The Multiple Endocrine Neoplasia Syndromes

  • Simona Grozinsky-GlasbergEmail author
  • David J. Gross


The term multiple endocrine neoplasia (MEN) refers to hereditary neoplastic disorder involving more than one endocrine organ and includes the MEN type 1 (MEN1), the MEN type 2 (MEN2), and the familial medullary thyroid carcinoma (FMTC). The estimated frequency of each of these syndromes is around 1 in 30,000 and is characterized by complete penetrance with variable expression [1, 2]. The recent progress in our knowledge of both the molecular and the clinical genetics of these syndromes has improved the clinical management of the patients [3]. On the one hand, the MEN1 gene, a tumor suppressor gene responsible of MEN1 syndrome, is involved in the regulation of several cell functions (e.g., DNA replication and repair and transcriptional machinery). On the other hand, the RET proto-oncogene encodes for a receptor tyrosine kinase protein whose expression is fundamental for appropriate migration, development, and differentiation of neuroendocrine cells originating from neural crest [4]. Currently, DNA testing allows the early identification of germline mutations in presymptomatic mutant gene carriers in the MEN syndromes [5]. Consequently, an early identification of the MEN-associated neoplasms and the genotype-phenotype correlation improve the outcome and the quality of life for affected subjects [6].


Hyperparathyroidism Pituitary adenoma Pancreatic neuroendocrine tumor Menin Medullary thyroid carcinoma RET Pheochromocytoma Chromogranin A Somatostatin Tyrosine kinase 


  1. 1.
    Yip L, Cote GJ, Shapiro SE, et al. Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg. 2003;138(4):409–16; discussion 16.PubMedGoogle Scholar
  2. 2.
    Huang SC, Torres-Cruz J, Pack SD, et al. Amplification and overexpression of mutant RET in multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma. J Clin Endocrinol Metab. 2003;88(1):459–63.PubMedGoogle Scholar
  3. 3.
    Falchetti A, Marini F, Tonelli F, Brandi ML. Lessons from genes mutated in multiple endocrine neoplasia (MEN) syndromes. Ann Endocrinol (Paris). 2005;66(3):195–205.Google Scholar
  4. 4.
    Kouvaraki MA, Shapiro SE, Perrier ND, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15(6):531–44.PubMedGoogle Scholar
  5. 5.
    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(12):5658–71.PubMedGoogle Scholar
  6. 6.
    Carling T. Multiple endocrine neoplasia syndrome: genetic basis for clinical management. Curr Opin Oncol. 2005;17(1):7–12.PubMedGoogle Scholar
  7. 7.
    Wermer P. Genetic aspects of adenomatosis of endocrine glands. Am J Med. 1954;16(3):363–71.PubMedGoogle Scholar
  8. 8.
    Thakker RV. Multiple endocrine neoplasia type 1. Endocrinol Metab Clin North Am. 2000;29(3):541–67.PubMedGoogle Scholar
  9. 9.
    Trump D, Farren B, Wooding C, et al. Clinical studies of multiple endocrine neoplasia type 1 (MEN1). QJM. 1996;89(9):653–69.PubMedGoogle Scholar
  10. 10.
    Grama D, Skogseid B, Wilander E, et al. Pancreatic tumors in multiple endocrine neoplasia type 1: clinical presentation and surgical treatment. World J Surg. 1992;16(4):611–8; discussion 18–19.PubMedGoogle Scholar
  11. 11.
    Skogseid B, Larsson C, Lindgren PG, et al. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 1992;75(1):76–81.PubMedGoogle Scholar
  12. 12.
    Duh QY, Hybarger CP, Geist R, et al. Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg. 1987;154(1):142–8.PubMedGoogle Scholar
  13. 13.
    Marx SJ, Vinik AI, Santen RJ, Floyd Jr JC, Mills JL, Green 3rd J. Multiple endocrine neoplasia type I: assessment of laboratory tests to screen for the gene in a large kindred. Medicine (Baltimore). 1986;65(4):226–41.Google Scholar
  14. 14.
    Brandi ML, Aurbach GD, Fitzpatrick LA, et al. Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1. N Engl J Med. 1986;314(20):1287–93.PubMedGoogle Scholar
  15. 15.
    Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM, Turner M. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol. 1997;133(7):853–7.PubMedGoogle Scholar
  16. 16.
    Asgharian B, Turner ML, Gibril F, Entsuah LK, Serrano J, Jensen RT. 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. J Clin Endocrinol Metab. 2004;89(11):5328–36.PubMedGoogle Scholar
  17. 17.
    Thakker RV. Multiple endocrine neoplasia. Horm Res. 2001;56 Suppl 1:67–72.PubMedGoogle Scholar
  18. 18.
    Kivlen MH, Bartlett DL, Libutti SK, et al. Reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1. Surgery. 2001;130(6):991–8.PubMedGoogle Scholar
  19. 19.
    Agha A, Carpenter R, Bhattacharya S, Edmonson SJ, Carlsen E, Monson JP. Parathyroid carcinoma in multiple endocrine neoplasia type 1 (MEN1) syndrome: two case reports of an unrecognised entity. J Endocrinol Invest. 2007;30(2):145–9.PubMedGoogle Scholar
  20. 20.
    Burgess JR, David R, Greenaway TM, Parameswaran V, Shepherd JJ. Osteoporosis in multiple endocrine neoplasia type 1: severity, clinical significance, relationship to primary hyperparathyroidism, and response to parathyroidectomy. Arch Surg. 1999;134(10):1119–23.PubMedGoogle Scholar
  21. 21.
