Skip to main content
SpringerLink
Log in

Multiple Endocrine Neoplasia Type 1 and Type 4

  • Chapter
  • First Online:
Endocrine Surgery in Children

  • 1311 Accesses

Abstract

Multiple Endocrine Neoplasia (MEN) syndromes are characterised by the combined occurrence of two or more endocrine tumours in a patient. These autosomal dominant conditions occur in four types: MEN type1 due to inactivating MEN1 gene mutations; MEN type 2A and MEN type 2B (also known as MEN type 3) due to activating mutations of the “rearranged during transfection” (RET) proto-oncogene; and MEN type 4 due to inactivating Cyclin-Dependent Kinase Inhibitor 1B (CDKN1B) mutations. Each MEN syndrome exhibits different combinations of pancreatic islet, anterior pituitary, parathyroid, medullary thyroid and adrenal endocrine tumours together with associated non-endocrine tumours. This chapter provides an overview of the clincial features, diagnosis, treatments and molecular genetics of Multiple Endocrine Neoplasia syndromes types 1 and 4.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab. 2010;24(3):355–70.

    Article  CAS  PubMed  Google Scholar 

  2. Newey PJ, Thakker RV. Role of multiple endocrine neoplasia type 1 mutational analysis in clinical practice. Endocr Pract. 2011;17(Suppl 3):8–17.

    Article  PubMed  Google Scholar 

  3. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990–3011.

    Article  CAS  PubMed  Google Scholar 

  4. Wells SA, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98(8):3149–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Calderon FR, Wittwer CT, et al. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat. 2009;30(4):548–56.

    Article  CAS  PubMed  Google Scholar 

  6. Lakhani VT, You YN, Wells SA. The multiple endocrine neoplasia syndromes. Annu Rev Med. 2007;58:253–65.

    Article  CAS  PubMed  Google Scholar 

  7. Thakker R. Multiple endocrine neoplasia type 1. In: DeGroot L, Jameson J, editors. Endocrinology: adult and pediatric, vol. 1–2. 6th ed. Philadelphia: Elsevier Saunders; 2010. p. 2719–41.

    Google Scholar 

  8. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A. 2006;103(42):15558–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Marinoni I, Pellegata NS. p27kip1: a new multiple endocrine neoplasia gene? Neuroendocrinology. 2011;93(1):19–28.

    Article  CAS  PubMed  Google Scholar 

  10. Molatore S, Marinoni I, Lee M, Pulz E, Ambrosio MR, degli Uberti EC, et al. A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization. Hum Mutat. 2010;31(11):E1825–35.

    Google Scholar 

  11. Lee M, Pellegata NS. Multiple endocrine neoplasia syndromes associated with mutation of p27. J Endocrinol Invest. 2013;36(9):781–7.

    CAS  PubMed  Google Scholar 

  12. Newey PJ, Bowl MR, Cranston T, Thakker RV. Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors. Hum Mutat. 2010;31(3):295–307.

    Article  CAS  PubMed  Google Scholar 

  13. Xia Y, Darling TN. Rapidly growing collagenomas in multiple endocrine neoplasia type I. J Am Acad Dermatol. 2007;56(5):877–80.

    Article  PubMed  Google Scholar 

  14. Waldmann J, Bartsch DK, Kann PH, Fendrich V, Rothmund M, Langer P. Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening. Langenbecks Arch Surg. 2007;392(4):437–43.

    Article  CAS  PubMed  Google Scholar 

  15. Trump D, Farren B, Wooding C, Pang JT, Besser GM, Buchanan KD, et al. Clinical studies of multiple endocrine neoplasia type 1 (MEN1). QJM. 1996;89(9):653–69.

    Article  CAS  PubMed  Google Scholar 

  16. Newey PJ, Jeyabalan J, Walls GV, Christie PT, Gleeson FV, Gould S, et al. Asymptomatic children with multiple endocrine neoplasia type 1 mutations may harbor nonfunctioning pancreatic neuroendocrine tumors. J Clin Endocrinol Metab. 2009;94(10):3640–6.

    Article  CAS  PubMed  Google Scholar 

  17. Farrell WE, Azevedo MF, Batista DL, Smith A, Bourdeau I, Horvath A, et al. Unique gene expression profile associated with an early-onset multiple endocrine neoplasia (MEN1)-associated pituitary adenoma. J Clin Endocrinol Metab. 2011;96(11):E1905–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Goudet P, Dalac A, Le Bras M, Cardot-Bauters C, Niccoli P, Lévy-Bohbot N, et al. MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d’étude des Tumeurs Endocrines. J Clin Endocrinol Metab. 2015;100(4):1568–77.

