Multiple endocrine neoplasia type 2: A review

Semin Cancer Biol. 2022 Feb:79:163-179. doi: 10.1016/j.semcancer.2021.03.035. Epub 2021 Apr 1.


Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.

Keywords: Genotype-phenotype; MEN 2; Medullary thyroid carcinoma; Prognosis; Prophylactic thyroidectomy; Risk stratification.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / pathology
  • Digestive System Neoplasms / genetics
  • Digestive System Neoplasms / pathology
  • Ganglioneuroma / genetics
  • Ganglioneuroma / pathology
  • Genetic Counseling
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing
  • Genotype
  • Germ-Line Mutation / genetics
  • Humans
  • Hyperparathyroidism / genetics
  • Hyperparathyroidism / pathology
  • Multiple Endocrine Neoplasia Type 2a* / genetics
  • Multiple Endocrine Neoplasia Type 2a* / pathology
  • Multiple Endocrine Neoplasia Type 2a* / therapy
  • Multiple Endocrine Neoplasia Type 2b* / genetics
  • Multiple Endocrine Neoplasia Type 2b* / pathology
  • Multiple Endocrine Neoplasia Type 2b* / therapy
  • Prognosis
  • Proto-Oncogene Proteins c-ret / genetics*
  • Risk Factors
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / pathology
  • Thyroidectomy


  • Proto-Oncogene Proteins c-ret
  • RET protein, human

Supplementary concepts

  • Ganglioneuromatosis of the Alimentary Tract
  • Thyroid cancer, medullary