Chemoreduction of Progressive Intraocular Retinoblastoma by Systemic Topotecan

Purpose: To evaluate our experience with systemic Toptecan (TPT) chemotherapy as a second-line systemic chemotherapeutic regimen for treatment of refractory or recurrent intraocular retinoblastoma (RB).

Methods and Materials: A retrospective case series of 14 eyes from patients with intraocular RB who received systemic TPT as second-line chemotherapy from April 2008 until June 2010. The following data were collected: patient demographics, laterality, international intraocular retinoblastoma stage (ICRB) at diagnosis, treatment received before and after TPT, side effects related to TPT, eye salvage, and survival.

Results: The median age at diagnosis was 5 months (range, 1–16 months), and the median age at starting TPT was 10 months (range, 8–24 months). There were 6 (60%) females and 9 (90%) patients; all with bilateral retinoblastoma. The median number of TPT cycles was three per patient (range, 1–6), and the total number of administered cycles was 29. After TPT therapy; 4 (29%) eyes showed favorable response, 3 (21%) eyes showed minimal regression, 5 (36%) eyes had stable disease, and 2 (14%) eyes showed tumor progression. At a median follow-up of 48 months; 9 (64%) eyes were salvaged, 3 (21%) eyes received radiation therapy, and 3 (21%) eyes were enucleated (one was post radiation). Grade 3/4 neutropenia were noticed in a total of 59% of given cycles and admission for febrile neutropenia was required after seven cycles.

Conclusions: Our report suggests that systemic TPT chemotherapy could be used as a salvage second-line regimen with low toxicity for patients with progressive intraocular retinoblastoma if systemic therapy is needed.     

Spectrum of RB1 Mutations in Argentine Patients: 20-years Experience in the Molecular Diagnosis of Retinoblastoma

ABSTRACT

Background: Retinoblastoma is a hereditary cancer of childhood caused by mutations in the RB1 tumor suppressor gene. An early diagnosis is critical for survival and eye preservation, thus identification of RB1 mutations is important for unequivocal diagnosis of hereditary retinoblastoma and risk assessment in relatives.

Methods: We studied 144 families for 20 years, performing methodological changes to improve detection of mutation. Segregation analysis of polymorphisms, MLPA, FISH and cytogenetic assays were used for detection of “at risk haplotypes” and large deletions. Small mutations were identified by heteroduplex/DNA sequencing.

Results: At risk haplotypes were identified in 11 familial and 26 sporadic cases, being useful for detection of asymptomatic carriers, risk exclusion from relatives and uncovering RB1 recombinations. Ten large deletions (eight whole gene deletions) were identified in six bilateral/familial and four unilateral retinoblastoma cases. Small mutations were identified in 29 cases (four unilateral retinoblastoma patients), being the majority nonsense/frameshift mutations. Genotype-phenotype correlations confirm that the retinoblastoma presentation is related to the type of mutation, but some exceptions may occur and it is crucial to be considered for genetic counseling. Three families included second cousins with retinoblastoma carrying different haplotypes, which suggest independent mutation events.

Conclusion: This study enabled us to obtain information about molecular and genetic features of patients with retinoblastoma in Argentina and correlate them to their phenotype.     

A novel translocation t(11;13) (q21;q14.2) in a child with suprasellar primitive neuroectodermal tumor and retinoblastoma

Purpose: To report on a novel translocation related to a suprasellar primitive neuroectodermal tumor (sPNET) and retinoblastoma.

Design: Case report.

Methods: A 6-year-old girl underwent genetic testing after developing unilateral retinoblastoma subsequent to treatment (surgery, chemotherapy, and stem-cell rescue) for a sPNET found at 1 year of age.

Results: Genetic testing found the girl’s karyotype to be 46,XX,t(11;13)(q21;q14.2); a novel translocation not previously reported in patients with either retinoblastoma or sPNET.

Conclusions: Our patient had a novel translocation affecting the retinoblastoma 1 (RB1) gene, 46,XX,t(11;13)(q21;q14.2) resulting in the late development of unilateral retinoblastoma. Although she only developed unilateral retinoblastoma, her central nervous system was affected at a very early age. How her complex mutation resulted in retinoblastoma and antecedent sPNET remains unknown.     

