary RB conferred an increased risk of the development of SPT, especially in patients treated with EBRT before 12 months of age. However, they concluded that the presence of similar numbers of SPTs inside and outside the irradiation field suggested that irradiation was not the cause. The authors concluded that their study did not show an age effect on radiation-related risk, but rather that early EBRT is probably a marker for other risk factors of SPT. Kivela et al. (2001) analyzed the association between retinoblastoma and sebaceous carcinoma (SC) of the eyelid to improve surveillance of RB survivors. They studied 11 children with hereditary RB who subsequently developed eyelid SC. Nine of the children developed SC within the field of radiation. All 9 had received a median of 46 Gy (range, 21-89) of EBRT at a median age of 16 months (range, 0.5-15 years of age). Their median age at SC diagnosis was 14 years (range, 8-30 years) and median interval from EBRT to SC diagnosis was 11 years (range, 5-26 years). The 2 children who had never received EBRT developed eyelid SC at ages 32 and 54 years. In this series, the cumulative probability of a 5-year survival of eyelid SC was 87%. The authors concluded that SC of the eyelid may occur in patients with hereditary RB regardless of primary treatment, especially within the EBRT field 5 to 15 years after radiotherapy. Brantley et al. (2002) examined expression of p53 and Rb tumor suppressor pathways in uveal melanomas following plaque radiotherapy. They found that plaque radiotherapy damaged DNA, inhibited cell division, and promoted cell death. They stated that these changes might be due, at least in part, to induction of p53, which activates genes involved both in cell cycle arrest and apoptosis. Their results also showed that plaque radiotherapy can cause alterations in the expression of Rb, but the authors noted that the significance of the latter finding would require further study. Gombos et al. (2007) identified 15 retinoblastoma patients with secondary acute myelogenous leukemia (sAML; see 601626), 13 of whom developed sAML in childhood. Mean latent period from RB to AML diagnosis was 9.8 years (median, 42 months). Nine cases were of the M2 or M5 French-American-British subtypes. Twelve patients (79%) had received chemotherapy with a topoisomerase II inhibitor, and 8 (43%) had received chemotherapy with an epipodophyllotoxin. Ten children died of their leukemia. Gombos et al. (2007) questioned whether chemotherapy was a risk factor for the development of sAML in this series of patients.
Lohmann et al. (1996) found no correlation between the location of frameshift or nonsense mutations and phenotypic features of retinoblastoma, including age at diagnosis, the number of tumor foci, and the manifestations of nonocular tumors.
Taylor ... Lohmann et al. (1996) found no correlation between the location of frameshift or nonsense mutations and phenotypic features of retinoblastoma, including age at diagnosis, the number of tumor foci, and the manifestations of nonocular tumors. Taylor et al. (2007) studied 165 RB1 mutation carriers from 50 unrelated pedigrees with a family history of retinoblastoma. Twenty-five (50%) families had nonsense or frameshift mutations and showed high or complete disease penetrance. Two families with nonsense mutations in exon 1 showed slightly reduced penetrance, suggesting transcriptional modifiers or resistance to nonsense-mediated decay. Aberrant splicing mutations were identified in 13 (26%) families and associated with incomplete penetrance and variable expressivity. Eight (16%) families had large gene rearrangements associated with high penetrance. Promoter and missense mutations were associated with low penetrance. Six fully penetrant mutation carriers developed a secondary sarcoma at a median age of 15 years, regardless of mutation type. Retinomas were observed in patients with truncating mutations or large gene rearrangements.
Fung et al. (1987) used a cDNA probe to determine the lesion in retinoblastomas. In 16 of 40 retinoblastomas studied with a cDNA probe by Fung et al. (1987), a structural change in the RB gene was identifiable, ... Fung et al. (1987) used a cDNA probe to determine the lesion in retinoblastomas. In 16 of 40 retinoblastomas studied with a cDNA probe by Fung et al. (1987), a structural change in the RB gene was identifiable, including, in some cases, homozygous internal deletions with corresponding truncated transcripts. An osteosarcoma also had a homozygous internal deletion with a truncated transcript. Possible hotspots for deletion were identified within the RB genomic locus. Among those tumors with no identifiable structural change, there was either absence of an RB transcript or abnormal expression of the RB transcript. Bookstein et al. (1988) identified at least 20 exons in genomic clones of the RB gene and provisionally numbered them. With a unique sequence probe from intron 1, they detected heterozygous deletions in genomic DNA from 3 retinoblastoma cell lines and genomic rearrangements in fibroblasts from 2 hereditary retinoblastoma patients, indicating that intron 1 includes a frequent site for mutations conferring predisposition to retinoblastoma. Demonstration of a DNA deletion of exons 2-6 from 1 RB allele, as well as the demonstration of other deletions, explains the origin of shortened RB mRNA transcripts. The retinoblastoma candidate gene, 4.7R, does not show gross deletion or rearrangement in most retinoblastomas. Dunn et al. (1988) searched for more subtle mutations using the ribonuclease protection method for analysis of 4.7R mRNA from retinoblastomas. In the ribonuclease (RNase) protection assay, RNases A and T1 cleave single-stranded RNA at basepair mismatches in RNA:RNA or RNA:DNA hybrids. The test identifies only about 50% of single basepair mutations. Dunn et al. (1988) found that 5 of 11 RB tumors, which exhibited normal 4.7R DNA and normal-sized RNA transcripts, showed abnormal ribonuclease cleavage patterns. Three of the 5 mutations affected the same region of the mRNA, consistent with an effect on splicing involving an as yet unidentified 5-prime exon. Canning and Dryja (1989) found deletions in the retinoblastoma gene in 12 of 49 tumors from patients with retinoblastoma or osteosarcoma. Mapping of the deletion breakpoints revealed coincidence of no 2 breakpoints. Thus they could not support the conclusion of others regarding the existence of a 'hotspot' for deletion breakpoints in this gene. In 4 tumors, they sequenced 200 basepairs surrounding each deletion breakpoint. Three deletions had termini within pairs of short, direct repeats ranging in size from 4 to 7 basepairs. They interpreted this as indicating that 'slipped mispairing' may predominate in the generation of deletions at the RB locus. Short, direct repeats were incriminated in 15 of 20 deletions in the beta-globin locus. In other loci, Alu sequences at breakpoints are frequently found, e.g., in the LDL receptor gene (606945), the ADA gene (608958) and the beta-hexosaminidase gene (606869). Efstratiadis et al. (1980) argued that the repeats found at the breakpoints of deletions of the beta-globin locus are not long enough to mediate unequal crossing over via homologous recombination, thus requiring the alternative model, 'slipped mispairing' during DNA replication. Dunn et al. (1989) extended the characterization of mutations in RB1 using RNase protection of RB1 transcripts to locate probable mutations, followed by polymerase chain reaction (PCR) to amplify and sequence the mutant allele. Mutations were identified in 15 of 21 RB tumors; in 8 tumors, the precise error in nucleotide sequence was characterized. Each of 4 germline mutations involved a small deletion or duplication while 3 somatic mutations were point mutations leading to splice alterations and loss of an exon from the mature RB1 mRNA. By PCR techniques, Yandell et al. (1989) demonstrated single nucleotide changes in tumors from 7 patients with simplex retinoblastoma (with no family history of the disease). In 4 patients, the mutation involved only the tumor cells, and in 3 it involved normal somatic cells as well as tumor cells but was not found in either parent. Thus, these 3 represent new germinal mutations. All 3 were C-to-T transitions in the coding strand in the retinoblastoma gene. Two of the 3 occurred at CpG pairs. Since new germinal mutations of the retinoblastoma gene are more likely to occur on the paternal allele (Dryja et al., 1989), the overrepresentation of C-to-T transitions is probably the result of processes