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RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease.
Surgery. 2002 Apr; 131(4):373-81.S

Abstract

BACKGROUND

RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene.

METHODS

Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients.

RESULTS

A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2.

CONCLUSIONS

This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded.

Authors+Show Affiliations

Department of Biomedical Sciences and Advanced Therapies, Section of Endocrinology, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11935126

Citation

Pasini, Barbara, et al. "RET Mutation Profile and Variable Clinical Manifestations in a Family With Multiple Endocrine Neoplasia Type 2A and Hirschsprung's Disease." Surgery, vol. 131, no. 4, 2002, pp. 373-81.
Pasini B, Rossi R, Ambrosio MR, et al. RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease. Surgery. 2002;131(4):373-81.
Pasini, B., Rossi, R., Ambrosio, M. R., Zatelli, M. C., Gullo, M., Gobbo, M., Collini, P., Aiello, A., Pansini, G., Trasforini, G., & degli Uberti, E. C. (2002). RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease. Surgery, 131(4), 373-81.
Pasini B, et al. RET Mutation Profile and Variable Clinical Manifestations in a Family With Multiple Endocrine Neoplasia Type 2A and Hirschsprung's Disease. Surgery. 2002;131(4):373-81. PubMed PMID: 11935126.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease. AU - Pasini,Barbara, AU - Rossi,Roberta, AU - Ambrosio,Maria Rosaria, AU - Zatelli,Maria Chiara, AU - Gullo,Maria, AU - Gobbo,Morena, AU - Collini,Paola, AU - Aiello,Antonella, AU - Pansini,Giancarlo, AU - Trasforini,Giorgio, AU - degli Uberti,Ettore Ciro, PY - 2002/4/6/pubmed PY - 2002/5/1/medline PY - 2002/4/6/entrez SP - 373 EP - 81 JF - Surgery JO - Surgery VL - 131 IS - 4 N2 - BACKGROUND: RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. METHODS: Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. RESULTS: A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. CONCLUSIONS: This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded. SN - 0039-6060 UR - https://www.unboundmedicine.com/medline/citation/11935126/RET_mutation_profile_and_variable_clinical_manifestations_in_a_family_with_multiple_endocrine_neoplasia_type_2A_and_Hirschsprung's_disease_ DB - PRIME DP - Unbound Medicine ER -