Enucleation for retinoblastoma: the experience of a single center in Jordan

Despite multiple advances in the management of retinoblastoma, enucleation remains an essential therapeutic modality. We studied patients who underwent enucleation at the King Hussein Cancer Center in Jordan. We retrospectively reviewed medical records of children with retinoblastoma who were treated at our center from June 2002 to February 2008. Twenty-eight eyes from 27 patients were enucleated. Median age at diagnosis was 1.1 years (range, 0.3–6.3 years). Twenty-six eyes (93%) had advanced disease (RE groups IV and V). Seventeen patients (61%) had unilateral retinoblastoma, and 11 (39%) had bilateral retinoblastoma. The median time from diagnosis to enucleation was 0.45 months (range, 0–45 months; mean, 4.4 months) and was longer for patients with bilateral retinoblastoma (median, 2.2 vs. 0.2 months; P = 0.034). Twenty enucleated eyes (71%) did not show high-risk pathologic features. Seventeen eyes with advanced intraocular disease were enucleated at the time of presentation, whereas chemoreduction was attempted for the other 19 eyes with advanced intraocular disease. Enucleation was then recommended for nine (47%) of those eyes. Enucleation at the time of diagnosis was feasible for most patients with advanced disease. Attempted salvage of eyes with advanced disease is justified, particularly in patients with bilateral disease. We were able to salvage almost half of these eyes. We hope our study provides new insights for counseling patients.     

VEC方案联合激光治疗RB眼内期患儿的效果与安全性

目的：评价VEC方案联合激光治疗不同年龄视网膜母细胞瘤(RB)眼内期患儿的效果与安全性。

方法：选择我院2016-01/2018-03 RB眼内期患儿63例作为研究对象,根据年龄分为≤1岁组23例36眼,>1岁组40例66眼,均给予VEC方案联合激光治疗,参照国际抗癌联盟制定的疗效标准评价疗效。治疗前、6个疗程结束后采用间接检眼镜与超声下测量肿瘤及肿瘤基底厚度与直径,记录治疗期间毒副反应。

结果：≤1岁组缓解率为75.0%,>1岁组缓解率为92.4%(P<0.05)。≤1岁组进展5眼,>1岁组进展1眼均行眼球摘除,其余患眼治疗后肿瘤厚度与基底直径明显小于治疗前(P<0.05)。>1岁组治疗后肿瘤厚度与基底直径均比≤1岁组小(P<0.05)。两组患儿均有轻度恶心呕吐等消化道症状及脱发,≤1岁组各有1例轻度骨髓抑制和肝功能损害,>1岁组有2例轻度骨髓抑制,1例轻度肝功能损害。

结论：VEC方案联合激光治疗RB眼内期患儿安全可行,>1岁患儿疗效优于≤1岁患儿。     

Genetic diagnosis of retinoblastoma by a combination of fluorescence in situ hybridization and restriction fragment length polymorphism

PURPOSE: It is important to exclude germ line mutation in cases of unilateral retinoblastoma(RB) to estimate hereditary or possible secondary cancer. We investigated whether genetic diagnosis is feasible in a health check screening program. METHODS: Five patients with RB had surgery for enucleation in Keio University Hospital. Tumor cells from enucleated eyes and lymphocytes representing systemic cells were collected and analyzed genetically by fluorescence in situ hybridization(FISH) and restriction fragment length polymorphism (RFLP). RESULTS: One out of three unilateral RB cases could be diagnosed as non-hereditary by the finding of no copies of the RB gene in the tumor cells using the FISH method and no signal in the RFLP method. A decrease of signal in tumor cells to less than 50% in the RFLP method was observed in another case of unilateral RB that seemed to be non-hereditary, but the case ultimately could not be diagnosed as non-hereditary because polycopies were found in the FISH method. No abnormality in tumor cells could be found in another unilateral case or in systemic cells of two bilateral cases. CONCLUSION: A combination of FISH and RFLP methods can be used to diagnose some cases of RB as non-hereditary.     

Retinoblastoma in Jordan, 2003–2013: Ocular Survival and Associated Factors

Purpose: To determine ocular survival and factors affecting globe survival in patients diagnosed with retinoblastoma at King Hussein Cancer Center (KHCC).

Methods: A retrospective review of medical records of 71 Jordanian patients (45 males and 26 females) diagnosed with retinoblastoma (114 eyes) between June 2003 and May 2013 was conducted. Patient sociodemographic and relevant characteristics were collected from records. Patients with bilateral retinoblastoma were treated with chemoreduction and focal consolidation. Lens-sparing radiation therapy and enucleation were reserved for eyes that failed chemoreduction combined with focal therapy. In cases of unilateral retinoblastoma, primary enucleation was recommended for eyes with advanced unilateral disease (Reese-Ellsworth classification groups IV and V). Kaplan-Meier survival and Cox regression multilevel analysis were used to analyze the data.