    Molino C, Fabbian F, Russo G, et al. MEN type 1 and chronic renal failure: a rarely reported association. G Ital Nefrol. 2007;24(1):79–82.PubMedGoogle Scholar
  22. 22.
    Satoh A, Iigaya T. Multiple endocrine neoplasia type 1 with pyonephrosis. Int J Urol. 2002;9(7):402–4.PubMedGoogle Scholar
  23. 23.
    Burgess JR, Greenaway TM, Shepherd JJ. Expression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1. J Intern Med. 1998;243(6):465–70.PubMedGoogle Scholar
  24. 24.
    Benson L, Ljunghall S, Akerstrom G, Oberg K. Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type 1. Am J Med. 1987;82(4):731–7.PubMedGoogle Scholar
  25. 25.
    Hagstrom E, Lundgren E, Rastad J, Hellman P. Metabolic abnormalities in patients with normocalcemic hyperparathyroidism detected at a population-based screening. Eur J Endocrinol. 2006;155(1):33–9.PubMedGoogle Scholar
  26. 26.
    Sukovaty RL, Lee JW, Fox J, et al. Quantification of recombinant human parathyroid hormone (rhPTH(1-84)) in human plasma by immunoassay: commercial kit evaluation and validation to support pharmacokinetic studies. J Pharm Biomed Anal. 2006;42(2):261–71.PubMedGoogle Scholar
  27. 27.
    Skandarajah A, Barlier A, Morlet-Barlat N, et al. Should routine analysis of the MEN1 gene be performed in all patients with primary hyperparathyroidism under 40 years of age? World J Surg. 2010;34(6):1294–8.PubMedGoogle Scholar
  28. 28.
    Tonelli F, Marcucci T, Giudici F, Falchetti A, Brandi ML. Surgical approach in hereditary hyperparathyroidism. Endocr J. 2009;56(7):827–41.PubMedGoogle Scholar
  29. 29.
    Akerstrom G, Stalberg P. Surgical management of MEN-1 and -2: state of the art. Surg Clin North Am. 2009;89(5):1047–68.PubMedGoogle Scholar
  30. 30.
    Salmeron MD, Gonzalez JM, Sancho Insenser J, et al. Causes and treatment of recurrent hyperparathyroidism after subtotal parathyroidectomy in the presence of multiple endocrine neoplasia 1. World J Surg. 2010;34(6):1325–31.PubMedGoogle Scholar
  31. 31.
    Burgess J. How should the patient with multiple endocrine neoplasia type 1 (MEN 1) be followed? Clin Endocrinol (Oxf). 2010;72(1):13–6.Google Scholar
  32. 32.
    Norton JA, Venzon DJ, Berna MJ, et al. Prospective study of surgery for primary hyperparathyroidism (HPT) in multiple endocrine neoplasia-type 1 and Zollinger-Ellison syndrome: long-term outcome of a more virulent form of HPT. Ann Surg. 2008;247(3):501–10.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2005;90(1):135–41.PubMedGoogle Scholar
  34. 34.
    Wada M, Furuya Y, Sakiyama J, et al. The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor. J Clin Invest. 1997;100(12):2977–83.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Moyes VJ, Monson JP, Chew SL, Akker SA. Clinical use of cinacalcet in MEN1 hyperparathyroidism. Int J Endocrinol. 2010;2010:906163.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Faggiano A, Tavares LB, Tauchmanova L, et al. Effect of treatment with depot somatostatin analogue octreotide on primary hyperparathyroidism (PHP) in multiple endocrine neoplasia type 1 (MEN1) patients. Clin Endocrinol (Oxf). 2008;69(5):756–62.Google Scholar
  37. 37.
    Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990–3011.PubMedGoogle Scholar
  38. 38.
    Tonelli F, Giudici F, Fratini G, Brandi ML. Pancreatic endocrine tumors in multiple endocrine neoplasia type 1 syndrome: review of literature. Endocr Pract. 2011;17 Suppl 3:33–40.PubMedGoogle Scholar
  39. 39.
    Machens A, Schaaf L, Karges W, et al. Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers. Clin Endocrinol (Oxf). 2007;67(4):613–22.Google Scholar
  40. 40.
    Newey PJ, Jeyabalan J, Walls GV, 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.PubMedGoogle Scholar
  41. 41.
    Triponez F, Dosseh D, Goudet P, et al. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg. 2006;243(2):265–72.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Anlauf M, Garbrecht N, Henopp T, et al. Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features. World J Gastroenterol. 2006;12(34):5440–6.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Fendrich V, Langer P, Waldmann J, Bartsch DK, Rothmund M. Management of sporadic and multiple endocrine neoplasia type 1 gastrinomas. Br J Surg. 2007;94(11):1331–41.PubMedGoogle Scholar
  44. 44.
    Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore). 2004;83(1):43–83.Google Scholar
  45. 45.
    Lowney JK, Frisella MM, Lairmore TC, Doherty GM. Pancreatic islet cell tumor metastasis in multiple endocrine neoplasia type 1: correlation with primary tumor size. Surgery. 1998;124(6):1043–8; discussion 48–49.PubMedGoogle Scholar
  46. 46.
    Yu F, Venzon DJ, Serrano J, et al. Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome. J Clin Oncol. 1999;17(2):615–30.PubMedGoogle Scholar
  47. 47.
    Goudet P, Murat A, Binquet C, et al. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients. World J Surg. 2010;34(2):249–55.PubMedGoogle Scholar
  48. 48.
    Geerdink EA, Van der Luijt RB, Lips CJ. Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening? Eur J Endocrinol. 2003;149(6):577–82.PubMedGoogle Scholar
  49. 49.
