Multiple Endocrine Neoplasia Syndromes

  • Barbara Zehnbauer


Multiple endocrine neoplasia (MEN) syndromes include several types of autosomal dominant inherited familial cancer syndromes, each characterized by a different pattern of endocrine gland tumors in affected individuals. The two major types are MEN1 (Wermer syndrome) and MEN2 (Sipple syndrome). MEN1 is an autosomal dominant disorder characterized by a high frequency of peptic ulcer disease and primary endocrine abnormalities involving the parathyroids (90–97% of patients), pancreatic islets (30–80% of patients; including adenoma, prolactinoma, insulinoma, glucagonoma, gastrinoma, etc.), and anterior pituitary (15–50% of patients).1 MEN2 includes subtypes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC, non-MEN), with the primary clinical features of medullary thyroid carcinoma (MTC; 95% of patients), pheochromocytoma (pheo; 50% of MEN2A and MEN2B), parathyroid hyperplasia (15–30% of MEN2A and rarely in MEN2B), plus mucosal neuromas (lips and tongue), ganglioneuromas of the gastrointestinal tract, and marfanoid habitus in MEN2B only.1 The MEN2A diagnostic category characterizes approximately 60% to 90% of patients with MEN2, FMTC accounts for 5% to 35%, and MEN2B for about 5%.2 In addition, MTC and pheo may be bilateral or multifocal with an earlier age of onset than sporadic occurrence of the same tumor type.


Medullary Thyroid Carcinoma Multiple Endocrine Neoplasia Type Multiple Endocrine Neoplasia Glial Cell Derive Neurotrophic Factor Familial Medullary Thyroid Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Phay JE, Moley JF, Lairmore TC. Multiple endocrine neoplasias. Semin Surg Oncol. 2000;18:324–332.PubMedCrossRefGoogle Scholar
  2. 2.
    Eng C. Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung’s disease. N Engl J Med. 1996;335:943–951.PubMedCrossRefGoogle Scholar
  3. 3.
    Wautot V, Vercherat C, Lespinasse J, et al. Germline mutation profile of MEN1 in multiple endocrine neoplasias type 1: search for correlations between phenotype and the functional domains of the MEN1 protein. Hum Mutat. 2002;20:35–47.PubMedCrossRefGoogle Scholar
  4. 4.
    Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276:404–407.PubMedCrossRefGoogle Scholar
  5. 5.
    Gagel RF, Marx SJ. In: Larsen PR, Kronenberg H, Melmed S, Polonsky K. eds. Multiple Endocrine Neoplasias. Williams Textbook of Endocrinology. 10th ed. Orlando, FL: WB Saunders; 2002:1717–1762.Google Scholar
  6. 6.
    Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell. 1999;96:143–152.PubMedCrossRefGoogle Scholar
  7. 7.
    Bertolino P, Radovanovic I, Casse H, et al. Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs. Mech Dev. 2003;120:549–560.PubMedCrossRefGoogle Scholar
  8. 8.
    Crabtre JS, Scacheri PC, Ward JM, et al. Of mice and MEN1: insulinomas in a conditional mouse knockout. Mol Cell Biol. 2003;23:6075–6085.CrossRefGoogle Scholar
  9. 9.
    Libutti SK, Crabtree JS, Lorang D, et al. Parathyroid gland-specific deletion of the mouse Men1 gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism. Cancer Res. 2003;63:8022–8028.PubMedGoogle Scholar
  10. 10.
    Guo SS, Sawicki MP. Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type 1. Mol Endocrinol. 2001;15:1653–1664.PubMedCrossRefGoogle Scholar
  11. 11.
    Marx SJ. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer. 2005;5:367–375.PubMedCrossRefGoogle Scholar
  12. 12.
    Mutch MG, Dilley WG, Sanjurjo F, et al. Germline mutations in the multiple endocrine neoplasias type 1 gene: evidence for frequent splicing defects. Hum Mutat. 1999;13:175–185.PubMedCrossRefGoogle Scholar
  13. 13.
    Agarwal SK, Kester MB, Debelenko LV, et al. Germline mutations in the MEN1 gene in familial multiple endocrine neoplasias type 1 and related states. Hum Mol Genet. 1997;6:1169–1175.PubMedCrossRefGoogle Scholar
  14. 14.