Results: Median age at diagnosis was 12 months. The follow-up period ranged from 0.25–160 months (mean 26.9 months). The Kaplan–Meier estimate of globe survival of the 114 eyes was 68.0% at 1 year, 63.3% at 2 years, and 62.1% at 5 years. The mean survival time was 101.6 months (95% confidence interval, CI, 87.6–115.6 months). In multivariable-adjusted analysis, advanced stage of the disease (hazard ratio, HR, 5.1, 95% CI 2.3–11.6), unilateral disease (HR 3.3, 95% CI 1.4–8.1), and delay in diagnosis (HR 2.4, 95% CI 1.1–5.5) were significantly associated with increased hazard of enucleation.

Conclusion: The overall ocular survival rate for eyes with retinoblastoma was close to regional and international figures. Disease stage, laterality, and delay in diagnosis were significant predictors of enucleation.     

视网膜母细胞瘤组织中HPV-DNA表达的研究

目的:研究我国视网膜母细胞瘤(retinoblastoma,RB)中HPV-DNA表达情况,为进一步揭示HPV在散发性RB中作用提供初步依据。方法:收集22例散发性RB患者新鲜肿瘤组织标本,应用PCR方法及引物MY09/11检测肿瘤组织中HPV-DNA表达情况。结果:选取22例RB肿瘤标本中7例HPV-DNA阳性(32%),均为单眼散发患者(包括男4例,女3例),2例双眼散发患者均为阴性。结论:HPV可能是我国散发性RB发病因素之一,但其明确作用及机制尚待进一步研究。     

血清肿瘤标记物在视网膜母细胞瘤诊断中的研究

目的:探讨血清肿瘤标记物神经元特异性烯醇化酶(NSE)、糖蛋白抗原CA153、CA199在视网膜母细胞瘤(RB)患者血清中的分泌水平。方法:选取2017-10/2019-10在深圳市人民医院进行化疗且临床资料完整的RB患儿42例为研究对象,检测首次化疗前空腹静脉血血清中肿瘤标记物NSE、CA153、CA199水平,比较不同性别、不同临床分期、单双眼受累患者血清肿瘤标记物水平的差异。结果:晚期组患儿血清肿瘤标记物NSE、CA153、CA199水平均高于早中期组(49.69±18.45ng/mL vs 36.18±14.92ng/mL,22.38±12.03U/mL vs 15.10±8.32U/mL,46.44±18.76U/mL vs 30.21±24.03U/mL,P<0.05),但不同性别、单双眼受累患儿血清各肿瘤标记物水平均无明显差异(P>0.05)。结论:血清NSE、CA153、CA199在临床晚期RB患者血清中的分泌水平明显高于早中期患者,其对RB分期诊疗可能具有重要意义。     

Surgical repair of rhegmatogenous retinal detachment in eyes harboring active retinoblastoma

Background: Intraocular surgeries are classically contraindicated for patients with active Retinoblastoma (RB) due to the risk of tumor dissemination. Unfortunately, RB treatment may be complicated by rhegmatogenous retinal detachment (RD) that necessitates surgical repair especially in a child who is monocular from enucleation of the contralateral eye.

Objective: To assess the outcome of surgical repair of rhegmatogenous RD in children with RB using non-drainage scleral buckling.

Results: Rhegmatogenous RD was diagnosed in three eyes of three children during treatment of RB; one of which had associated tractional RD. All patients received systemic chemotherapy, cryotherapy, and thermal therapy. RD was present at the site of the most recent cryotherapy in all of the three eyes. RD was repaired externally with a scleral buckling procedure without subretinal fluid drainage in each of the three eyes. The retina reattached completely after surgery in two eyes and only partially in one eye. In one eye, which had the tractional component, complete retinal attachment was not achieved and thus enucleation was performed. Orbital or metastatic retinoblastoma was detected in none of the cases on follow-up at 6–36 months.

Conclusions: Scleral buckling without subretinal fluid drainage is a useful technique for repairing rhegmatogenous RD in eyes with RB mainly in the absence of a tractional component.     

