Case records of the Massachusetts General Hospital. Case 5-2006. An 11-year-old girl with loss of vision in the right eye.
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Blindness↗
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Focal therapy in the management of retinoblastoma: when to start and when to stop.
PURPOSE: To describe the treatment effects and side effects of different modalities of focal treatment used for retinoblastoma. METHODS: Green (532-nm) laser, continuous wave Nd:YAG (1064-nm) laser, transpupillary or transcleral (810-nm) laser, and cryotherapy were used in the treatment of 46 eyes in 35 patients affected with retinoblastoma. The number of treatment sessions and the amount of energy applied were recorded in an attempt to determine the amount of energy required to adequately treat tumors of various sizes. In addition, we have attempted to determine when treatment becomes overtreatment and is likely to lead to complications. RESULTS: The treatment endpoint for laser in this study was calcific, gliotic, or flat scars. Small tumors (<2 mm in height, <4 DD) were successfully treated in 3 or fewer sessions of 532-nm laser. Anterior small tumors were successfully treated with transcleral 810-nm laser or cryotherapy. Medium tumors, between 2.0 and 4.0 mm in thickness, required 2 to 9 treatments to achieve a good response and often required the addition of chemotherapy to reduce the size of the tumor before or during laser treatment. Large tumors required chemotherapy combined with many laser treatments for complete control. Complications associated with excessive laser were vitreous condensation with traction, vitreous hemorrhage, retinal detachment, tumor break, cataract formation, and iris burns. CONCLUSION: Laser treatment alone for small tumors, and combined with cryotherapy and chemotherapy for larger tumors, is effective in the treatment of retinoblastoma. Complications of focal therapy can most often be avoided by using the minimal effective laser power.
Antineoplastic Agents↗
Retinoblastoma in older children.
PURPOSE: Retinoblastoma (RB) is known to present with atypical signs and symptoms in older patients. Our article reviews the clinical and histopathological features of RB encountered in children older than 5 years of age. METHODS: A total of 337 consecutive patients with RB were reviewed. Eighteen (5.3%; 10 males, 8 females) who presented after the age of 5 were selected for further analysis of clinical data and histopathological material in this retrospective, non-comparative case series. RESULTS: The age range was from 5 to 12 years (mean age 6.4). Unilateral disease was seen in 14 children, bilateral disease in 4 children. Eleven children were the product of consanguineous marriages. Seven patients had leukocoria; the others presented with signs of uveitis, cellulitis, and/or trauma. Three patients had flat, plaque-like lesions on histopathologic evaluation. CONCLUSIONS: Clinical and histopathologic features were atypical in 47% and 21% respectively in the retinoblastoma patients who presented after the age of 5 years.
Child↗
Functional results after treatment of retinoblastoma.
PURPOSE: Because of the long-term complications associated with external beam radiation in retinoblastoma, alternative treatment methods have been investigated. We conducted a retrospective study to evaluate the functional results of new treatment modalities. METHODS: Thirty-seven eyes were treated without external beam irradiation in 31 patients. The median diameter of the largest tumor in each eye was 6 mm. Primary chemotherapy was used in 25 cases, chemothermotherapy was used in 32 cases, cryotherapy was used in 28 cases, iodine 125 Plaques were used in 15 cases, diode laser thermotherapy was used alone in 11 cases, and photocoagulation was performed in 5 cases. The median follow-up after diagnosis of retinoblastoma was 41 months. The visual results were evaluated at a median age of 54 months. RESULTS: The median visual acuity of the treated eyes was 20/33. Twenty-four eyes presented a visual acuity better than 20/40, 4 eyes had a visual acuity between 20/200 and 20/40, and 9 eyes had a visual acuity less than 20/200. Maculopathy was observed in 16 cases, associated with papillopathy in 1 case. A cataract was observed in 1 case and a vitreous hemorrhage was observed in another case. Twenty-one eyes did not develop any complications. No corneal dryness and very few lens changes were observed. CONCLUSION: The functional results after local treatments for retinoblastoma are very good. The most frequent complication is maculopathy, particularly when the tumor involves or is situated close to the macula.