    Article  CAS  PubMed  Google Scholar 

  19. Romero Arenas MA, Morris LF, Rich TA, Cote GJ, Grubbs EG, Waguespack SG, et al. Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg. 2014;49(4):546–50.

    Article  PubMed  Google Scholar 

  20. Nilubol N, Weinstein LS, Simonds WF, Jensen RT, Marx SJ, Kebebew E. limited parathyroidectomy in multiple endocrine neoplasia type 1-associated primary hyperparathyroidism: a setup for failure. Ann Surg Oncol. 2016;23(2):416–23.

    Article  PubMed  Google Scholar 

  21. Langusch CC, Norlen O, Titmuss A, Donoghue K, Holland AJ, Shun A, et al. Focused image-guided parathyroidectomy in the current management of primary hyperparathyroidism. Arch Dis Child. 2015;100(10):924–7.

    Article  PubMed  Google Scholar 

  22. Goudet P, Cougard P, Verges B, Murat A, Carnaille B, Calender A, et al. Hyperparathyroidism in multiple endocrine neoplasia type I: surgical trends and results of a 256-patient series from Groupe D’etude des Neoplasies Endocriniennes Multiples Study Group. World J Surg. 2001;25(7):886–90.

    Article  CAS  PubMed  Google Scholar 

  23. Goudet P, Bonithon-Kopp C, Murat A, Ruszniewski P, Niccoli P, Ménégaux F, et al. Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d’etude des Tumeurs Endocrines. Eur J Endocrinol. 2011;165(1):97–105.

    Article  CAS  PubMed  Google Scholar 

  24. Melmed S. Medical progress: acromegaly. N Engl J Med. 2006;355(24):2558–73.

    Article  CAS  PubMed  Google Scholar 

  25. Sztal-Mazer S, Topliss DJ, Simpson RW, Hamblin PS, Rosenfeld JV, McLean CA. Gonadotroph adenoma in multiple endocrine neoplasia type 1. Endocr Pract. 2008;14(5):592–4.

    Article  PubMed  Google Scholar 

  26. Gatta-Cherifi B, Chabre O, Murat A, Niccoli P, Cardot-Bauters C, Rohmer V, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’etude des Tumeurs Endocrines database. Eur J Endocrinol. 2012;166(2):269–79.

    Article  CAS  PubMed  Google Scholar 

  27. Zeiger MA, Siegelman SS, Hamrahian AH. Medical and surgical evaluation and treatment of adrenal incidentalomas. J Clin Endocrinol Metab. 2011;96(7):2004–15.

    Article  CAS  PubMed  Google Scholar 

  28. Schaefer S, Shipotko M, Meyer S, Ivan D, Klose KJ, Waldmann J, et al. Natural course of small adrenal lesions in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study. Eur J Endocrinol. 2008;158(5):699–704.

    Article  CAS  PubMed  Google Scholar 

  29. Faggiano A, Ferolla P, Grimaldi F, Campana D, Manzoni M, Davì MV, et al. Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian Epidemiological study: The NET management study. J Endocrinol Invest. 2011.

    Google Scholar 

  30. Goudet P, Murat A, Cardot-Bauters C, Emy P, Baudin E, du Boullay Choplin H, et al. Thymic neuroendocrine tumors in multiple endocrine neoplasia type 1: a comparative study on 21 cases among a series of 761 MEN1 from the GTE (Groupe des Tumeurs Endocrines). World J Surg. 2009;33(6):1197–207.

    Article  PubMed  Google Scholar 

  31. Beckers A, Betea D, Valdes Socin H, Stevenaert A. The treatment of sporadic versus MEN1-related pituitary adenomas. J Intern Med. 2003;253(6):599–605.

    Article  CAS  PubMed  Google Scholar 

  32. Bartsch DK, Fendrich V, Langer P, Celik I, Kann PH, Rothmund M. Outcome of duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Ann Surg. 2005;242(6):757–64, discussion 64–6.

    Google Scholar 

  33. Akerstrom G, Hellman P. Surgery on neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. 2007;21(1):87–109.

    Article  PubMed  Google Scholar 

  34. Wu ZB, Su ZP, Wu JS, Zheng WM, Zhuge QC, Zhong M. Five years follow-up of invasive prolactinomas with special reference to the control of cavernous sinus invasion. Pituitary. 2008;11(1):63–70.