    Gite S, Lim M, Carlson R, et al. A high-throughput non-isotopic protein truncation test. Nat Biotech. 2003;21:194–197.CrossRefGoogle Scholar
  15. 15.
    Traverso G, Shuber A, Levin B, et al. Detection of APC mutations in fecal DNA from patients with colorectal tumors. N Engl J Med. 2002;346:311–320.PubMedCrossRefGoogle Scholar
  16. 16.
    Kishi M, Tsukada T, Shimizu S, et al. A large germline deletion of the MEN1 gene in a family with multiple endocrine neoplasia type 1. Jpn J Cancer Res. 1998;89:1–5.PubMedGoogle Scholar
  17. 17.
    Lairmore TC, Piersall LD, DeBenedetti MK, et al. Clinical genetic testing and early surgical intervention in patients with multiple endocrine neoplasias type1 (MEN1). Ann Surg. 2004;239:637–647.PubMedCrossRefGoogle Scholar
  18. 18.
    Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci U S A. 2001;98:1118–1123.PubMedCrossRefGoogle Scholar
  19. 19.
    Cupisti K, hoppner W, Dotzenrath C, et al. Lack of MEN1 gene mutations in 27 sporadic insulinomas. Eur J Clin Invest. 2000;30:325–329.PubMedCrossRefGoogle Scholar
  20. 20.
    Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasias type 2A. Nature. 1993;363:458–460.PubMedCrossRefGoogle Scholar
  21. 21.
    Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET protooncogene are associated with MEN2A and FMTC. Hum Mol Genet. 1993;2:851–856.PubMedCrossRefGoogle Scholar
  22. 22.
    Pichel JG, Shen L, Sheng HZ, et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature. 1996;382:73–76.PubMedCrossRefGoogle Scholar
  23. 23.
    Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasias type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367:375–376.PubMedCrossRefGoogle Scholar
  24. 24.
    Carlson KM, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET proto-oncogene associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994;91:1579–1583.PubMedCrossRefGoogle Scholar
  25. 25.
    Santoro M, Carlomagno F, Romano A, et al. Activation of RET as a dominantly transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995;267:381–383.PubMedCrossRefGoogle Scholar
  26. 26.
    Bolino A, Schuffernecker I, Luo Y, et al. RET mutations in exons 13 and 14 of FMTC patients. Oncogene. 1995;10:2415–2419.PubMedGoogle Scholar
  27. 27.
    Eng C, Smith DP, Mulligan LM, et al. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma. Oncogene. 1995;10:509–513.PubMedGoogle Scholar
  28. 28.
    Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the RET protooncogene in Hirschsprung’s disease. Nature. 1994;367:378–380.PubMedCrossRefGoogle Scholar
  29. 29.
    Romeo G, Ronchetto P, Luo Y, et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature. 1994;367:377–378.PubMedCrossRefGoogle Scholar
  30. 30.
    Borst MJ, VanCamp JM, Peacock ML, Decker RA. Mutational analysis of multiple endocrine neoplasias type 2A associated with Hirschsprung’s disease. Surgery. 1995;117:386–391.PubMedCrossRefGoogle Scholar
  31. 31.
    Grieco M, Santoro M, Berlingieri MT, et al. PTC is a novel rearranged form of the RET proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell. 1990;60:557–563.PubMedCrossRefGoogle Scholar
  32. 32.
    Musholt PB, Musholt TJ, Goodfellow PJ, et al. Cold single-stranded conformational variants for mutation analysis of the RET protooncogene. Surgery. 1997;122:363–370.PubMedCrossRefGoogle Scholar
  33. 33.
    Peacock ML, Borst MJ, Sweet JD, Decker RA. Detection of RET mutations in multiple endocrine neoplasias type 2A and familial medullary thyroid carcinoma by denaturing gradient gel electrophoresis. Hum Mutat. 1996;7:100–104.PubMedCrossRefGoogle Scholar
  34. 34.
