The relationship between specific ret proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET mutation consortium analysis

Charis Eng, David Clayton, Isabelle Schuffenecker, Gilbert Lenoir, Gilbert Cote, Robert F. Gagel, Hans Kristian Ploos Van Amstel, Cornelis J.M. Lips, Isamu Nishisho, Shin Ichiro Takai, Debbie J. Marsh, Bruce G. Robinson, Karin Frank-Raue, Friedhelm Raue, Feiyu Xue, Walter W. Noll, Cristina Romei, Furio Pacini, Monika Fink, Bruno NiederleJan Zedenius, Magnus Nordenskjöld, Paul Komminoth, Geoffrey N. Hendy, Hossein Gharib, Stephen N. Thibodeau, André Lacroix, Andrea Frilling, Bruce A.J. Ponder, Lois M. Mulligan

Research output: Contribution to journalArticlepeer-review

949 Scopus citations

Abstract

Objective. - Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making. Design. - Correlative survey study of 477 MEN 2 families. Setting. - Eighteen tertiary referral centers worldwide. Patients. - A total of 477 independent MEN 2 families. Main Outcome Measures. - Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family. Results. - There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B- specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors. Conclusions. - This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.

Original languageEnglish (US)
Pages (from-to)1575-1579
Number of pages5
JournalJournal of the American Medical Association
Volume276
Issue number19
DOIs
StatePublished - Nov 20 1996

ASJC Scopus subject areas

  • Medicine(all)

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