Immunohistochemical and Immunocytochemical Analyses in Patients with Vitreoretinal Lymphoma

ABSTRACT

Purpose: The aim of this study was to analyze immunohistochemical and immunocytological findings by examining enucleated eyes and vitreous cell block (CB) in patients with vitreoretinal lymphoma (VRL).

Methods: Histological specimens were obtained from two enucleated eyes with VRL associated with neovascular glaucoma. CB specimens were prepared in 18 patients from diluted waste fluids containing shredded vitreous. Histological and cytological specimens were submitted for hematoxylin-eosin staining and immunopathological analyses.

Results: Both specimens demonstrated massive infiltration of large lymphoma cells. The lymphoma cells were positive for CD20 and MUM-1 in enucleated eyes. Membranous immunoreactivity for CD20 was observed in lymphoma cells in CB with VRL. Bcl-6 and MUM-1 were marked in five and eight out of nine cases examined, respectively

Conclusions: Cytological findings in CB specimens indicated similar histopathological characteristics of enucleated eyes. CB specimens obtained from vitreous waste diluted fluids may serve as effective materials for cytological diagnosis of VRL.     

Ultrasound biomicroscopy in the management of retinoblastoma

Purpose

To determine the role of ultrasound biomicroscopy (UBM) in the management of children affected with retinoblastoma.

Methods

A review of clinical records of children with the diagnosis of retinoblastoma at the Hospital for Sick Children from January 1995 to December 2007, for whom UBM was used to determine the extent of intraocular tumor. Clinical characteristics were compared with UBM. Pathological correlation was performed for enucleated eyes.

Results

In total, 101 eyes of 75 patients were included in the final analysis. Only 11 eyes were diagnosed on UBM to have extension of the tumor anterior to the ora serrata, and were enucleated. Histopathological examination confirmed the anterior extension in all the 11 eyes. In total, 50 eyes were enucleated because of various reasons, such as poor visual prognosis (12 eyes), unilateral group D or E (23 eyes), recurrences (8 eyes), and treatment failure (7 eyes). None of those patients were found to have anterior extension of the disease on histopathological examination. UBM did not yield any false negative (0/50) or any false positives (0/11).

Conclusions

The UBM provided a sensitive and reproducible visualization of the anterior retina, ciliary region, and anterior segment allowing a better staging of the advanced disease process. Primary assessment of the true extent of retinoblastoma is critical for the selection of an optimal management approach.     

Detection and reporting of RB1 promoter hypermethylation in diagnostic screening

Background: RB1 gene screening aids clinical management and genetic counselling in retinoblastoma families. Here we present epigenetic changes identified during routine molecular RB1 screening of tumor and blood samples. Complications in interpreting RB1 methylation are discussed.

Materials and Methods: Screening for RB1 promoter hypermethylation was carried out by Methylation Specific PCR (MS-PCR) after bisulphite modification of DNA. The cohort consisted of 315 tumors, and 204 blood samples, from 497 retinoblastoma patients (22 patients had both blood and tumor screened).

Results: 11.4% of retinoblastoma tumors had promoter hypermethylation. It was not routinely detected in blood samples, or in tumors with two other oncogenic RB1 changes. One blood sample had promoter hypermethylation due to an X;13 translocation. One tumor had low level methylation as well as two other oncogenic changes. Histopathological analysis of a small subset of age-matched tumors was similar regardless of promoter hypermethylation status.

Conclusions: Promoter hypermethylation was detected in 11.4% of the retinoblastoma tumors and should be tested for in routine RB1 screening programmes. Constitutional samples are not expected to display RB1 hypermethylation. In a small proportion of cases it may not be possible to use this somatic change in patient management.     

Stage of presentation and visual outcome of patients screened for familial retinoblastoma: nationwide registration in the Netherlands

