• C Eng, D Clayton, I Schuffenecker, G Lenoir, G Cote, R F Gagel, H K van Amstel, C J Lips, I Nishisho, S I Takai, D J Marsh, B G Robinson, K Frank-Raue, F Raue, F Xue, W W Noll, C Romei, F Pacini, M Fink, B Niederle, J Zedenius, M Nordenskjöld, P Komminoth, G N Hendy, and L M Mulligan.
• Division of Cancer Epidemiology and Control, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115-6084, USA. charis_eng@macmailgw.dfci.harvard.edu
• JAMA. 1996 Nov 20; 276 (19): 1575-9.

ObjectiveMultiple 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.DesignCorrelative survey study of 477 MEN 2 families.SettingEighteen tertiary referral centers worldwide.PatientsA total of 477 independent MEN 2 families.Main Outcome MeasuresAssociation 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.ResultsThere 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.ConclusionsThis 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.

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