ABSTRACT
INTRODUCTION: The most common gene involved in Hirschsprung's disease (HD) is protooncogene RET. More than 100 mutations of this gene have been described associated with HD. The mutations that change a cysteine with another aminoacid (mainly in exons 10 and 11) give a risk of familial medullary thyroid carcinoma (FTMC) and MEN 2A. These mutations are found in 5% of patients with HD and have an autosomal dominant inheritance. The FTMC is aggressive and the prophylactic thyroidectomy is the best treatment. We present our results in screening for RET protooncogene mutations associated with TMC in patients with HD. PATIENTS AND METHODS: We have treated 40 patients with HD in the last 15 years. We have classified the patients into two groups: A) high risk of RET protooncogene mutation associated with FTMC (family history of HD, long-segment and/or associated syndromes) and B) low risk (rectosigmoid involvement). We have identified the exons 7, 8, 9, 10, 11, 13, 14 and 15 of the RET protooncogene in 12 of 15 children from group A and 6 from 25 from group B. RESULTS: We have found the p.Cys620Ser mutation (exon 10) in a girl from group A (long-segment). In the family study, we have found the same mutation in her mother, her oncle and her cousin. CONCLUSION: The comprehensive management of children with HD requires screening for RET protooncogene mutations associated with FTMC. In the first-degree relatives of children with a mutation risk, screening is required.
Subject(s)
Carcinoma, Medullary/complications , Carcinoma, Medullary/genetics , Hirschsprung Disease/complications , Hirschsprung Disease/genetics , Thyroid Neoplasms/complications , Thyroid Neoplasms/genetics , Child, Preschool , Female , Humans , Male , Mutation , Proto-Oncogene Proteins c-ret/geneticsABSTRACT
Introducción. Las mutaciones del protooncogén RET son las más frecuentes en la enfermedad de Hirschsprung (EH). Hay descritas más de 100 mutaciones de este gen asociadas a EH, pero aquellas en que el error reemplaza una cisteína por otro aminoácido (principalmente en exones 10 y 11) presentan riesgo de MEN 2A y carcinoma medular de tiroides familiar (CMTF). Estas mutaciones de riesgo se hallan en un 5% de los pacientes con EH y presentan una herencia autosómica dominante. El CMTF tiene un comportamiento agresivo y la tiroidectomía profiláctica es el mejor tratamiento. Presentamos nuestros resultados en el cribado de las mutaciones del gen RET asociado a CMT en pacientes afectos de EH. Pacientes y método. Se han tratado en nuestro hospital 40 pacientes con EH en los últimos 15 años. Hemos clasificado a los pacientes en dos grupos: A) alto riesgo de mutación del gen RET asociada a CMTF (antecedentes familiares de EH, segmento largo y/o síndromes asociados) y B) bajo riesgo (afectación rectosigmo idea exclusiva).Se han determinado los exones 7, 8, 9, 10, 11, 13, 14 y 15 del protooncogén RET en 12/15 niños del grupo A y en 6/25 del grupo B. Resultados. Una niña del grupo A presenta la mutación p.Cys620Ser (exón 10). En el estudio familiar se ha encontrado esta misma mutación en la madre, el tío materno y una de sus hijas. Conclusiones. El manejo integral de los niños con EH exige el despistaje de mutaciones del gen RET asociadas a CMTF. En los familiares de primer grado de los niños con una mutación de riesgo, el cribado es obligatorio (AU)
Introduction. The most common gene involved in Hirschsprungs disease (HD) is protooncogene RET. More than 100 mutations of this gene have been described associated with HD. The mutations that change a cysteine with another aminoacid (mainly in exons 10 and 11) give a risk of familial medullary thyroid carcinoma (FTMC) and MEN 2A. These mutations are found in 5% of patients with HD and have an autosomal dominant inheritance. The FTMC is aggressive and the prophylactic thyroidectomy is the best treatment. We present our results in screening for RET protooncogene mutations associated with TMC in patients with HD. Patients and methods. We have treated 40 patients with HD in the last 15 years. We have classifi ed the patients into two groups: A) high risk of RET protooncogene mutation associated with FTMC (family history of HD, long-segment and/or associated syndromes) and B) low risk (rectosigmoid involvement).We have identified the exons 7, 8, 9, 10, 11, 13, 14 and 15 of the RET protooncogene in 12 of 15 children from group A and 6 from 25 from group B. Results. We have found the p.Cys620Ser mutation (exon 10) in a girl from group A (long-segment). In the family study, we have found the same mutation in her mother, her oncle and her cousin. Conclusion. The comprehensive management of children with HD requires screening for RET protooncogene mutations associated with FTMC. In the fi rst-degree relatives of children with a mutation risk, screening is required (AU)
