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Multiple endocrine neoplasia type 1: Definition and genetics

Author
Andrew Arnold, MD
Section Editors
Marc K Drezner, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Jean E Mulder, MD

INTRODUCTION

The multiple endocrine neoplasia (MEN) syndromes are rare, but recognition is important both for treatment and for evaluation of family members (table 1).

This topic will review the classification and genetics of the MEN type 1 (MEN1) syndrome (OMIM ID +131100). The clinical manifestations, diagnosis, and therapy of MEN type 1 and the MEN type 2 (MEN2) syndromes are discussed separately. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis" and "Multiple endocrine neoplasia type 1: Treatment" and "Classification and genetics of multiple endocrine neoplasia type 2" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Approach to therapy in multiple endocrine neoplasia type 2".)

DEFINITION

Multiple endocrine neoplasia type 1 (MEN1) is a rare heritable disorder classically characterized by a predisposition to tumors of the parathyroid glands, anterior pituitary, and pancreatic islet cells [1]. The presence of MEN1 is defined clinically as the occurrence of two or more primary MEN1 tumor types, or in family members of a patient with a clinical diagnosis of MEN1, the occurrence of one of the MEN1-associated tumors. Multiple parathyroid tumors causing primary hyperparathyroidism are the most common component of MEN1, occurring in nearly all patients by age 50 years, and is the initial manifestation of the disorder in most patients. In one series of 220 patients with MEN1, parathyroid, pituitary glands, and pancreatic islet cell tumors occurred in 95, 30, and 41 percent of affected patients, respectively [2].

The prevalence of MEN1 is approximately 2 per 100,000 [3]. The incidence ranges from 1 to 18, 16 to 38, and less than 3 percent in patients with parathyroid adenomas, gastrinomas, and pituitary adenomas, respectively [1].

Patients with MEN1 may have tumors other than those in the parathyroid and pituitary, and pancreatic islet cells. The duodenum is a common site of tumors (gastrinomas) in these patients, and thymic or bronchial carcinoid tumors, enterochromaffin cell-like gastric tumors, adrenocortical adenomas, and lipomas are more frequent than in the general population. Other associated tumors include angiofibromas, angiomyolipomas, and spinal cord ependymomas (table 2).

       

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Literature review current through: Nov 2016. | This topic last updated: Wed Aug 26 00:00:00 GMT+00:00 2015.
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References
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  1. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012; 97:2990.
  2. Trump D, Farren B, Wooding C, et al. Clinical studies of multiple endocrine neoplasia type 1 (MEN1). QJM 1996; 89:653.
  3. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86:5658.
  4. Larsson C, Skogseid B, Oberg K, et al. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 1988; 332:85.
  5. Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997; 276:404.
  6. Bassett JH, Forbes SA, Pannett AA, et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 1998; 62:232.
  7. Agarwal SK, Lee Burns A, Sukhodolets KE, et al. Molecular pathology of the MEN1 gene. Ann N Y Acad Sci 2004; 1014:189.
  8. 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; 29:22.
  9. Turner JJ, Christie PT, Pearce SH, et al. Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1). Hum Mutat 2010; 31:E1089.
  10. Concolino P, Rossodivita A, Carrozza C, et al. A novel MEN1 frameshift germline mutation in two Italian monozygotic twins. Clin Chem Lab Med 2008; 46:824.
  11. Heppner C, Kester MB, Agarwal SK, et al. Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet 1997; 16:375.
  12. Carling T, Correa P, Hessman O, et al. Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. J Clin Endocrinol Metab 1998; 83:2960.
  13. Farnebo F, Teh BT, Kytölä S, et al. Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 1998; 83:2627.
  14. Zhuang Z, Vortmeyer AO, Pack S, et al. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 1997; 57:4682.
  15. Toliat MR, Berger W, Ropers HH, et al. Mutations in the MEN I gene in sporadic neuroendocrine tumours of gastroenteropancreatic system. Lancet 1997; 350:1223.
  16. Debelenko LV, Brambilla E, Agarwal SK, et al. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Hum Mol Genet 1997; 6:2285.
  17. Zhuang Z, Ezzat SZ, Vortmeyer AO, et al. Mutations of the MEN1 tumor suppressor gene in pituitary tumors. Cancer Res 1997; 57:5446.
  18. Asa SL, Somers K, Ezzat S. The MEN-1 gene is rarely down-regulated in pituitary adenomas. J Clin Endocrinol Metab 1998; 83:3210.
  19. Teh BT, Kytölä S, Farnebo F, et al. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab 1998; 83:2621.
  20. Stock JL, Warth MR, Teh BT, et al. A kindred with a variant of multiple endocrine neoplasia type 1 demonstrating frequent expression of pituitary tumors but not linked to the multiple endocrine neoplasia type 1 locus at chromosome region 11q13. J Clin Endocrinol Metab 1997; 82:486.
  21. Agarwal SK, Ozawa A, Mateo CM, Marx SJ. The MEN1 gene and pituitary tumours. Horm Res 2009; 71 Suppl 2:131.
  22. Belar O, De La Hoz C, Pérez-Nanclares G, et al. Novel mutations in MEN1, CDKN1B and AIP genes in patients with multiple endocrine neoplasia type 1 syndrome in Spain. Clin Endocrinol (Oxf) 2012; 76:719.
  23. Agarwal SK, Kester MB, Debelenko LV, et al. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 1997; 6:1169.
  24. Simonds WF, Robbins CM, Agarwal SK, et al. Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 2004; 89:96.
  25. Tanaka C, Yoshimoto K, Yamada S, et al. Absence of germ-line mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in familial pituitary adenoma in contrast to MEN1 in Japanese. J Clin Endocrinol Metab 1998; 83:960.
  26. Jorge BH, Agarwal SK, Lando VS, et al. Study of the multiple endocrine neoplasia type 1, growth hormone-releasing hormone receptor, Gs alpha, and Gi2 alpha genes in isolated familial acromegaly. J Clin Endocrinol Metab 2001; 86:542.
  27. Pellegata NS, Quintanilla-Martinez L, Siggelkow 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; 103:15558.
  28. Georgitsi M, Raitila A, Karhu A, et al. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab 2007; 92:3321.
  29. Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab 2009; 94:1826.
  30. Pellegata NS. MENX and MEN4. Clinics (Sao Paulo) 2012; 67 Suppl 1:13.
  31. Klein RD, Salih S, Bessoni J, Bale AE. Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med 2005; 7:131.
  32. Ozawa A, Agarwal SK, Mateo CM, et al. The parathyroid/pituitary variant of multiple endocrine neoplasia type 1 usually has causes other than p27Kip1 mutations. J Clin Endocrinol Metab 2007;92:1948.].