BACKGROUND: In the Netherlands a comprehensive programme for screening just after birth for familial retinoblastoma is taking place. In this report the stage of the disease at the time of detection, by way of screening, and the long term visual outcome in these patients was evaluated. METHODS: A nationwide, retrospective study. From January 1992-July 2004, patients at risk for familial retinoblastoma were screened 1-2 weeks after birth, and investigated for laterality, Reese-Ellsworth classification/International Classification of Retinoblastoma, macular involvement, age of primary retinoblastoma, initial therapy, and visual outcome. RESULTS: 17 patients were diagnosed with familial retinoblastoma. 88.3% developed bilateral, 11.7% unilateral retinoblastoma. Of the 34 eyes, 56% were R-E group I, 16% were group II A-B, 16% were group III A-B, 9% were group IV, 3% were group V. Using the International Classification of Retinoblastoma, 72% were group A, 19% were group B, 6% were group C, 3% were group E. The visual outcome revealed 73.5% of eyes with 20/20-20/40, 26.5% eyes with < or = 20/100-no light perception; 5.9% of eyes were enucleated, all other eyes were treated with local or conservative treatment methods. Of all eyes, 59% had extramacular retinoblastoma, 98% of patients had at least one eye with extramacular retinoblastoma. CONCLUSION: Most familial retinoblastoma patients present as a R-E group I or group A when screened within 2 weeks after birth. Nearly 90% of patients had a long term visual acuity of 20/20-20/40. Despite the common occurrence of macula involvement, bilateral macula involvement was infrequent, and since most eyes were salvaged, good vision was obtained in the majority of patients.     

Three presentations of CNS disease in patients with intraocular retinoblastoma at a tertiary medical center in the United States

Background: Patients with intraocular retinoblastoma who present with central nervous (CNS) disease at diagnosis is very rare in developed countries.

Methods: Herein, we report a review of patients with intraocular retinoblastoma diagnosed with concurrent CNS disease in the United States between January 2011 and June 2013.

Results: Three patients were identified in this review. The first case is a 2-year old male who presented with unilateral Group E retinoblastoma, optic nerve infiltration to the orbital apex, and a suprasellar mass. The second case is a 5-month old female with bilateral retinoblastoma, who had no optic nerve invasion, but demonstrated a temporal lobe lesion that was biopsy-proven to be metastatic retinoblastoma. The third case is a 10-month old girl with bilateral retinoblastoma who presented with a sellar mass and no evidence of optic nerve invasion in the enucleated Group E eye.

Conclusions: Although rare in developed countries, patients with intraocular retinoblastoma can present with a spectrum of CNS findings at the time of diagnosis. Magnetic resonance imaging of the brain and orbits is a critical component of the staging evaluation.     

Ischemic necrosis and atrophy of the optic nerve after periocular carboplatin injection for intraocular retinoblastoma

PURPOSE: To report four cases of optic nerve neuropathy in three children treated with periocular carboplatin injections for unilateral or bilateral intraocular retinoblastoma. DESIGN: Retrospective, observational case series. METHODS: Setting: University-based Ophthalmology Practice. Study population: Four eyes of three children with retinoblastoma enucleated after nonsuccessful multimodality treatment including periocular carboplatin injections. Observation procedures: The enucleated eyes were routinely processed and evaluated by light microscopy. A retrospective chart review of all four cases was performed. RESULTS: Three enucleated eyes (Reese-Ellsworth groups III and VB) were obtained from two children with bilateral multifocal retinoblastoma, and one eye (Reese-Ellsworth group IIB) was harvested from a child with unilateral retinoblastoma. All affected eyes underwent three to seven periocular carboplatin injections before enucleation. Additional treatment modalities included systemic chemotherapy, transpupillary thermotherapy, transscleral cryotherapy, and external beam radiotherapy. Histopathologic evaluation of the enucleated eyes revealed focal areas of ischemic necrosis or atrophy of the optic nerve along with dystrophic calcification and mild inflammation in the surrounding fibrovascular adipose tissue. CONCLUSIONS: Periocular injections of carboplatin may be a useful treatment approach in the management of patients with advanced intraocular retinoblastoma and may minimize systemic side-effects. However, ophthalmologists and pediatric oncologists should be aware of potential marked local complications with periocular carboplatin delivery, including ischemic optic neuropathy. Modifying the injection site/location (for example, subtenon space) or adding other delivery routes adjuncts (for example, fibrin sealant) deserves further study.     

Hereditary Diffuse Infiltrating Retinoblastoma

Retinoblastoma is one of the most common childhood cancers. The diffuse infiltrating retinoblastoma is a rare subtype of this neoplasm. The majority of cases of diffuse infiltrating retinoblastoma are unilateral and occur sporadically. Herein we report on a family with three children affected by retinoblastoma, among them one girl with diffuse infiltrating retinoblastoma. This girl was diagnosed at the age of 8 years with a unilateral diffuse infiltrating retinoblastoma. By contrast, the two brothers became clinically apparent in the first 2 years of life with bilateral retinoblastoma. The parents were clinically unremarkable. Genetic analysis of RB1 gene was performed. The girl with diffuse infiltrating RB was found to be heterozygous for an oncogenic mutation in the RB1 gene that was also carried by both brothers and the father of the family. These results show that diffuse infiltrating retinoblastoma can develop on the background of a hereditary predisposition to retinoblastoma.     

Full-field electroretinography under general anesthesia in retinoblastoma

Purpose

To investigate the electrical responses of the retina in retinoblastoma (RB), by recording full-field electroretinography (ERG) under general anesthesia.

Methods

The ERG was recorded using Ephios hand-held portable ERG system, according to International Standards for Clinical Electrophysiology of Vision. Forty-eight eyes of 43 cases and 33 eyes of 33 controls were enrolled. The cases were classified based on international intraocular retinoblastoma classification (IIRC). Forty-eight eyes of cases were divided into 30 cases with active RB and 18 cases with regressed RB.

Results

The amplitudes of a- and b-waves were decreased as compared to controls in all subgroups. The implicit times of all RB patients from group A to C differed statistically from controls (p value < 0.05) except for single-flash rod response. The ERG waveforms in group E eyes were non-recordable. The comparison of ERG parameters between active and regressed groups (IIRC groups A and B) was statistically insignificant. Single case follow-up of unilateral RB after systemic chemotherapy showed improvement in amplitudes compared to baseline parameters.

Conclusions

Reduced amplitudes and delayed implicit times were noted in advanced disease. The ERG of RB cases did not follow any specific pattern of waveform. ERG appears to be a dynamic parameter to observe changes following treatment for RB. Although ERG is not a diagnostic test for RB, it can be used as a complementary test to assess the residual retinal function in RB eyes.     

Current treatment of retinoblastoma. 153 children treated between 1995 and 1998

PURPOSE: Treatment of retinoblastoma has changed significantly over the past few years. There are fewer indications for external beam radiation and a new treatment modality, chemotherapy, has appeared. MATERIAL: and methods: We reviewed a series of 153 children treated for retinoblastoma between 1995 and 1998. There were 67 boys and 86 girls: 76 unilateral and 77 bilateral retinoblastomas. Indications for treatments and outcome were reviewed for 230 eyes and for each tumor. Age at diagnosis varied from 0 to 94 months with a median age of 12 months. A family history of retinoblastoma was found in 24 cases. Three children were seen for treatment of recurrence. RESULTS: Among the 76 cases of unilateral retinoblastoma, 56 were enucleated and 20 were treated conservatively (5 with external beam radiation). Among the 154 eyes with bilateral retinoblastoma, 48 were enucleated and 106 were treated conservatively (49 by external beam radiation). Local treatments included chemothermotherapy, laser alone, cryotherapy, and (125)I plaques. Conservative management other than external beam radiation was used for 81 eyes and was successful in 72 (89%). CONCLUSION: We discuss the indications and results of primary chemotherapy and local treatments. External beam radiation is still often indicated in bilaterally advanced cases. In other forms of retinoblastoma, chemothermotherapy is a very reliable and useful treatment.     

Risk assessment of recurrence in sporadic retinoblastoma using a molecular-based algorithm

Purpose: Most RB1 mutations are unique and distributed throughout the RB1 gene. Their detection can be time-consuming and the yield especially low in cases of conservatively-treated sporadic unilateral retinoblastoma (Rb) patients. In order to identify patients with true risk of developing Rb, and to reduce the number of unnecessary examinations under anesthesia in all other cases, we developed a universal sensitive, efficient and cost-effective strategy based on intragenic haplotype analysis.

Methods: This algorithm allows the calculation of the a posteriori risk of developing Rb and takes into account (a) RB1 loss of heterozygosity in tumors, (b) preferential paternal origin of new germline mutations, (c) a priori risk derived from empirical data by Vogel, and (d) disease penetrance of 90% in most cases. We report the occurrence of Rb in first degree relatives of patients with sporadic Rb who visited the Jules Gonin Eye Hospital, Lausanne, Switzerland, from January 1994 to December 2006 compared to expected new cases of Rb using our algorithm.

Results: A total of 134 families with sporadic Rb were enrolled; testing was performed in 570 individuals and 99 patients younger than 4 years old were identified. We observed one new case of Rb. Using our algorithm, the cumulated total a posteriori risk of recurrence was 1.77.

Conclusions: This is the first time that linkage analysis has been validated to monitor the risk of recurrence in sporadic Rb. This should be a useful tool in genetic counseling, especially when direct RB1 screening for mutations leaves a negative result or is unavailable.