    Pipeleers-Marichal M, Donow C, Heitz PU, Kloppel G. Pathologic aspects of gastrinomas in patients with Zollinger-Ellison syndrome with and without multiple endocrine neoplasia type I. World J Surg. 1993;17(4):481–8.PubMedGoogle Scholar
  50. 50.
    Thakker RV. Multiple endocrine neoplasia type 1. Indian J Endocrinol Metab. 2012;16 Suppl 2:S272–4.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Anlauf M, Perren A, Kloppel G. Gastrin cell hyperplasia associated with duodenal MEN1-related gastrinomas: histopathology and genetics. Verh Dtsch Ges Pathol. 2007;91:320–9.PubMedGoogle Scholar
  52. 52.
    Jensen RT. Gastrinomas: advances in diagnosis and management. Neuroendocrinology. 2004;80 Suppl 1:23–7.PubMedGoogle Scholar
  53. 53.
    Imamura M, Komoto I, Ota S, et al. Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients. World J Gastroenterol. 2011;17(10):1343–53.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Roy PK, Venzon DJ, Feigenbaum KM, et al. Gastric secretion in Zollinger-Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis–a prospective NIH study of 235 patients and a review of 984 cases in the literature. Medicine (Baltimore). 2001;80(3):189–222.Google Scholar
  55. 55.
    Dean PG, van Heerden JA, Farley DR, et al. Are patients with multiple endocrine neoplasia type I prone to premature death? World J Surg. 2000;24(11):1437–41.PubMedGoogle Scholar
  56. 56.
    Berna MJ, Hoffmann KM, Long SH, et al. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features. Medicine (Baltimore). 2006;85(6):331–64.Google Scholar
  57. 57.
    Gibril F, Reynolds JC, Doppman JL, et al. Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Ann Intern Med. 1996;125(1):26–34.PubMedGoogle Scholar
  58. 58.
    Turner JJ, Wren AM, Jackson JE, Thakker RV, Meeran K. Localization of gastrinomas by selective intra-arterial calcium injection. Clin Endocrinol (Oxf). 2002;57(6):821–5.Google Scholar
  59. 59.
    Thompson NW, Pasieka J, Fukuuchi A. Duodenal gastrinomas, duodenotomy, and duodenal exploration in the surgical management of Zollinger-Ellison syndrome. World J Surg. 1993;17(4):455–62.PubMedGoogle Scholar
  60. 60.
    Jensen RT. Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. J Intern Med. 1998;243(6):477–88.PubMedGoogle Scholar
  61. 61.
    Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med. 1999;341(9):635–44.PubMedGoogle Scholar
  62. 62.
    Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT. Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome? Ann Surg. 2004;239(5):617–25; discussion 26.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Grozinsky-Glasberg S, Shimon I, Korbonits M, Grossman AB. Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms. Endocr Relat Cancer. 2008;15(3):701–20.PubMedGoogle Scholar
  64. 64.
    Arnold R, Wied M, Behr TH. Somatostatin analogues in the treatment of endocrine tumors of the gastrointestinal tract. Expert Opin Pharmacother. 2002;3(6):643–56.PubMedGoogle Scholar
  65. 65.
    Shojamanesh H, Gibril F, Louie A, et al. Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma. Cancer. 2002;94(2):331–43.PubMedGoogle Scholar
  66. 66.
    Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab. 2010;24(3):355–70.PubMedGoogle Scholar
  67. 67.
    Grozinsky-Glasberg S, Barak D, Fraenkel M, et al. Peptide receptor radioligand therapy is an effective treatment for the long-term stabilization of malignant gastrinomas. Cancer. 2011;117(7):1377–85.PubMedGoogle Scholar
  68. 68.
    Vasen HF, Lamers CB, Lips CJ. Screening for the multiple endocrine neoplasia syndrome type I. A study of 11 kindreds in The Netherlands. Arch Intern Med. 1989;149(12):2717–22.PubMedGoogle Scholar
  69. 69.
    Fabbri HC, Mello MP, Soardi FC, et al. Long-term follow-up of an 8-year-old boy with insulinoma as the first manifestation of a familial form of multiple endocrine neoplasia type 1. Arq Bras Endocrinol Metabol. 2010;54(8):754–60.PubMedGoogle Scholar
  70. 70.
    Giudici F, Nesi G, Brandi ML, Tonelli F. Surgical management of insulinomas in multiple endocrine neoplasia type 1. Pancreas. 2012;41(4):547–53.PubMedGoogle Scholar
  71. 71.
    Langer P, Kann PH, Fendrich V, et al. Prospective evaluation of imaging procedures for the detection of pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. World J Surg. 2004;28(12):1317–22.PubMedGoogle Scholar
  72. 72.
    Levy-Bohbot N, Merle C, Goudet P, et al. Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol. 2004;28(11):1075–81.PubMedGoogle Scholar
  73. 73.
    Zhang M, Xu X, Shen Y, et al. Clinical experience in diagnosis and treatment of glucagonoma syndrome. Hepatobiliary Pancreat Dis Int. 2004;3(3):473–5.PubMedGoogle Scholar
  74. 74.
    van Beek AP, de Haas ER, van Vloten WA, Lips CJ, Roijers JF, Canninga-van Dijk MR. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol. 2004;151(5):531–7.PubMedGoogle Scholar
  75. 75.
    Yamazaki M, Suzuki S, Kosugi S, et al. Delay in the diagnosis of multiple endocrine neoplasia type 1: typical symptoms are frequently overlooked. Endocr J. 2012;59(9):797–807.PubMedGoogle Scholar
  76. 76.