that occur during male gametogenesis. Direct analysis of disease-causing mutations are particularly applicable to diseases characterized by a high proportion of new mutations. This approach had been used successfully with Lesch-Nyhan syndrome (380000) and Duchenne muscular dystrophy (310200), which are associated with high frequencies of new point mutations and new deletions, respectively. Analysis of genomic DNA obviates the difficulty of having an RNA transcript or protein gene product for analysis and allows the detection of mutations that may occur at splice sites or other sequences that are excluded from the RNA transcript. Of the 10 mutations (7 retinoblastoma tumors plus 3 others), 5 occurred in the exon 21-24 region which represents only 15% of the coding sequence of the retinoblastoma gene. It has been found that aberrant proteins from which amino acids coded by these exons have been deleted lack binding activity for the adenovirus E1A dominant transforming protein. Blanquet et al. (1995) performed a mutation survey of the RB1 gene in 232 patients with hereditary or nonhereditary retinoblastoma. They systematically explored all 27 exons and flanking sequences, as well as the promoter. All types of point mutations were represented and found to be unequally distributed along the RB1 gene sequence. In the population studied, exons 3, 8, 18, and 19 were preferentially altered. Correlations between the phenotypic expression and molecular alterations were difficult to discern, at least for the missense and in-frame mutations. However, Blanquet et al. (1995) observed that some patients carrying mutations in exon 19 also developed nonocular tumors such as pineoblastoma, fibrosarcoma, or osteosarcoma. Germline mutations were detected in 36% of 25 familial cases, in 20.5% of bilateral sporadic or unilateral multifocal cases, and in 7.1% of unilateral sporadic cases. Because of the low level of detection of germline mutations in hereditary cases, they reasoned that other mechanisms of inactivation of RB1 must be involved. Lohmann et al. (1996) studied 119 patients with hereditary retinoblastoma for germline RB1 mutations. Southern blot hybridization and PCR fragment-length analysis revealed mutations in 48 patients. In the remaining 71 patients, they detected mutations in 51 (72%) by applying heteroduplex analysis, nonisotopic SSCP, and direct sequencing. Rare sequence variants were also found in 4 patients. No region of the RB1 gene was preferentially involved in single base substitutions. Recurrent transitions were observed at most of the 14 CGA codons within the RB1 gene. No mutation was observed in exons 25-27, although this region contains 2 CGA codons. This suggested to the authors that mutations within the 3-prime terminal region of the RB1 gene may not be oncogenic. For the entire series of 119 patients, mutations were identified in 99 (83%). The spectrum comprised 15% large deletions, 26% small length alterations, and 42% base substitutions. Lohmann et al. (1997) investigated the frequency and nature of constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma. A total of 45 mutations were detected in tumors from 36 patients. Thirty-nine of the mutations--including 34 small mutations, 2 large structural alterations, and hypermethylation in 3 tumors--were not detected in the corresponding peripheral blood DNA. In 6 (17%) of the 36 patients, a mutation was detected in constitutional DNA, and 1 of these mutations was known to be associated with reduced expressivity. The presence of a constitutional mutation was not associated with an early age at treatment. In 1 patient, somatic mosaicism was demonstrated by molecular analysis of DNA and RNA from peripheral blood. In 2 patients without a detectable mutation in peripheral blood, mosaicism was suggested because 1 of the patients showed multifocal tumors and the other later developed bilateral retinoblastoma. Hagstrom and Dryja (1999) investigated loss of heterozygosity in a set of matched retinoblastoma and leukocyte DNA samples from 158 patients informative for DNA polymorphisms. Loss of heterozygosity at the RB locus was observed in 101 cases, comprising 7 cases with a somatic deletion causing hemizygosity and 94 with homozygosity (isodisomy). Homozygosity was approximately equally frequent in tumors from male and female patients, among patients with a germline versus somatic initial mutation, and among patients in whom the initial mutation occurred on the maternal versus paternal allele. A set of 75 tumors exhibiting homozygosity was investigated with markers distributed in the interval 13cen-q14. Forty-one tumors