Multiple Endocrine Neoplasias

Abstract

Multiple endocrine neoplasia (MEN), types 1 and 2 (MEN1, MEN2) are autosomal dominant hereditary syndromes that predispose to wide variety of both hormone‐secreting and nonsecreting tumours throughout the body. MEN1 most classically demonstrates neoplasia of the parathyroid glands, anterior pituitary and neuroendocrine tumours of the pancreas and foregut. MEN2 has several variants, but medullary carcinoma of the thyroid is the dominant feature in all. Understanding of the molecular genetics of each disease has greatly affected treatment, especially for MEN2, which generally carries a worse prognosis. Therapy has evolved from symptomatic management of clinically detected tumours to resection of susceptible tissues even prior to tumour development based on genetic testing. This has vastly improved the outcomes for patients with these disorders.

Key Concepts:

  • The multiple endocrine neoplasia (MEN) syndromes are hereditary cancer syndromes that drive selected tissues in the body to develop both benign and malignant tumours.

  • Like most other hereditary cancer syndromes, MEN syndromes cause tumour growth by causing unregulated cell growth in susceptible tissues.

  • Unlike most hereditary cancer syndromes, MEN syndromes predominantly cause tumour growth in endocrine tissues, which can produce manifestations of hormone excess in affected patients.

  • Although MEN syndromes are relatively rare, patients with suspicious clinical presentations should undergo genetic testing, as the consequences of a missed MEN diagnosis can be catastrophic in certain variants of the disease.

  • Treatment of MEN syndromes is primarily via surgery, although medical therapy plays an important role for certain manifestations of the disease.

  • The evolution of MEN therapy is a prototype for demonstrating how molecular genetics can improve disease management.

Keywords: endocrine; neoplasia; tumour; genetics; tumour suppressor gene; oncogene; surgery

References

Agarwal SK, Impey S, McWeeney S et al. (2007) Distribution of menin‐occupied regions in chromatin specifies a broad role of menin in transcriptional regulation. Neoplasia 9: 101–107.

Agarwal SK, Kennedy PA, Scacheri PC et al. (2005) Menin molecular interactions: insights into normal functions and tumorigenesis. Hormone and Metabolic Research 37: 369–374.

Agarwal SK, Kester MB, Debelenko LV et al. (1997) Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Human Molecular Genetics 6: 1169–1175.

Agarwal SK, Lee Burns A, Sukhodolets KE et al. (2004) Molecular pathology of the MEN1 gene. Annals of The New York Academy of Sciences 1014: 189–198.

Agarwal SK, Mateo CM and Marx SJ (2009) Rare germline mutations in cyclin‐dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. Journal of Clinical Endocrinology and Metabolism 94: 1826–1834.

Asgharian B, Turner ML, Gibril F et al. (2004) Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1. Journal of Clinical Endocrinology and Metabolism 89: 5328–5336.

Bassett JH, Forbes SA, Pannett AA et al. (1998) Characterization of mutations in patients with multiple endocrine neoplasia type 1. American Journal of Human Genetics 62: 232–244.

Bilezikian JP, Potts JT Jr, Fuleihan Gel H et al. (2002) Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. Journal of Clinical Endocrinology and Metabolism 87: 5353–5361.

Brandi ML, Gagel RF, Angeli A et al. (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology and Metabolism 86: 5658–5671.

Carling T, Correa P, Hessman O et al. (1998) Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism 83: 2960–2963.

Carling T and Udelsman R (2005) Parathyroid surgery in familial hyperparathyroid disorders. Journal of Internal Medicine 257: 27–37.

Chandrasekharappa SC, Guru SC, Manickam P et al. (1997) Positional cloning of the gene for multiple endocrine neoplasia‐type 1. Science 276: 404–407.

Crabtree JS, Scacheri PC, Ward JM et al. (2003) Of mice and MEN1: Insulinomas in a conditional mouse knockout. Molecular and Cellular Biology 23: 6075–6085.

Dean PG, van Heerden JA, Farley DR et al. (2000) Are patients with multiple endocrine neoplasia type I prone to premature death? World Journal of Surgery 24: 1437–1441.

Demeure MJ, Klonoff DC, Karam JH, Duh QY and Clark OH (1991) Insulinomas associated with multiple endocrine neoplasia type I: the need for a different surgical approach. Surgery 110: 998–1004. (discussion ‐5).

Doherty GM, Lairmore TC and DeBenedetti MK (2004) Multiple endocrine neoplasia type 1 parathyroid adenoma development over time. World Journal of Surgery 28: 1139–1142.

Edery P, Lyonnet S, Mulligan LM et al. (1994) Mutations of the RET proto‐oncogene in Hirschsprung's disease. Nature 367: 378–380.

Elaraj DM, Skarulis MC, Libutti SK et al. (2003) Results of initial operation for hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Surgery 134: 858–864 (discussion 64‐5).

Elisei R, Cosci B, Romei C et al. (2008) Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10‐year follow‐up study. Journal of Clinical Endocrinology and Metabolism 93: 682–687.

Eller‐Vainicher C, Chiodini I, Battista C et al. (2009) Sporadic and MEN1‐related primary hyperparathyroidism: differences in clinical expression and severity. Journal of Bone and Mineral Research 24: 1404–1410.

Eng C, Clayton D, Schuffenecker I et al. (1996) The relationship between specific RET proto‐oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276: 1575–1579.

Gagel RF, Tashjian AH Jr, Cummings T et al. (1988) The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18‐year experience. New England Journal of Medicine 318: 478–484.