    Sakurai A, Suzuki S, Kosugi S, et al. Multiple endocrine neoplasia type 1 in Japan: establishment and analysis of a multicentre database. Clin Endocrinol (Oxf). 2012;76(4):533–9.Google Scholar
  77. 77.
    Soga J, Yakuwa Y. Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. J Hepatobiliary Pancreat Surg. 1998;5(3):312–9.PubMedGoogle Scholar
  78. 78.
    Kindmark H, Sundin A, Granberg D, et al. Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years. Med Oncol. 2007;24(3):330–7.PubMedGoogle Scholar
  79. 79.
    Wermers RA, Fatourechi V, Wynne AG, Kvols LK, Lloyd RV. The glucagonoma syndrome. Clinical and pathologic features in 21 patients. Medicine (Baltimore). 1996;75(2):53–63.Google Scholar
  80. 80.
    O’Toole D, Salazar R, Falconi M, et al. Rare functioning pancreatic endocrine tumors. Neuroendocrinology. 2006;84(3):189–95.PubMedGoogle Scholar
  81. 81.
    Eldor R, Glaser B, Fraenkel M, Doviner V, Salmon A, Gross DJ. Glucagonoma and the glucagonoma syndrome – cumulative experience with an elusive endocrine tumour. Clin Endocrinol (Oxf). 2011;74(5):593–8.Google Scholar
  82. 82.
    Brown CH, Crile Jr G. Pancreatic adenoma with intractable diarrhea, hypokalemia, and hypercalcemia. JAMA. 1964;190:30–4.PubMedGoogle Scholar
  83. 83.
    Scarsbrook AF, Thakker RV, Wass JA, Gleeson FV, Phillips RR. Multiple endocrine neoplasia: spectrum of radiologic appearances and discussion of a multitechnique imaging approach. Radiographics. 2006;26(2):433–51.PubMedGoogle Scholar
  84. 84.
    Thomas-Marques L, Murat A, Delemer B, et al. Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. Am J Gastroenterol. 2006;101(2):266–73.PubMedGoogle Scholar
  85. 85.
    Doherty GM, Olson JA, Frisella MM, et al. Lethality of multiple endocrine neoplasia type I. World J Surg. 1998;22(6):581–6; discussion 86–87.PubMedGoogle Scholar
  86. 86.
    Kann PH, Balakina E, Ivan D, et al. Natural course of small, asymptomatic neuroendocrine pancreatic tumours in multiple endocrine neoplasia type 1: an endoscopic ultrasound imaging study. Endocr Relat Cancer. 2006;13(4):1195–202.PubMedGoogle Scholar
  87. 87.
    Triponez F, Goudet P, Dosseh D, et al. Is surgery beneficial for MEN1 patients with small (< or = 2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J Surg. 2006;30(5):654–62; discussion 63–64.PubMedGoogle Scholar
  88. 88.
    Kouvaraki MA, Shapiro SE, Cote GJ, et al. Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World J Surg. 2006;30(5):643–53.PubMedGoogle Scholar
  89. 89.
    Akerstrom G, Hessman O, Hellman P, Skogseid B. Pancreatic tumours as part of the MEN-1 syndrome. Best Pract Res Clin Gastroenterol. 2005;19(5):819–30.PubMedGoogle Scholar
  90. 90.
    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 64–66.PubMedCentralPubMedGoogle Scholar
  91. 91.
    Dralle H, Krohn SL, Karges W, Boehm BO, Brauckhoff M, Gimm O. Surgery of resectable nonfunctioning neuroendocrine pancreatic tumors. World J Surg. 2004;28(12):1248–60.PubMedGoogle Scholar
  92. 92.
    You YN, Thompson GB, Young Jr WF, et al. Pancreatoduodenal surgery in patients with multiple endocrine neoplasia type 1: operative outcomes, long-term function, and quality of life. Surgery. 2007;142(6):829–36; discussion 36 e1.PubMedGoogle Scholar
  93. 93.
    Anlauf M, Schlenger R, Perren A, et al. Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. Am J Surg Pathol. 2006;30(5):560–74.PubMedGoogle Scholar
  94. 94.
    Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13.PubMedGoogle Scholar
  96. 96.
    Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117(2):268–75.PubMedGoogle Scholar
  97. 97.
    Koumarianou A, Antoniou S, Kanakis G, et al. Combination treatment with metronomic temozolomide, bevacizumab and long-acting octreotide for malignant neuroendocrine tumours. Endocr Relat Cancer. 2012;19(1):L1–4.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J. Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. J Hematol Oncol. 2011;4:29.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Grozinsky-Glasberg S, Grossman AB, Korbonits M. The role of somatostatin analogues in the treatment of neuroendocrine tumours. Mol Cell Endocrinol. 2008;286(1–2):238–50.PubMedGoogle Scholar
  100. 100.
    Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Oberg K. Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer. 2011;117(20):4617–22.PubMedGoogle Scholar
  101. 101.
    Sano T, Yamasaki R, Saito H, et al. Growth hormone-releasing hormone (GHRH)-secreting pancreatic tumor in a patient with multiple endocrine neoplasia type I. Am J Surg Pathol. 1987;11(10):810–9.PubMedGoogle Scholar
  102. 102.
    Kloppel G, Anlauf M. Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2005;19(4):507–17.PubMedGoogle Scholar
  103. 103.
    Trouillas J, Labat-Moleur F, Sturm N, et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol. 2008;32(4):534–43.PubMedGoogle Scholar
  104. 104.
    Melmed S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol. 2011;7(5):257–66.PubMedGoogle Scholar
  105. 105.