developed homozygosity at all informative marker loci, suggesting that homozygosity occurred through chromosomal nondisjunction. The remaining cases exhibited mitotic recombination. There was no statistically significant bias in apparent nondisjunction versus mitotic recombination among male versus female patients or among patients with germline versus somatic initial mutations. Hagstrom and Dryja (1999) compared the positions of somatic recombination events in the analyzed interval with a previously reported meiotic recombination map. Although mitotic crossovers occurred throughout the assayed interval, they were more likely to occur proximally than a comparable number of meiotic crossovers. They observed 4 triple-crossover cases, suggesting negative interference for mitotic recombination, the opposite of what is usually observed for meiotic recombination. Bremner et al. (1997) studied a 4-kb deletion spanning exons 24 and 25 of the RB1 gene and associated with low penetrance, since only 39% of eyes at risk in this family developed retinoblastoma. This was said to have been the largest deletion observed in a low penetrance family. Unlike the usual RB mutations, which cause retinoblastoma in 95% of at-risk eyes and yield no detectable protein, the del24-25 allele transcribed a message splicing exon 23 to exon 26, resulting in a detectable protein that lacks 58 amino acids from the C-terminal domain, proving that this domain is essential for suppression of retinoblastoma. Two functions were partially impaired by del24-25, namely, nuclear localization and repression of E2F, consistent with the idea that low penetrance mutations generate 'weak alleles' by reducing but not eliminating essential activities. However, del24-25 ablated interaction of the RB protein with MDM2. Sampieri et al. (2006) identified mutations in the RB1 gene in 13 (37%) of 35 unrelated Italian patients with retinoblastoma. Mutations were identified in 6 of 9 familial cases and 7 of 26 sporadic cases. Eleven of the 13 mutations were novel. Gratias et al. (2007) analyzed 22 short tandem repeat loci on chromosome 16q in 58 patients with known RB1 mutations and detected loss of heterozygosity in 18 (31%) of 58 tumors, with a 5.7-Mb minimum deleted region in the telomeric part of 16q24 with a centromeric boundary at Mb 82.7 in exon 10 of the CDH13 gene (601364). There was no loss of expression of CDH13 or 2 other candidate suppressors at 16q24, CBFA2T3 (603870) and WFDC1 (605322), in retina compared to retinoblastoma tissue. Gratias et al. (2007) noted that almost all retinoblastomas with chromosome 16q24 loss showed diffuse intraocular seeding, suggesting that genetic alterations in the minimal deleted region are associated with impaired cell-to-cell adhesion. Zhang et al. (2012) showed that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss in retinoblastoma, Zhang et al. (2012) performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. Zhang et al. (2012) then evaluated the role of RB1 in genome stability and considered nongenetic mechanisms of cancer pathway deregulation. For example, the protooncogene SYK (600085) is upregulated in retinoblastoma and is required for tumor cell survival. Targeting SYK with a small molecule inhibitor induced retinoblastoma tumor cell death in vitro and in vivo. Thus, Zhang et al. (2012) concluded that retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.
Macklin (1960) stated that in the U.S. the frequency of retinoblastoma is about 1 in 23,000 live births. Jensen and Miller (1971) found that at ages 2 to 3 years a peak of mortality occurred which was 2.5 ... Macklin (1960) stated that in the U.S. the frequency of retinoblastoma is about 1 in 23,000 live births. Jensen and Miller (1971) found that at ages 2 to 3 years a peak of mortality occurred which was 2.5 times greater in blacks than in whites. Whether this reflects a truly high frequency in blacks or some other factor such as higher mortality from delayed diagnosis is not clear. Pendergrass and Davis (1980) found an incidence of 3.58 cases among each million children under age 15 years. Over 90% were diagnosed before age 5 years. No difference was found between whites and blacks, but other non-whites had rates more than 4 times greater than those of whites. Bilateral disease occurred in 20%. No nonhereditary retinoblastomas (which represent 55-65% of all retinoblastoma cases) are bilateral. Bilateral and unilateral hereditary retinoblastoma represent, respectively, about 25-30% and 10-15% of all cases.
Guidelines for diagnosis and care of children and families affected by Rb have been published. See ....