Antineoplastic Agents↗
Mitotic recombination map of 13cen-13q14 derived from an investigation of loss of heterozygosity in retinoblastomas.
Loss of heterozygosity at tumor-suppressor loci is an important oncogenic mechanism first discovered in retinoblastomas. We explored this phenomenon by examining a set of matched retinoblastoma and leukocyte DNA samples from 158 patients informative for DNA polymorphisms. Loss of heterozygosity at the retinoblastoma locus (13q14) 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 germ-line vs. somatic initial mutation, and among patients in whom the initial mutation occurred on the maternal vs. paternal allele. A set of 75 tumors exhibiting homozygosity was investigated with markers distributed in the interval 13cen-13q14. 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 vs. mitotic recombination among male vs. female patients or among patients with germ-line vs. somatic initial mutations. We 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. Finally, we observed four triple-crossover cases, suggesting negative interference for mitotic recombination, the opposite of what is usually observed for meiotic recombination.
Chromosome Mapping↗
Elements regulating the transcription of human interstitial retinoid-binding protein (IRBP) gene in cultured retinoblastoma cells.
PURPOSE: To identify cis-acting elements and trans-acting factors involved in the expression of human IRBP gene. METHODS: Transient transfection of WERI-Rb1 and HeLa cells, DNase 1 footprinting, gel mobility-shift assay and yeast one-hybrid system were used to study the regulatory elements that are involved in the expression of human IRBP gene. RESULTS: A region between -1620 and -1411 was shown to have enhancer properties. Using nuclear extracts from WERI-Rb1 and HeLa cells, four footprints were identified in the proximal promoter region (-206 to +68). The core promoter element IP1 binds to OTX2 in the yeast one-hybrid system. By cotransfecting HeLa cells, OTX2 could transactivate the irbp promoter. The functions of IP2 (from -119 to -86) and IP3 (from -183 to -147) remain to be determined. The region containing the HeLa cell-specific footprint IP4 (from -202 to -180) could silence the OTX2 transactivation of the irbp promoter. CONCLUSION: The 5'-flanking region of irbp contains an enhancer sequence. The possible silencer upstream from the core promoter may serve to suppress expression of irbp in HeLa cells. When the proximal promoter is used to identify binding proteins in a human retina library by the yeast one hybrid system, nine of the identified clones contained the cDNA sequence for the homeodomain protein OTX2. Since no clones for the homeodomain protein CRX were found, and since OTX2 can transcriptionally activate irbp in normally non-expressing HeLa cells, it is possible that OTX2 rather than CRX is the transcriptional activator for irbp in human photoreceptors.
Amino Acid Sequence↗
Mutant herpes simplex virus-mediated suppression of retinoblastoma.
PURPOSE: To test the ability of a mutant herpes simplex virus (HSV) hrR3 to inhibit growth of Y79 human retinoblastoma in vitro and in vivo. METHODS: Cultured Y79 cells were infected with multiplicities of infection (MOI) ranging from 0.004 to 0.1 of hrR3. Surviving cells were counted using trypan blue dye exclusion. Using X-gal staining, expression of the lacZ gene was examined in vitro on day 3 postinfection to evaluate viral replication. Nude mice harboring Y79 tumors subcutaneously received an intraneoplasmic injection of 5 x 10(7) plaque-forming units of hrR3. The tumor sizes were measured weekly. Expression of the lacZ gene was also examined on one week postinfection. RESULTS: There are 31% and 13% cells surviving in cultured Y79 cells infected by hrR3 at an MOI of 0.1 on days 3 and 5 postinfection respectively compared to those of mock-infected cells. Also more than 70% of Y79 cells were stained with X-gal at an MOI of 0.1 which demonstrated active viral replication in vitro. Virus-treated subcutaneous tumors were smaller than control tumors (p<<0.05, Student's t-test) on days 14, 21, and 28 postinfection. Positive X-gal staining was also observed in the tumor nodule which was challenged with this viral vector. CONCLUSIONS: We have demonstrated that hrR3 is capable of inhibiting Y79 tumor growth both in cell culture and in nude mice. These data suggest that gene therapy using this mutant HSV vector can be a new supplementary therapeutic modality for retinoblastoma.
Animals↗
Expression of glutamate transporter subtypes in cultured retinal pigment epithelial and retinoblastoma cells.
PURPOSE: Glutamate is the major excitatory neurotransmitter in the retina and glutamate uptake is essential for normal glutamate signalling. Retinal diseases may induce neurochemical changes which affect retinal cells including retinal pigment epithelium (RPE). The aim of the study was to investigate the expression of glutamate transporter subtypes in RPE and retinoblastoma cells and to clarify the effect of proliferation modulators on the levels of the expressed transporter in the RPE cell line. METHODS: Cultured pig RPE cells and two human RPE cell lines, D407 and ARPE-19, as well as the human retinoblastoma cell line Y79 were used. Glutamate transporter expression was evaluated with Western blot analysis and immunocytochemistry. RESULTS: The study revealed unexpected expression of neuronal glutamate transporter/chloride channel EAAT4 in these three cell lines, but not in cultured pig RPE cells, whereas another glutamate carrier, EAAC1, was present in all cell types utilized. Other transporter subtypes, GLT1, GLAST and EAAT5 were not found. Neither tamoxifen, known to inhibit both proliferation and glutamate uptake in RPE cells, nor retinoic acid nor insulin, also known to affect cell proliferation rates, were capable of changing the total levels of EAAT4 in APRE-19 cells. CONCLUSIONS: Neuronal glutamate transporter EAAC1 is expressed in RPE cells. The robust expression of EAAT4 in cell lines may reflect a role of EAAT4 in cell proliferation and migration. Unaltered steady-state expression of this carrier and chloride-channel protein hints at posttranslational mechanisms of regulation of EAAT4.
Amino Acid Transport System X-AG↗
The molecular biology of retinoblastoma.
Retinoblastoma, a rare pediatric eye tumor, has served as an important model for the heritable predisposition to cancer. The retinoblastoma protein, Rb, functions as a tumor suppressor by controlling progression through the cell cycle. Rb function is regulated primarily by its phosphorylation state, which is determined by the complex interaction of multiple kinases and their inhibitors that together form the 'Rb pathway'. This pathway has been found to be functionally inactivated in almost all types of cancer. Despite recent advances in our understanding of Rb function, the precise role of Rb loss in the development of retinoblastoma remains unclear. Recent work in genetically altered mice has suggested that an additional mutation in another gene is required for retinal tumor formation. An alternative model presented here is based on the noncell-autonomous functions of Rb contributing to tumorigenesis.
Genes, Retinoblastoma↗
Parental age in Indian patients with sporadic hereditary retinoblastoma.
There is a consistent correlation between sporadic hereditary retinoblastoma and parental age. It has been proven beyond doubt that the birth rank is correlated with parental age. In the present study, a test for the effect of birth rank was performed in order to assess the risk of developing retinoblastoma with increased parental age. The study of the effect of birth rank showed a significant association between sporadic retinoblastoma (bilateral and unilateral) and late para, indicating that fresh germline mutations must have taken place in some of the sporadic cases. An investigation of the effect of birth rank on familial cases, obtained from published papers and our own series, showed that familial retinoblastoma is significantly associated with early para, suggesting early parental age. Further analysis of the mean paternal and maternal ages of sporadic cases (bilateral and unilateral) showed that the mean paternal age of sporadic bilateral (sporadic hereditary) cases was higher than that of sporadic unilateral cases (p<0.05). No such correlation was seen with mean maternal age. Thus, the present study shows that a high paternal age may be associated with sporadic bilateral (sporadic hereditary) retinoblastoma.
Adult↗
Distribution of tumors in the retina in hereditary retinoblastoma patients.
We have compared the location of the ocular tumors in hereditary retinoblastoma in relation to the age of the patients at time of diagnosis. Eighty fundus drawings were analyzed from 59 hereditary patients containing I 59 tumors. At the time of diagnosis, indirect ophthalmoscopy was performed under general anaesthesia in all patients and standard drawings of the retina were made depicting the number and relative location of all tumors. The distance between the center of the tumor and the center of the macula was measured and plotted against the age of the patients at time of diagnosis. The results show that the distance between the center of the tumor and the center of the macula at time of diagnosis increases with age during the first seven months after birth.