    Article  CAS  PubMed  Google Scholar 

  35. Qu X, Wang M, Wang G, Han T, Mou C, Han L, et al. Surgical outcomes and prognostic factors of transsphenoidal surgery for prolactinoma in men: a single-center experience with 87 consecutive cases. Eur J Endocrinol. 2011;164(4):499–504.

    Article  CAS  PubMed  Google Scholar 

  36. Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, et al. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet. 1997;6(7):1177–83.

    Article  CAS  PubMed  Google Scholar 

  37. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276(5311):404–7.

    Article  CAS  PubMed  Google Scholar 

  38. Lemos MC, Thakker RV. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat. 2008;29(1):22–32.

    Article  CAS  PubMed  Google Scholar 

  39. La P, Yang Y, Karnik SK, Silva AC, Schnepp RW, Kim SK, et al. Menin-mediated caspase 8 expression in suppressing multiple endocrine neoplasia type 1. J Biol Chem. 2007;282(43):31332–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schnepp RW, Chen YX, Wang H, Cash T, Silva A, Diehl JA, et al. Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells. Cancer Res. 2006;66(11):5707–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, et al. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature. 2012;482(7386):542–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci U S A. 2005;102(3):749–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Harding B, Lemos MC, Reed AA, Walls GV, Jeyabalan J, Bowl MR, et al. Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr Relat Cancer. 2009;16(4):1313–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Walls GV, Lemos MC, Javid M, Bazan-Peregrino M, Jeyabalan J, Reed AA, et al. MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas. Cancer Res. 2012;72(19):5060–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Piret SE, Thakker RV. Mouse models for inherited endocrine and metabolic disorders. J Endocrinol. 2011;211(3):211–30.

    Article  CAS  PubMed  Google Scholar 

  46. Walls GV, Reed AA, Jeyabalan J, Javid M, Hill NR, Harding B, et al. Proliferation rates of multiple endocrine neoplasia type 1 (MEN1)-associated tumors. Endocrinology. 2012;153(11):5167–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Quinn TJ, Yuan Z, Adem A, Geha R, Vrikshajanani C, Koba W, et al. Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model. Surgery. 2012;152(6):1068–77.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Walls GV, Stevenson M, Soukup B, Lines KE, Christie PT, Grossman AB, et al. Treatment with pasireotide, a somatostatin analogue, results in decreased proliferation and increased apoptosis in pancreatic and pituitary neuroendocrine tumors (NETs), in a mouse model for multiple endocrine neoplasia type 1 (MEN1). Endocr Rev. 2015;36(2):OR02–3.

    Google Scholar 

  49. Lee M, Pellegata NS. Multiple endocrine neoplasia type 4. Front Horm Res. 2013;41:63–78.

    Article  CAS  PubMed  Google Scholar 

  50. Bugalho MJ, Domingues R. Uncommon association of cerebral meningioma, parathyroid adenoma and papillary thyroid carcinoma in a patient harbouring a rare germline variant in the CDKN1B gene. BMJ Case Rep. 2016;. doi:10.1136/bcr-2015-213934.

    Google Scholar 

  51. Iacobone M, Carnaille B, Palazzo FF, Vriens M. Hereditary hyperparathyroidism-a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg. 2015;400(8):867–86.

    Article  PubMed  Google Scholar 

  52. Costa-Guda J, Marinoni I, Molatore S, Pellegata NS, Arnold A. Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. J Clin Endocrinol Metab. 2011;96(4):E701–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Royal Lancaster Infirmary, University Hospitals of Morecambe Bay NHS Foundation Trust, Ashton Road, Lancaster, LA1 4RP, UK

    Gerard V. Walls

Authors
  1. Gerard V. Walls
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerard V. Walls .

Editor information

Editors and Affiliations

  1. Seattle Children’s Hospital, Seattle, Washington, USA

    Daniel J. Ledbetter

  2. Academic Pediatric Surgery Unit, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, United Kingdom

    Paul R.V. Johnson

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer-Verlag GmbH Germany

About this chapter

Cite this chapter

Walls, G.V. (2018). Multiple Endocrine Neoplasia Type 1 and Type 4. In: Ledbetter, D., Johnson, P. (eds) Endocrine Surgery in Children. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-54256-9_30

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-54256-9_30

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-54254-5

  • Online ISBN: 978-3-662-54256-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation