Faculty Collaboration Database

Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg 2003 Apr;138(4):409-16; discussion 416

Date

04/11/2003

Pubmed ID

12686527

DOI

10.1001/archsurg.138.4.409

Scopus ID

2-s2.0-0344716605 (requires institutional sign-in at Scopus site)   197 Citations

Abstract

HYPOTHESIS: Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC.

DESIGN: Review of endocrine surgery database from 1951 through 2002.

SETTING: Tertiary referral center.

PATIENTS: Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918).

MAIN OUTCOME MEASURES: Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism.

RESULTS: RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations.

CONCLUSION: Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.

Author List

Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV, Sherman SI, Gagel RF, Lee JE, Evans DB

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Child
Child, Preschool
Follow-Up Studies
Genotype
Humans
Middle Aged
Multiple Endocrine Neoplasia Type 2a
Multiple Endocrine Neoplasia Type 2b
Multivariate Analysis
Mutation
Oncogene Proteins
Phenotype
Proto-Oncogene Proteins c-ret
Receptor Protein-Tyrosine Kinases
Thyroid Neoplasms
Thyroidectomy