    Verges B, Boureille F, Goudet P, et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J Clin Endocrinol Metab. 2002;87(2):457–65.PubMedGoogle Scholar
  106. 106.
    Delemer B. MEN1 and pituitary adenomas. Ann Endocrinol (Paris). 2012;73(2):59–61.Google Scholar
  107. 107.
    Biondi CA, Gartside MG, Waring P, et al. Conditional inactivation of the MEN1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues. Mol Cell Biol. 2004;24(8):3125–31.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Bertolino P, Tong WM, Galendo D, Wang ZQ, Zhang CX. Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Mol Endocrinol. 2003;17(9):1880–92.PubMedGoogle Scholar
  109. 109.
    Beckers A, Daly AF. The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol. 2007;157(4):371–82.PubMedGoogle Scholar
  110. 110.
    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.PubMedGoogle Scholar
  111. 111.
    Tichomirowa MA, Lee M, Barlier A, et al. Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. Endocr Relat Cancer. 2012;19(3):233–41.PubMedGoogle Scholar
  112. 112.
    Burgess JR, Shepherd JJ, Parameswaran V, Hoffman L, Greenaway TM. Spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN 1): clinical, biochemical, and radiological features of pituitary disease in a large MEN 1 kindred. J Clin Endocrinol Metab. 1996;81(7):2642–6.PubMedGoogle Scholar
  113. 113.
    Vortmeyer AO, Lubensky IA, Skarulis M, et al. Multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors. Mod Pathol. 1999;12(9):919–24.PubMedGoogle Scholar
  114. 114.
    Chandrasekharappa SC, Teh BT. Clinical and molecular aspects of multiple endocrine neoplasia type 1. Front Horm Res. 2001;28:50–80.PubMedGoogle Scholar
  115. 115.
    Goudet P, Bonithon-Kopp C, Murat A, 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.PubMedGoogle Scholar
  116. 116.
    Goudet P, Murat A, Cardot-Bauters C, 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.PubMedGoogle Scholar
  117. 117.
    Scarsbrook AF, Ganeshan A, Statham J, et al. Anatomic and functional imaging of metastatic carcinoid tumors. Radiographics. 2007;27(2):455–77.PubMedGoogle Scholar
  118. 118.
    Gibril F, Chen YJ, Schrump DS, et al. Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 2003;88(3):1066–81.PubMedGoogle Scholar
  119. 119.
    Berna MJ, Annibale B, Marignani M, et al. A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors. J Clin Endocrinol Metab. 2008;93(5):1582–91.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Tomassetti P, Migliori M, Caletti GC, et al. Treatment of type II gastric carcinoid tumors with somatostatin analogues. N Engl J Med. 2000;343(8):551–4.PubMedGoogle Scholar
  121. 121.
    Oberg K, Jelic S. Neuroendocrine bronchial and thymic tumors: ESMO clinical recommendation for diagnosis, treatment and follow-up. Ann Oncol. 2008;19 Suppl 2:ii102–3.PubMedGoogle Scholar
  122. 122.
    Gatta-Cherifi B, Chabre O, Murat A, 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.PubMedGoogle Scholar
  123. 123.
    Schaefer S, Shipotko M, Meyer S, 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.PubMedGoogle Scholar
  124. 124.
    Langer P, Cupisti K, Bartsch DK, et al. Adrenal involvement in multiple endocrine neoplasia type 1. World J Surg. 2002;26(8):891–6.PubMedGoogle Scholar
  125. 125.
    Asgharian B, Chen YJ, Patronas NJ, et al. Meningiomas may be a component tumor of multiple endocrine neoplasia type 1. Clin Cancer Res. 2004;10(3):869–80.PubMedGoogle Scholar
  126. 126.
    Vidal A, Iglesias MJ, Fernandez B, Fonseca E, Cordido F. Cutaneous lesions associated to multiple endocrine neoplasia syndrome type 1. J Eur Acad Dermatol Venereol. 2008;22(7):835–8.PubMedGoogle Scholar
  127. 127.
    Lemmens I, Van de Ven WJ, Kas K, 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.PubMedGoogle Scholar
  128. 128.
    Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276(5311):404–7.PubMedGoogle Scholar
  129. 129.
    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.PubMedGoogle Scholar
  130. 130.
    Tham E, Grandell U, Lindgren E, et al. Clinical testing for mutations in the MEN1 gene in Sweden: a report on 200 unrelated cases. J Clin Endocrinol Metab. 2007;92(9):3389–95.PubMedGoogle Scholar
  131. 131.
    Turner JJ, Christie PT, Pearce SH, Turnpenny PD, Thakker RV. Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1). Hum Mutat. 2010;31(1):E1089–101.PubMedGoogle Scholar
  132. 132.
    Karges W, Jostarndt K, Maier S, et al. Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region. J Endocrinol. 2000;166(1):1–9.PubMedGoogle Scholar
  133. 133.
    Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199–203.PubMedCentralPubMedGoogle Scholar
  134. 134.
    Hannan FM, Nesbit MA, Christie PT, et al. Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene. Nat Clin Pract Endocrinol Metab. 2008;4(1):53–8.PubMedGoogle Scholar
  135. 135.
    Agarwal SK, Ozawa A, Mateo CM, Marx SJ. The MEN1 gene and pituitary tumours. Horm Res. 2009;71 Suppl 2:131–8.PubMedGoogle Scholar
  136. 136.
    Olufemi SE, Green JS, Manickam P, et al. Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1Burin) in four kindreds from Newfoundland. Hum Mutat. 1998;11(4):264–9.PubMedGoogle Scholar
  137. 137.