    Ceccherini I, Hofstra RMW, Luo Y. DNA polymorphisms and conditions for SSCP analysis of the 20 exons of the RET proto-oncogene. Oncogene. 1994;9:3025–3029.PubMedGoogle Scholar
  35. 35.
    Siegelman M, mohabeer A, Fahey TJ III, et al. Rapid, nonradioactive screening for mutations in exons 10, 11, and 16 of the RET protooncogene associated with inherited medullary thyroid carcinoma. Clin Chem. 1997;43:453–457.PubMedGoogle Scholar
  36. 36.
    Liu W, Smith DI, Rechtzigel KJ, et al. Denaturing high performance liquid chromatography (DHPLC) used in the detection of germline and somatic mutations. Nucleic Acids Res. 1998;26:1396–1400.PubMedCrossRefGoogle Scholar
  37. 37.
    Wells SA Jr, Chi DD, Toshima K, et al. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg. 1994;220:237–250.PubMedCrossRefGoogle Scholar
  38. 38.
    Chen X, Zehnbauer B, Gnirke A, et al. Fluorescence energy transfer detection as a homogeneous DNA diagnostic method. Proc Natl Acad Sci U S A. 1997;94:10756–10761.PubMedCrossRefGoogle Scholar
  39. 39.
    Howe JR, Lairmore TC, Mishra SK, et al. Improved predictive test for MEN2, using flanking dinucleotide repeats and RFLPs. Am J Hum Genet. 1992;51:1430–1442.PubMedGoogle Scholar
  40. 40.
    Noll WW. Utility of RET mutation analysis in multiple endocrine neoplasia type 2. Arch Pathol Lab Med. 1999;123:1047–1049.PubMedGoogle Scholar
  41. 41.
    Baloh RH, Tansey MG, Lampe PA, et al. Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRa3-RET receptor complex. Neuron. 1998;21:1291–1302.PubMedCrossRefGoogle Scholar
  42. 42.
    Zedenius J, Larsson C, Bergholm U, et al. Mutations of codon 918 in the RET proto-oncogene correlate with poor prognosis in sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab. 1995;80:3088–3090.PubMedCrossRefGoogle Scholar
  43. 43.
    Eng C, Mulligan LM. Mutations of the RET proto-oncogene in the multiple endocrine neoplasias type 2 syndromes, related sporadic tumors, and Hirschsprung disease. Hum Mutat. 1997;9:97–109.PubMedCrossRefGoogle Scholar
  44. 44.
    Neumann HPH, Eng C, Mulligan LM, et al. Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia type II. JAMA. 1995;274:1149–1151.PubMedCrossRefGoogle Scholar
  45. 45.
    Ledger GA, Khosla S, Lindor NM, et al. Genetic testing in the diagnosis and management of multiple endocrine neoplasia type II. Ann Intern Med. 1995;122:118–124.PubMedGoogle Scholar
  46. 46.
    Gagel RF, Core GJ, Bugalho MJMG, et al. Clinical use of molecular information in the management of multiple endocrine neoplasia type 2A. J Intern Med. 1995;238:331–341.CrossRefGoogle Scholar
  47. 47.
    Lips CJM, Landsvater RM, Hoppener JWM, et al. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med. 1994;331:828–835.PubMedCrossRefGoogle Scholar
  48. 48.
    Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res. 2002;62:7284–7290.PubMedGoogle Scholar
  49. 49.
    Moley JF. Medullary thyroid carcinoma. Curr Treat Options Oncol. 2003;4:339–347.PubMedCrossRefGoogle Scholar
  50. 50.
    Kruckeberg KE, Thibodeau SN. Pyrosequencing technology as a method for the diagnosis of multiple endocrine neoplasia type 2. Clin Chem. 2004;50:522–529.PubMedCrossRefGoogle Scholar
  51. 51.
    Ahmed SA, Snow-Bailey K, Highsmith WE, et al. Nine novel germline gene variants in the RET proto-oncogene identified in twelve unrelated cases. J Mol Diagn. 2005;7:283–288.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Barbara Zehnbauer
    • 1
  1. 1.Molecular Diagnostic Laboratory, Department of Pathology and ImmunologyWashington University School of MedicineSt LouisUSA

Personalised recommendations