Molecular analysis of the PAX6 gene in Mexican patients with congenital aniridia: report of four novel mutations.

PURPOSE: Paired box gene 6 (PAX6) heterozygous mutations are well known to cause congenital non-syndromic aniridia. These mutations produce primarily protein truncations and have been identified in approximately 40%-80% of all aniridia cases worldwide. In Mexico, there is only one previous report describing three intragenic deletions in five cases. In this study, we further analyze PAX6 variants in a group of Mexican aniridia patients and describe associated ocular findings. METHODS: We evaluated 30 nonrelated probands from two referral hospitals. Mutations were detected by single-strand conformation polymorphism (SSCP) and direct sequencing, and novel missense mutations and intronic changes were analyzed by in silico analysis. One intronic variation (IVS2+9G>A), which in silico analysis suggested had no pathological effects, was searched in 103 unaffected controls. RESULTS: Almost all cases exhibited phenotypes that were at the severe end of the aniridia spectrum with associated ocular alterations such as nystagmus, macular hypoplasia, and congenital cataracts. The mutation detection rate was 30%. Eight different mutations were identified: four (c.184_188dupGAGAC, c.361T>C, c.879dupC, and c.277G>A) were novel, and four (c.969C>T, IVS6+1G>C, c.853delC, and IVS7-2A>G) have been previously reported. The substitution at position 969 was observed in two patients. None of the intragenic deletions previously reported in Mexican patients were found. Most of the mutations detected predict either truncation of the PAX6 protein or conservative amino acid changes in the paired domain. We also detected two intronic non-pathogenic variations, IVS9-12C>T and IVS2+9G>A, that had been previously reported. Because the latter variation was considered potentially pathogenic, it was analyzed in 103 healthy Mexican newborns where we found an allelic frequency of 0.1116 for the A allele. CONCLUSIONS: This study adds four novel mutations to the worldwide PAX6 mutational spectrum, and reaffirms the finding that c.969C>T is one of the three more frequent causal mutations in aniridia cases. It also provides evidence that IVS2+9G>A is an intronic change without pathogenic effect.

Survival in extra-orbital metastatic retinoblastoma:treatment results.

INTRODUCTION: Retinoblastoma (RB) is the most frequent malignant eye tumor in childhood. In developing countries advanced stages are common. The purpose of this paper is to present our 21-year clinical experience with metastatic extra ocular RB patients treated with 5 different chemotherapy schemas at a single Mexican Pediatric referral center. MATERIALS AND METHODS: A retrospective analysis was carried out reviewing the clinical characteristics of patients with metastatic RB. The information analyzed included the delay in diagnosis after first symptoms, age, sex, ocular staging, and anatomic site of metastases, treatment scheme, initial response and status at the last contact or date of death. RESULTS: Eighty-one patients were included; age range was from 3 to 80 months. The most common site of metastasis was central nervous system (83.9%). From those patients treated with chemotherapy (n = 74), 89.2% presented a complete initial response (n = 66). Early mortality occurred in 7 cases before any treatment. Fifty-six received treatment and died with progressive disease. All patients without radiotherapy died with tumor activity (n = 15). The use of cisplatin was related with longer disease free intervals; no other variable was related with survival. Four patients were alive and disease free at 33 to 144.3 months of follow up from diagnosis. The prevalent cause of death was tumor progression. CONCLUSIONS: In our experience, metastatic RB has a very high mortality rate in spite of the use of different chemotherapy regimens.

Survival in extra-orbital metastatic retinoblastoma: treatment results

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Introduction. Retinoblastoma (RB) is the most frequentmalignant eye tumor in childhood. In developingcountries advanced stages are common. The purposeof this paper is to present our 21-year clinicalexperience with metastatic extra ocular RB patientstreated with 5 different chemotherapy schemas at asingle Mexican Pediatric referral center.Materials and methods. A retrospective analysiswas carried out reviewing the clinical characteristicsof patients with metastatic RB. The information analyzedincluded the delay in diagnosis after firstsymptoms, age, sex, ocular staging, and anatomicsite of metastases, treatment scheme, initial responseand status at the last contact or date of death.Results. Eighty-one patients were included; agerange was from 3 to 80 months. The most commonsite of metastasis was central nervous system (83.9%).From those patients treated with chemotherapy(n = 74), 89.2% presented a complete initial response(n = 66). Early mortality occurred in 7 cases beforeany treatment. Fifty-six received treatment anddied with progressive disease. All patients withoutradiotherapy died with tumor activity (n = 15). Theuse of cisplatin was related with longer disease freeintervals; no other variable was related with survival.Four patients were alive and disease free at 33to 144.3 months of follow up from diagnosis. Theprevalent cause of death was tumor progression.Conclusions. In our experience, metastatic RB hasa very high mortality rate in spite of the use of differentchemotherapy regimens