    Hao W, Skarulis MC, Simonds WF, et al. Multiple endocrine neoplasia type 1 variant with frequent prolactinoma and rare gastrinoma. J Clin Endocrinol Metab. 2004;89(8):3776–84.PubMedGoogle Scholar
  138. 138.
    Burgess JR, Nord B, David R, et al. Phenotype and phenocopy: the relationship between genotype and clinical phenotype in a single large family with multiple endocrine neoplasia type 1 (MEN 1). Clin Endocrinol (Oxf). 2000;53(2):205–11.Google Scholar
  139. 139.
    Newey PJ, Thakker RV. Role of multiple endocrine neoplasia type 1 mutational analysis in clinical practice. Endocr Pract. 2011;17 Suppl 3:8–17.PubMedGoogle Scholar
  140. 140.
    Langer P, Wild A, Hall A, Celik I, Rothmund M, Bartsch DK. Prevalence of multiple endocrine neoplasia type 1 in young patients with apparently sporadic primary hyperparathyroidism or pancreaticoduodenal endocrine tumours. Br J Surg. 2003;90(12):1599–603.PubMedGoogle Scholar
  141. 141.
    Stratakis CA, Schussheim DH, Freedman SM, et al. Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 2000;85(12):4776–80.PubMedGoogle Scholar
  142. 142.
    Skogseid B, Eriksson B, Lundqvist G, et al. Multiple endocrine neoplasia type 1: a 10-year prospective screening study in four kindreds. J Clin Endocrinol Metab. 1991;73(2):281–7.PubMedGoogle Scholar
  143. 143.
    Skogseid B, Larsson C, Oberg K. Genetic and clinical characteristics of multiple endocrine neoplasia type 1. Acta Oncol. 1991;30(4):485–8.PubMedGoogle Scholar
  144. 144.
    Keiser HR, Beaven MA, Doppman J, Wells Jr S, Buja LM. Sipple’s syndrome: medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease. Studies in a large family. NIH conference. Ann Intern Med. 1973;78(4):561–79.PubMedGoogle Scholar
  145. 145.
    Carney JA. Familial multiple endocrine neoplasia: the first 100 years. Am J Surg Pathol. 2005;29(2):254–74.PubMedGoogle Scholar
  146. 146.
    Easton DF, Ponder MA, Cummings T, et al. The clinical and screening age-at-onset distribution for the MEN-2 syndrome. Am J Hum Genet. 1989;44(2):208–15.PubMedCentralPubMedGoogle Scholar
  147. 147.
    Ponder BA, Ponder MA, Coffey R, et al. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet. 1988;1(8582):397–401.PubMedGoogle Scholar
  148. 148.
    Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994;6(1):70–4.PubMedGoogle Scholar
  149. 149.
    Frank-Raue K, Hoppner W, Frilling A, et al. Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group. J Clin Endocrinol Metab. 1996;81(5):1780–3.PubMedGoogle Scholar
  150. 150.
    Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing’s disease: multiple endocrine neoplasia, type 2. Medicine (Baltimore). 1968;47(5):371–409.Google Scholar
  151. 151.
    Melvin KE, Tashjian Jr AH, Miller HH. Studies in familial (medullary) thyroid carcinoma. Recent Prog Horm Res. 1972;28:399–470.PubMedGoogle Scholar
  152. 152.
    Gagel RF, Tashjian Jr AH, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med. 1988;318(8):478–84.PubMedGoogle Scholar
  153. 153.
    Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276(19):1575–9.PubMedGoogle Scholar
  154. 154.
    Farndon JR, Leight GS, Dilley WG, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg. 1986;73(4):278–81.PubMedGoogle Scholar
  155. 155.
    Nunziata V, Giannattasio R, Di Giovanni G, et al. Hereditary localized pruritus in affected members of a kindred with multiple endocrine neoplasia type 2A (Sipple’s syndrome). Clin Endocrinol (Oxf). 1989;30(1):57–63.Google Scholar
  156. 156.
    Donovan DT, Levy ML, Furst EJ, et al. Familial cutaneous lichen amyloidosis in association with multiple endocrine neoplasia type 2A: a new variant. Henry Ford Hosp Med J. 1989;37(3–4):147–50.PubMedGoogle Scholar
  157. 157.
    Verdy M, Weber AM, Roy CC, et al. Hirschsprung’s disease in a family with multiple endocrine neoplasia type 2. J Pediatr Gastroenterol Nutr. 1982;1(4):603–7.PubMedGoogle Scholar
  158. 158.
    Kakudo K, Carney JA, Sizemore GW. Medullary carcinoma of thyroid. Biologic behavior of the sporadic and familial neoplasm. Cancer. 1985;55(12):2818–21.PubMedGoogle Scholar
  159. 159.
    Pacini F, Fontanelli M, Fugazzola L, et al. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 1994;78(4):826–9.PubMedGoogle Scholar
  160. 160.
    Guyetant S, Josselin N, Savagner F, et al. C-cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients. Mod Pathol. 2003;16(8):756–63.PubMedGoogle Scholar
  161. 161.
    Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med. 2003;349(16):1517–25.PubMedGoogle Scholar
  162. 162.
    Cohen MS, Moley JF. Surgical treatment of medullary thyroid carcinoma. J Intern Med. 2003;253(6):616–26.PubMedGoogle Scholar
  163. 163.
    Robbins J, Merino MJ, Boice Jr JD, et al. Thyroid cancer: a lethal endocrine neoplasm. Ann Intern Med. 1991;115(2):133–47.PubMedGoogle Scholar
  164. 164.
    Kebebew E, Ituarte PH, Siperstein AE, et al. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer. 2000;88(5):1139–48.PubMedGoogle Scholar
  165. 165.