Goudet P, Murat A, Binquet C et al. (2010) Risk factors and causes of death in MEN1 disease. A GTE (Groupe d'Etude des Tumeurs Endocrines) cohort study among 758 patients. World Journal of Surgery 34: 249–255.

Guru SC, Goldsmith PK, Burns AL et al. (1998) Menin, the product of the MEN1 gene, is a nuclear protein. Proceedings of the National Academy of Sciences of USA 95: 1630–1634.

Hughes CM, Rozenblatt‐Rosen O, Milne TA et al. (2004) Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Molecular Cell 13: 587–597.

Jain S, Watson MA, DeBenedetti MK et al. (2004) Expression profiles provide insights into early malignant potential and skeletal abnormalities in multiple endocrine neoplasia type 2B syndrome tumors. Cancer Research 64: 3907–3913.

Jensen RT (1998) Management of the Zollinger‐Ellison syndrome in patients with multiple endocrine neoplasia type 1. Journal of Internal Medicine 243: 477–488.

Kloos RT, Eng C, Evans DB et al. (2009) Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19: 565–612.

La P, Silva AC, Hou Z et al. (2004) Direct binding of DNA by tumor suppressor menin. Journal of Biological Chemistry 279: 49045–49054.

Lairmore TC, Chen VY, DeBenedetti MK et al. (2000) Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Annals of Surgery 231: 909–918.

Lairmore TC, Piersall LD, DeBenedetti MK et al. (2004) Clinical genetic testing and early surgical intervention in patients with multiple endocrine neoplasia type 1 (MEN 1). Annals of Surgery 239: 637–645, discussion 45–47.

Larsson C, Skogseid B, Oberg K, Nakamura Y and Nordenskjold M (1988) Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 332: 85–87.

Lemos MC and Thakker RV (2008) Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Human Mutation 29: 22–32.

Lodish MB and Stratakis CA (2008) RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer. Expert Review of Anticancer Therapy 8: 625–632.

Machens A, Brauckhoff M, Holzhausen HJ et al. (2005) Codon‐specific development of pheochromocytoma in multiple endocrine neoplasia type 2. Journal of Clinical Endocrinology and Metabolism 90: 3999–4003.

Machens A, Niccoli‐Sire P, Hoegel J et al. (2003) Early malignant progression of hereditary medullary thyroid cancer. New England Journal of Medicine 349: 1517–1525.

Marsh D and Zori R (2002) Genetic insights into familial cancers – update and recent discoveries. Cancer Letters 181: 125–164.

Marsh DJ, Learoyd DL, Andrew SD et al. (1996) Somatic mutations in the RET proto‐oncogene in sporadic medullary thyroid carcinoma. Clinical Endocrinology (Oxford) 44: 249–257.

Marx SJ (2005) Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nature Reviews Cancer 5: 367–375.

Mulligan LM, Marsh DJ, Robinson BG et al. (1995) Genotype–phenotype correlation in multiple endocrine neoplasia type 2: Report of the International RET Mutation Consortium. Journal of Internal Medicine 238: 343–346.

Pellegata NS, Quintanilla‐Martinez L, Siggelkow H et al. (2006) Germ‐line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proceedings of the National Academy of Sciences of USA 103: 15558–15563.

Powell AC, Alexander HR, Pingpank JF et al. (2008) The utility of routine transcervical thymectomy for multiple endocrine neoplasia 1‐related hyperparathyroidism. Surgery 144: 878–883. (discussion 83‐48).

Rizzoli R, Green J 3rd and Marx SJ (1985) Primary hyperparathyroidism in familial multiple endocrine neoplasia type I. Long‐term follow‐up of serum calcium levels after parathyroidectomy. American Journal of Medicine 78: 467–474.

Santoro M, Melillo RM, Carlomagno F, Vecchio G and Fusco A (2004) Minireview: RET: normal and abnormal functions. Endocrinology 145: 5448–5451.

Scacheri PC, Davis S, Odom DT et al. (2006) Genome‐wide analysis of menin binding provides insights into MEN1 tumorigenesis. PLoS Genetics 2: e51.

Takahashi M, Ritz J and Cooper GM (1985) Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42: 581–588.

Triponez F, Dosseh D, Goudet P et al. (2006) Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Annals of Surgery 243: 265–272.

Verges B, Boureille F, Goudet P et al. (2002) Pituitary disease in MEN type 1 (MEN1): data from the France–Belgium MEN1 multicenter study. Journal of Clinical Endocrinology and Metabolism 87: 457–465.

Yaguchi H, Ohkura N, Takahashi M et al. (2004) Menin missense mutants associated with multiple endocrine neoplasia type 1 are rapidly degraded via the ubiquitin‐proteasome pathway. Molecular and Cellular Biology 24: 6569–6580.

Further Reading

Carling T (2005) Multiple endocrine neoplasia syndrome: genetic basis for clinical management. Current Opinion in Oncology 17: 7–12.

Carling T and Udelsman R (2008) Thyroid Tumors. In: DeVita VT Jr, Hellman S and Rosenberg SA (eds) Cancer: Principles & Practice of Oncology, 8th edn. 1663–1682. Philadelphia: Lippincott‐Raven.

Stalberg P and Carling T (2009) Familial parathyroid tumors: diagnosis and management. World Journal of Surgery.

Thompson JC and Townsend C (2008) Endocrine Pancreas. In: Beauchamp BD, Townsend C, Evers BM and Mattox KL (eds) Sabiston's Textbook of Surgery: the Biological Basis of Modern Surgical Practice, pp. 976–996. chap. 38. Philadelphia: WB Saunders.

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How to Cite close
Kunstman, John W, and Carling, Tobias(May 2011) Multiple Endocrine Neoplasias. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006060]