Child, Preschool↗
The two-stage mutation model in retinal hemangioblastoma.
BACKGROUND: The two-stage mutation model involving successive inactivation of both alleles of a tumor suppressor gene was originally proposed by Knudson, who analyzed the age incidence curves for unilateral and bilateral retinoblastoma, and suggested that hereditary tumors arise by a single somatic event superimposed on a defective genetic background and sporadic tumors by a two-stage somatic process. In this study, the age-incidence curve of patients with retinal hemangioblastoma with and without associated von Hippel-Lindau disease were analyzed. METHODS: We reviewed the literature between 1964 and 1998 to find all reported cases of retinal hemangioblastoma and classified patients in a type A group (n = 223) when associated with von Hippel-Lindau disease and a type B group (n = 30) when not associated with von Hippel-Lindau disease. We analyzed and compared the age incidence of these two groups. RESULTS: There was a statistically significant difference between the mean age at diagnosis of retinal hemangioblastoma in the two groups, i.e., 48.4 +/- 16.6 years for type B patients and 24.9 +/- 12.0 years for type A patients (p < 0.0001). The age incidence curve for type A retinal hemangioblastoma fit a first-order equation (log S = 0.411-0.034t) with r = 0.97, indicating a single somatic mutation, whereas the age incidence curve for type B retinal hemangioblastoma fit a second-order equation (log S = 0.184-2.25 x 10(-4)t2) with r = 0.97, indicating two somatic mutations. CONCLUSIONS: Type B (sporadic) retinal hemangioblastoma may arise from two separate somatic mutations inactivating both alleles at the von Hippel-Lindau locus, whereas patients with von Hippel-Lindau disease (type A) inherit a defective allele and require only one additional somatic mutation.
Adolescent↗
Intraocular carboplatin concentrations following intravenous administration for human intraocular retinoblastoma.
Previous studies of the penetration of carboplatin into the vitreous have depended on unaffected animals or on animal models for other cancers. The objective of this study was to determine the intraocular levels of carboplatin following intravenous administration of carboplatin in the treatment of human intraocular retinoblastoma. Eight patients with bilateral intraocular retinoblastoma were treated in a consistent fashion with intravenous carboplatin. One additional patient was similarly treated, but enucleated one month later. Samples were taken from those nine eyes after enucleation one to two hours after the administration of 18.7 mg/kg (560 mg/m( 2) for patients more than 12 kg) of intravenous carboplatin, and carboplatin concentrations in the aqueous and vitreous were then measured by atomic absorption spectrometry. The mean concentration measured in the aqueous was 5.13 microg/ml and in the vitreous 4.05 microg/ml, and vitreal concentrations were an average of 80% of aqueous concentrations. In one patient, a vitreous concentration of carboplatin was detected after an interval of one month that was 10% of the levels found in the samples enucleated one hour post-administration. These concentrations are much higher than previous animal studies would predict, and are similar to levels measured in unaffected animals when the drug is given after the use of cryotherapy. The concentration also approaches levels previously shown to be toxic to the retina. This elevation in carboplatin concentration may be due to disruption of the blood-vitreous barrier by active tumor.
Antineoplastic Agents↗
Second nonocular cancers in retinoblastoma: a unified hypothesis. The Franceschetti Lecture.
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Hodgkin Disease↗
A possible hot spot in exon 21 of the retinoblastoma gene predisposing to a low penetrant retinoblastoma phenotype?
PURPOSE: To identify the mutation in the RB1 gene in a Syrian family showing incomplete penetrance of retinoblastoma (RB). METHODS: Genomic DNA was used as a template for the PCR reaction to amplify all exons as well as the promoter region of RB1 gene. These PCR products were screened by conformational sensitive gel electrophoresis and the 331-bp product containing exon 21 showing anomalous migration was sequenced directly to identify the mutation. RESULTS: We identified the missense point mutation in exon 21 of the RB1 gene converting a Cys-->Arg (codon 712) in one family with a low penetrant phenotype. The proband was unilaterally affected, whereas the paternal uncle was bilaterally affected and the mutation carrier father was unaffected. The T-->C substitution abolished a cleavage site for the Nde I restriction enzyme, enabling rapid detection of the mutant allele. CONCLUSION: Phenotypically, this family is different from the previously described low penetrant phenotype pedigree with the same mutation whose affected members all had unilateral tumors. These results suggest that codon 712 may represent a mutational 'hot spot' for the low penetrant phenotypes and that the mutation codes for retinoblastoma protein with an apparently residual tumor-suppressive function give rise to low penetrance. These results also raise the interesting question: what other factors influence the phenotype of mutation carriers in addition to the predisposing missense mutation.
Adult↗
Molecular characterization of the deletion in retinoblastoma patients with 13q14 cytogenetic anomalies.
We investigated the molecular deletions of twelve patients presenting with retinoblastoma and a cytogenetic abnormality including band 13q14. Dinucleotide markers spanning the complete chromosome 13 as well as two intragenic markers were analyzed in patients and their two parents. The deletion was considered confirmed when one heterozygous allele was missing, potential when a homozygous allele was observed in continuity with a clearly deleted allele, and noninformative when a homozygous allele was observed adjacent to a nondeleted region. The patients could be classified into three groups based on their cytogenetic abnormalities. In group 1, the cytogenetic deletion was restricted to band13q14 with confirmed or potential molecular deletions extending from D13S328 to D13S153. Although a possible common centromeric deletion breakpoint could exist for three of the patients and a common telomeric deletion breakpoint for two, the cytogenetic deletion was different for most of them. Group 2 included patients with a cytogenetic deletion extending up to 13q22. At the molecular level, the telomeric breakpoints were between the RB1 gene and D13S156. Here again, it is quite unlikely that a common telomeric breakpoint was responsible for the deletion. Group 3 consisted of special cases with either a paracentric inversion or a complex translocation. The cytogenetic abnormalities around 13q14 correlate with the molecular deletions that were observed in this study. Associated malformations cannot be easily predicted from the size of the deletions.
Child, Preschool↗
Further delineation of the facial 13q14 deletion syndrome in 13 retinoblastoma patients.
Thirteen years ago, Motegi and colleagues (J Med Genet 1987;24:696-697) summarized the specific facial phenotype of six Japanese retinoblastoma patients with interstitial 13q14 deletions. Among a series of 228 propositi with retinoblastoma referred to the Lausanne Retinoblastoma Clinic for treatment and genetic counseling between 1986 and 1997, 13 (5.7%) were diagnosed with a cytogenetic de-novo 13q14 deletion. We confirm the presence of the reported facial phenotype in our population of Caucasian patients and describe additional clinical traits, thus extending the facial phenotype associated with the 13q14 deletion. Del(13q14) comprises, among others, cranial anomalies, frontal bossing, deeply grooved and long philtrum, depressed and broad nasal bridge, bulbous tip of the nose, thick lower lip, thin upper lip, broad cheeks, and large ears and lobules. Recognition of this particular facial appearance was instrumental in the genetic diagnosis of 13q deletions and in the presymptomatic diagnosis of retinoblastoma in a significant number of our cases. Identification of this phenotype in a retinoblastoma patient allows for efficient diagnosis of recurrence in his progeny and/or sibship, while its ignorance will compromise genetic counseling due to the possible difficulties in detecting large deletions by standard molecular mutation analysis. Recognition of this syndrome in newborns without known familial risk for retinoblastoma is even more important as it is a clear warning sign that indicates immediate ophthalmic examination.
Child, Preschool↗
An infant with Down syndrome and retinoblastoma. A possible non-fortuitous association.
AIM: To evaluate the association between Down syndrome and retinoblastoma. METHOD: Presentation of a case report and review of the literature. RESULTS: A retinoblastoma was observed in a 10-month-old boy with Down syndrome. A review of the literature yielded 14 other cases, suggesting a possible excess of retinoblastoma in Down syndrome, as previously proposed by two epidemiological studies. The possible roles of external physical agents and hyperplastic and dysplastic lesions of the retina in subjects with Down syndrome is discussed. CONCLUSION: A positive association between Down syndrome and retinoblastoma is possible. An epidemiological study on this subject is needed to better ascertain this potential link.
Child↗