    Sippel RS, Kunnimalaiyaan M, Chen H. Current management of medullary thyroid cancer. Oncologist. 2008;13(5):539–47.PubMedGoogle Scholar
  166. 166.
    Inabnet WB, Caragliano P, Pertsemlidis D. Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery. 2000;128(6):1007; discussion 11–12.PubMedGoogle Scholar
  167. 167.
    Rodriguez JM, Balsalobre M, Ponce JL, et al. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008;32(11):2520–6.PubMedGoogle Scholar
  168. 168.
    Frank-Raue K, Rybicki LA, Erlic Z, et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011;32(1):51–8.PubMedGoogle Scholar
  169. 169.
    Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ. Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma. Clin Endocrinol (Oxf). 1998;48(2):195–200.Google Scholar
  170. 170.
    Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med. 2005;257(1):60–8.PubMedGoogle Scholar
  171. 171.
    Pacak K, Eisenhofer G, Ilias I. Diagnosis of pheochromocytoma with special emphasis on MEN2 syndrome. Hormones (Athens). 2009;8(2):111–6.Google Scholar
  172. 172.
    Modigliani E, Vasen HM, Raue K, et al. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med. 1995;238(4):363–7.PubMedGoogle Scholar
  173. 173.
    Schuffenecker I, Virally-Monod M, Brohet R, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D’etude des Tumeurs a Calcitonine. J Clin Endocrinol Metab. 1998;83(2):487–91.PubMedGoogle Scholar
  174. 174.
    Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metab. 2013;98(2):E336–45.PubMedGoogle Scholar
  175. 175.
    Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T, Tschen JA. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. 1989;111(10):802–6.PubMedGoogle Scholar
  176. 176.
    Ceccherini I, Romei C, Barone V, et al. Identification of the Cys634→Tyr mutation of the RET proto-oncogene in a pedigree with multiple endocrine neoplasia type 2A and localized cutaneous lichen amyloidosis. J Endocrinol Invest. 1994;17(3):201–4.PubMedGoogle Scholar
  177. 177.
    Machens A, Dralle H. Multiple endocrine neoplasia type 2 and the RET protooncogene: from bedside to bench to bedside. Mol Cell Endocrinol. 2006;247(1–2):34–40.PubMedGoogle Scholar
  178. 178.
    Machens A, Gimm O, Hinze R, Hoppner W, Boehm BO, Dralle H. Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endocrinol Metab. 2001;86(3):1104–9.PubMedGoogle Scholar
  179. 179.
    Angrist M, Kauffman E, Slaugenhaupt SA, et al. A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10. Nat Genet. 1993;4(4):351–6.PubMedGoogle Scholar
  180. 180.
    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(6461):377–8.PubMedGoogle Scholar
  181. 181.
    Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature. 1994;367(6461):378–80.PubMedGoogle Scholar
  182. 182.
    Tallini G, Santoro M, Helie M, et al. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res. 1998;4(2):287–94.PubMedGoogle Scholar
  183. 183.
    Santoro M, Papotti M, Chiappetta G, et al. RET activation and clinicopathologic features in poorly differentiated thyroid tumors. J Clin Endocrinol Metab. 2002;87(1):370–9.PubMedGoogle Scholar
  184. 184.
    Brauckhoff M, Gimm O, Hinze R, Ukkat J, Brauckhoff K, Dralle H. Papillary thyroid carcinoma in patients with RET proto-oncogene germline mutation. Thyroid. 2002;12(7):557–61.PubMedGoogle Scholar
  185. 185.
    Shifrin AL, Xenachis C, Fay A, Matulewicz TJ, Kuo YH, Vernick JJ. One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: is this a new syndrome – MEN 2C. Surgery. 2009;146(6):998–1005.PubMedGoogle Scholar
  186. 186.
    Williams ED, Pollock DJ. Multiple mucosal neuromata with endocrine tumours: a syndrome allied to von Recklinghausen’s disease. J Pathol Bacteriol. 1966;91(1):71–80.PubMedGoogle Scholar
  187. 187.
    Shekitka KM, Sobin LH. Ganglioneuromas of the gastrointestinal tract. Relation to Von Recklinghausen disease and other multiple tumor syndromes. Am J Surg Pathol. 1994;18(3):250–7.PubMedGoogle Scholar
  188. 188.
    Skinner MA, DeBenedetti MK, Moley JF, Norton JA, Wells Jr SA. Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg. 1996;31(1):177–81; discussion 81–82.PubMedGoogle Scholar
  189. 189.
    Shapiro B, Fig LM. Management of pheochromocytoma. Endocrinol Metab Clin North Am. 1989;18(2):443–81.PubMedGoogle Scholar
  190. 190.
    Carney JA, Sizemore GW, Sheps SG. Adrenal medullary disease in multiple endocrine neoplasia, type 2: pheochromocytoma and its precursors. Am J Clin Pathol. 1976;66(2):279–90.PubMedGoogle Scholar
  191. 191.
    Wray CJ, Rich TA, Waguespack SG, Lee JE, Perrier ND, Evans DB. Failure to recognize multiple endocrine neoplasia 2B: more common than we think? Ann Surg Oncol. 2008;15(1):293–301.PubMedGoogle Scholar
  192. 192.
    Brauckhoff M, Machens A, Hess S, et al. Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: An exploratory analysis. Surgery. 2008;144(6):1044–50; discussion 50–53.PubMedGoogle Scholar
  193. 193.
    Kasprzak L, Nolet S, Gaboury L, et al. Familial medullary thyroid carcinoma and prominent corneal nerves associated with the germline V804M and V778I mutations on the same allele of RET. J Med Genet. 2001;38(11):784–7.PubMedCentralPubMedGoogle Scholar
  194. 194.