DiagnosisGuidelines for diagnosis and care of children and families affected by Rb have been published. See .Clinical DiagnosisThe diagnosis of retinoblastoma (Rb) is usually established by examination of the retina of the eye using indirect ophthalmoscopy. Fundus imaging, MRI, and ultrasonography are used to support the diagnosis and stage the tumor.Retinoblastoma is:Unilateral if only one eye is affected by retinoblastoma. Usually, in individuals with unilateral retinoblastoma the tumor is also unifocal, i.e., only a single retinoblastoma tumor is present. However, in most persons with unilateral retinoblastoma 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 retinoblastoma. In individuals with bilateral retinoblastoma both eyes clearly may show multiple tumors. Some individuals have multifocal tumors in one eye (unilateral multifocal retinoblastoma). Intraocular seeding may mimic true multifocal tumor growth. Trilateral if bilateral (or, rarely, unilateral) retinoblastoma and a pinealoblastoma co-occur. TestingHistopathology. Diagnosis of retinoblastoma can be confirmed by histopathologic investigation. Careful investigation of the optic nerve is required to identify possible invasion of tumor cells. Chromosome analysis. Cytogenetic analysis of peripheral blood lymphocytes has been used to detect deletions or rearrangements involving 13q14.1-q14.2, which are present in approximately 5% of individuals with unilateral Rb and approximately 7.5% of individuals with bilateral Rb. Cytogenetic resolution at the 600-650 band level is recommended and at least 30 metaphases should be analyzed in order to detect mosaic aberrations that are present in about 1% of individuals with Rb. Molecular Genetic Testing Gene. RB1 is the only gene in which mutations are known to initiate retinoblastoma. Clinical testingFor an integrated view of the use of different testing methods, see Interpretation of Test Results and Testing Strategy. Table 1. Summary of Molecular Genetic Testing Used in RetinoblastomaView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2Test AvailabilityRB1Sequence analysis / mutation scanning (genomic) 3Single-base substitutions, small intragenic deletions, insertions70%-75%Clinical Targeted mutation analysis 4Panel of recurrent point mutations 25% 5Sequence analysis of RNA from blood 6 Deep intronic splice mutations, gross rearrangements<5% 7Gross deletion / duplication analysis 8Deletion / duplication analysis 8Exonic, multiexonic, and whole-gene deletions along with large insertions, rearrangements 916% FISH 10Submicroscopic deletions and translocations >8% Heterozygosity testing De novo submicroscopic germline deletions 11,128% Methylation analysisHypermethylation of the promoter region10%-12% 131. The ability of the test method used to detect a mutation that is present in the indicated gene2. Lohmann et al [2002]. In individuals with normal chromosome studies; refers to the ability to detect a germline mutation if one is present. Note: Table 2 lists the probability that a germline mutation would be present based on family history and tumor presentation. 3. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.4. Particularly useful for detecting mosaic recurrent mutations in blood and can detect mutant DNA levels that are below the limit of conventional sequence analysis. Low levels of mutational mosaicism have been identified in probands with bilateral disease and in individuals with unilateral disease who have affected children who inherited the mutation; therefore, detecting mosaic recurrent mutations is clinically relevant [Rushlow et al 2009].5. Rushlow et al [2009]. Panel of targeted mutations and detection frequency may vary.6. May be useful when sequence analysis or mutation scanning of genomic DNA purified from peripheral blood is negative. 7. In individuals without a mutation identified by DNA-based analyses [Zhang et al 2008]8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.9. Mutations detected may vary with the method chosen for deletion/duplication analysis.10. Deletions of all or parts of RB1 have been identified by FISH analysis using probes derived from sequences of RB1 (e.g., LSI 13 [RB1] 13q14 SpectrumOrange Probe).11. The genotype of RB1 in peripheral blood DNA of the parents may suggest absence of the mutant RB1 allele of the proband, suggesting a de novo germline mutation, or low-level mosaicism for the mutant allele in the parent. 12. 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 mutant allele constitutes the somatic mutation. 13. 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.Linkage analysis. Linkage analysis using highly informative microsatellite markers within and tightly linked to RB1 can be used in two settings: To track the mutant allele in families with more than two affected individuals Note: Indirect testing in a two-generation family with an affected parent and an affected child may be unreliable because of the possibility of germline mosaicism in the "founder" parent [Rushlow et al 2009].To determine if an individual at risk in a family with only one affected individual has inherited either RB1 allele present in the affected individual. If the individual at risk does not have either RB1 allele in common with the affected relative, the individual's risk of developing retinoblastoma decreases to the risk level in the general population [Greger et al 1988, Wiggs et al 1988]. Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at Lohmann et al [2011] (click here for full text). Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here. A combination of clinical presentation, family history, and molecular genetic testing is used to determine if a proband has a germline (heritable) mutation or two somatic (non-heritable) mutations in the tumor. See Table 2. If a disease-causing RB1 mutation is found in the DNA of white blood cells of the affected individual, (s)he has a high probability of having a germline mutation. If neither disease-causing RB1 mutation identified in tumor tissue is found in the DNA of white blood cells, the affected individual has a low probability of having an RB1 germline mutation. Note: Because blood mosaicism as low as 20% can usually be detected by conventional molecular analysis such as sequencing, the failure to detect an RB1 disease-causing mutation in the DNA of white blood cells reduces but cannot eliminate the probability that the individual has an RB1 mutation in his/her germline.Table 2. Probability of Germline Mutation Being Present in a Proband with Rb Based on Family History and Tumor PresentationView in own windowFamily History Rb Presentation Probability that an RB1 Germline Mutation is PresentUnilateralBilateralMultifocalUnifocal 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 mutations are identified by conventional molecular testing in 90%-95% of simplex cases with bilateral involvement; the remaining 5% may have translocations, deep intronic splice mutations, or low-level mosaic mutations which may or may not be in the germline. Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a probandIndividuals with familial or bilateral retinoblastoma. The goal is to identify the constitutional RB1 mutation that caused inactivation of one RB1 allele. Molecular genetic testing including sequence analysis and some form of deletion/duplication analysis (e.g., MLPA, FISH, CMA, heterozygosity testing) is performed on peripheral blood DNA to identify the constitutional RB1 mutation. About 90%-95% of individuals have a detectable RB1 mutation in blood. In some individuals with bilateral retinoblastoma and no family history of retinoblastoma, an oncogenic RB1 mutation is not detected in peripheral blood. In such cases, tumor DNA may be studied. If tumor DNA demonstrates that both RB1 alleles in the tumor have an RB1 mutation or hypermethylation of the RB1 promoter region, peripheral blood DNA can be tested for the presence of the RB1 mutations identified in the tumor. If neither of the two RB1 mutations identified in the tumor is detected in DNA from peripheral blood, mutational mosaicism can be assumed. If one of the RB1 mutations identified in the tumor is a large deletion, testing for mutational mosaicism in peripheral blood cells may include FISH analysis. Individuals with unilateral retinoblastoma and no family history of retinoblastoma (simplex cases). The goal is to identify the two RB1 mutations that caused inactivation of both RB1 alleles in the tumor, if available. Molecular genetic testing including sequence analysis, some form of deletion/duplication analysis (e.g., MLPA, FISH, CMA, heterozygosity testing), and methylation analysis is first performed on tumor tissue. If tumor DNA demonstrates that each of the two tumor alleles have an RB1 mutation or hypermethylation of the RB1 promoter region, peripheral blood DNA can be tested for the presence of the RB1 mutations identified in the tumor. In about 14% of individuals with unilateral retinoblastoma and no family history of retinoblastoma (see Table 2), one of the RB1 mutations identified in the tumor is also detected in peripheral blood, either as a heterozygous mutation, or in a mosaic state (indicating a mutation that occurred after conception) which may or may not be present in the germline of the proband.In the future, MYCN amplification may be useful for analysis of tumors. About 1.5% of children with sporadic unilateral Rb have high level MYCN amplification but no mutational inactivation of RB1 [Rushlow et al 2013].Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo phenotypes other than hereditary predisposition to retinoblastoma and second cancers (see Natural History, Related tumors) are known to be associated with mutation of RB1.
Probands with retinoblastoma (Rb) usually present in one of the following clinical settings: ...
Natural HistoryProbands with retinoblastoma (Rb) usually present in one of the following clinical settings: 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 chromosomal deletion of 13q14. Such chromosomal abnormalities are often associated with developmental delay and birth defects [Mitter et al 2011, Castéra et al 2013]. Normal cytogenetic study and one of the following Positive family history and unilateral or bilateral Rb (~10% of index cases) Negative family history and bilateral Rb (30% of index cases) Negative family history and unilateral Rb (60% of index cases) About 60% of individuals with Rb have unilateral retinoblastoma with a mean age at diagnosis of 24 months. About 40% have bilateral retinoblastoma with a mean age at diagnosis of 15 months. In individuals with a positive family history (~10%) who undergo clinical surveillance via serial retinal examinations, tumors are often identified in the first month of life. The most common presenting sign of Rb 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 symptoms 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.In most children with bilateral tumors, both eyes are affected at the time of initial diagnosis. Some children who are initially diagnosed with unilateral retinoblastoma later develop a tumor in the contralateral unaffected eye. Retinoma and associated eye lesions. These lesions range from retinal scars to calcified phthisical eyes resulting from spontaneous regression of retinoblastoma, and include benign retinal tumors (called retinoma) that have undergone spontaneous growth arrest [Dimaras et al 2008]. Related tumors. Individuals with germline RB1 mutations are at increased risk of developing tumors outside the eye. Pinealoblastomas occur in "retina-like" tissue in the pineal gland of the brain. Co-occurrence of pinealoblastomas or primitive neuroectodermal tumors and retinoblastoma is referred to as trilateral retinoblastoma. Pinealoblastoma is rare and usually fatal, unlike retinoblastoma of the eye which is generally curable [Kivelä 1999]. The risk for other specific extraocular primary neoplasms (collectively called second primary tumors) is increased in individuals with heritable Rb and in heterozygous carriers of a cancer-predisposing RB1 mutation. Most of the second primary cancers 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 retinoblastoma who have received external beam radiation therapy [Wong et al 1997]. Survivors of hereditary 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].
Several ocular conditions of childhood can clinically simulate retinoblastoma (Rb): ...
Differential DiagnosisSeveral ocular conditions of childhood can clinically simulate retinoblastoma (Rb): Sporadic congenital disorders including persistent hyperplastic primary vitreous and Coat's disease Hereditary disorders including tuberous sclerosis, Norrie disease, incontinentia pigmenti, familial exudative vitreoretinopathy (see Autosomal Dominant Familial Exudative Vitreoretinopathy), and von Hippel-Lindau disease. Ocular infestation by Toxocara canis Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Guidelines for retinoblastoma care have been developed [Canadian Retinoblastoma Society 2009 (click for full text)]....
ManagementGuidelines for retinoblastoma care have been developed [Canadian Retinoblastoma Society 2009 (click for full text)].Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with retinoblastoma, 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. In the absence of family history, most commonly the affected eye(s) contain large tumors, directly visible through the pupil as a white pupillary reflex. Extent of tumor is estimated by clinical examination under anesthetic and imaging techniques such as ultrasound and MRI, particularly focusing on the tumor-optic nerve relationship. CT scan is contraindicated because of the risk of radiation in children with germline RB1 mutations. 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 choroidal invasion.If retinoblastoma has spread outside the eye, the stage of cancer will need to be evaluated to set out the most appropriate care of the child.In those individuals with a family history of retinoblastoma (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 anesthetic. Medical genetics consultation at the time of diagnosis is recommended to clarify for the family the heritable aspects of retinoblastoma, especially as pertains to their child. Molecular diagnosis now has a sensitivity of 96% in identifying the precise RB1 mutant allele in each child and is an important component of care of the affected individual and the family.Treatment of ManifestationsGoals of treatment are first preservation of life, and then of sight. As optimum treatment may be complex, specialists skilled in the treatment of retinoblastoma from various fields including ophthalmology, pediatric oncology, pathology and radiation oncology should collaborate in 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 combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy. Prevention of Secondary ComplicationsIf 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. If such tests are absolutely necessary in essential health care, then they should be used.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 (see ). 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 mutation have an eye examination under anesthesia every three to four weeks until age six months, then less frequently until age three years. Clinic 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 retinoblastoma are at risk of developing tumors in their normal eye [Temming et al 2013]. If the two RB1 mutant alleles are identified in the tumor and if the individual is shown to have one of those two mutations in leukocyte DNA (~14% of individuals), the children are followed as described above. Mosaicism involving more than 15% of blood cells is molecularly detectable by conventional methods. If the RB1 mutant alleles identified in the tumor are not detected in leukocyte DNA, there is still risk that the individual has low-level mosaicism (involving <15% of blood cells) for the mutant allele and will develop a tumor in the other eye [Rushlow et al 2009]. This risk is small enough that examination under anesthesia may be replaced with regular clinical examination of the eyes, including clinical ultrasound (a simple, non-invasive procedure). 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. Where available, total body MRI at regular intervals may be indicated. No specific screening protocols have been published. Individuals at risk for retinoblastoma who warrant surveillance for early manifestations of Rb include the following: Individuals with retinomas (premalignant retinal lesions associated with Rb)Children who have inherited an RB1 cancer-predisposing mutation OR children at risk for Rb who have not undergone molecular genetic testing: Eye examinations by an ophthalmologist experienced in the treatment of retinoblastoma starting directly after birth as described above in Detection of subsequent Rb after initial diagnosis. Young or uncooperative children may require examination under anesthesia. At-risk children who have not inherited the cancer-predisposing mutation known to be present in the family as determined by RB1 mutation analysis: Examination by an ophthalmologist familiar with retinoblastoma shortly after birth. Subsequent eye examinations should be performed as needed for routine pediatric care. Agents/Circumstances to AvoidIt has been suggested by Fletcher et al [2004] that cancer risks in hereditary retinoblastoma survivors may be reduced by limiting exposure to DNA-damaging agents (radiotherapy, tobacco, and UV light). Evaluation of Relatives at RiskAsymptomatic at-risk children. Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the disease-causing mutation [Noorani et al 1996, Richter et al 2003]. The American Society of Clinical Oncologists identifies Rb 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]. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management When there is a family history of Rb, various options are available to optimize management of an at-risk pregnancy [Canadian Retinoblastoma Society 2009] When the RB1 mutant allele of the proband is known:Most commonly, the fetus can be tested for that specific RB1 mutant allele at any time, including amniocentesis at 32 weeks’ gestation.If the fetus does not carry the mutation, the risk for Rb is the same as that for any individual in the general population.If the fetus carries the RB1 mutant allele present in the family, it is recommended that early delivery at 36 weeks’ gestation be performed, which is within the normal range for spontaneous birth. This will allow the earliest detection of visually threatening tumors at a time that they can still be treated with minimally invasive therapies to achieve potential good vision. Rb tumors grow rapidly around the time of birth, and every day can make a difference in the ultimate outcome.If the RB1 mutant allele of the proband is NOT known:Obstetric ultrasound or MRI may reveal a large Rb in the eye of a fetus; however, these tests are not sensitive to small Rb tumors. Depending on the relationship of the infant to the proband, children should have examination of both retinas with the pupils widely dilated by an ophthalmologist knowledgeable about Rb within a few days of birth, or in the first few weeks after birth. Clinic examinations by an ophthalmologist knowledgeable about Rb can then follow as described above; if a tumor is seen, the child needs an examination under anesthesia to fully evaluate the stage and extent of disease to help direct appropriate treatment (see Evaluations Following Initial Diagnosis).Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDRB113q14.2Retinoblastoma-associated proteinRetinoblastoma Genetics Mutation Database RB1 homepage - Mendelian genes RB1 homepage - Mendelian genesRB1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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) View in own window 180200RETINOBLASTOMA; RB1 614041RB1 GENE; RB1Molecular 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.FigureFigure 1. Schematic of the molecular genetic mechanisms that result in non-hereditary and hereditary retinoblastoma (Rb). The development of Rb is initiated if both alleles of RB1 are mutated (rb rb). In non-hereditary Rb, both mutations (more...)Normal allelic variants. Twenty-seven exons are transcribed and spliced into a 4.7-kb mRNA. There is no indication of functional alternative splicing. No frequent polymorphic sites within the 2.7-kb open reading frame are known, but there are intronic variants and two highly polymorphic microsatellites (Rb1.20, Rbi2) and one minisatellite (RBD). Pathologic allelic variants. More than 2500 distinct point mutations have been observed in white blood-cell DNA of individuals with retinoblastoma or in tumors, 1400 are archived (see Table A, Locus Specific). The majority of RB1 mutations result in a premature termination codon, usually through single base substitutions, frameshift mutations, or splice mutations. Mutations have been found scattered throughout exon 1 to exon 25 of RB1 and its promoter region. In a single family, a possible disease-causing variant in exon 27 was identified [Mitter et al 2009]. Recurrent mutations are observed at 14 methylated CpG dinucleotides. Other important types of pathogenic allelic variants are gross 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. Upon phosphorylation, the binding activity of the pocket domain is lost, resulting in the release of cellular proteins. For a review see Goodrich [2006]. Abnormal gene product. The majority of mutant alleles, if expressed at all, code for proteins that have lost cell cycle-regulating functions. Retention of partial activities has been observed in proteins resulting from mutant alleles that are associated with low-penetrance retinoblastoma [Lohmann et al 1994, Bremner et al 1997, Otterson et al 1997].
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