    Lee R, Hyer J, Chowdhury H, Teimory M. Ocular signs of multiple endocrine neoplasia type 2B (MEN2B). J Clin Endocrinol Metab. 2012;97(3):725–6.PubMedGoogle Scholar
  195. 195.
    Eter N, Klingmuller D, Hoppner W, Spitznas M. Typical ocular findings in a patient with multiple endocrine neoplasia type 2b syndrome. Graefes Arch Clin Exp Ophthalmol. 2001;239(5):391–4.PubMedGoogle Scholar
  196. 196.
    Jacobs JM, Hawes MJ. From eyelid bumps to thyroid lumps: report of a MEN type IIb family and review of the literature. Ophthal Plast Reconstr Surg. 2001;17(3):195–201.PubMedGoogle Scholar
  197. 197.
    Parker DG, Robinson BG, O’Donnell BA. External ophthalmic findings in multiple endocrine neoplasia type 2B. Clin Experiment Ophthalmol. 2004;32(4):420–3.PubMedGoogle Scholar
  198. 198.
    Shields JA, Shields CL, Perez N. Choroidal metastasis from medullary thyroid carcinoma in multiple endocrine neoplasia. Am J Ophthalmol. 2002;134(4):607–9.PubMedGoogle Scholar
  199. 199.
    D’Amore ES, Manivel JC, Pettinato G, Niehans GA, Snover DC. Intestinal ganglioneuromatosis: mucosal and transmural types. A clinicopathologic and immunohistochemical study of six cases. Hum Pathol. 1991;22(3):276–86.PubMedGoogle Scholar
  200. 200.
    Lips CJ. Clinical management of the multiple endocrine neoplasia syndromes: results of a computerized opinion poll at the Sixth International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau disease. J Intern Med. 1998;243(6):589–94.PubMedGoogle Scholar
  201. 201.
    Cohen R, Campos JM, Salaun C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab. 2000;85(2):919–22.PubMedGoogle Scholar
  202. 202.
    Ismailov SI, Piulatova NR. Postoperative calcitonin study in medullary thyroid carcinoma. Endocr Relat Cancer. 2004;11(2):357–63.PubMedGoogle Scholar
  203. 203.
    Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565–612.PubMedGoogle Scholar
  204. 204.
    Costante G, Meringolo D, Durante C, et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 2007;92(2):450–5.PubMedGoogle Scholar
  205. 205.
    Pomares FJ, Rodriguez JM, Nicolas F, et al. Presurgical assessment of the tumor burden of familial medullary thyroid carcinoma by calcitonin testing. J Am Coll Surg. 2002;195(5):630–4.PubMedGoogle Scholar
  206. 206.
    Ilias I, Pacak K. Diagnosis, localization and treatment of pheochromocytoma in MEN 2 syndrome. Endocr Regul. 2009;43(2):89–93.PubMedGoogle Scholar
  207. 207.
    Ilias I, Chen CC, Carrasquillo JA, et al. Comparison of 6-18F-fluorodopamine PET with 123I-metaiodobenzylguanidine and 111in-pentetreotide scintigraphy in localization of nonmetastatic and metastatic pheochromocytoma. J Nucl Med. 2008;49(10):1613–9.PubMedCentralPubMedGoogle Scholar
  208. 208.
    Brenner ME, Jacene HA. Recurrent or residual hyperparathyroidism and thyroid cancer effectively evaluated with scintigraphy. Otolaryngol Clin North Am. 2008;41(6):1117–33, viii–ix.PubMedGoogle Scholar
  209. 209.
    Yen TW, Shapiro SE, Gagel RF, et al. Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients. Surgery. 2003;134(6):890–9; discussion 99–901.PubMedGoogle Scholar
  210. 210.
    Buhr HJ, Kallinowski F, Raue F, Frank-Raue K, Herfarth C. Microsurgical neck dissection for occultly metastasizing medullary thyroid carcinoma. Three-year results. Cancer. 1993;72(12):3685–93.PubMedGoogle Scholar
  211. 211.
    Ukkat J, Gimm O, Brauckhoff M, Bilkenroth U, Dralle H. Single center experience in primary surgery for medullary thyroid carcinoma. World J Surg. 2004;28(12):1271–4.PubMedGoogle Scholar
  212. 212.
    Gimm O, Ukkat J, Niederle BE, et al. Timing and extent of surgery in patients with familial medullary thyroid carcinoma/multiple endocrine neoplasia 2A-related RET mutations not affecting codon 634. World J Surg. 2004;28(12):1312–6.PubMedGoogle Scholar
  213. 213.
    Brauckhoff M, Lorenz K, Ukkat J, et al. Medullary thyroid carcinoma. Scand J Surg. 2004;93(4):249–60.PubMedGoogle Scholar
  214. 214.
    Scollo C, Baudin E, Travagli JP, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2003;88(5):2070–5.PubMedGoogle Scholar
  215. 215.
    Niccoli-Sire P, Murat A, Baudin E, et al. Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC). Eur J Endocrinol. 1999;141(5):468–74.PubMedGoogle Scholar
  216. 216.
    Machens A, Hauptmann S, Dralle H. Prediction of lateral lymph node metastases in medullary thyroid cancer. Br J Surg. 2008;95(5):586–91.PubMedGoogle Scholar
  217. 217.
    Dralle H, Machens A. Surgical management of the lateral neck compartment for metastatic thyroid cancer. Curr Opin Oncol. 2013;25(1):20–6.PubMedGoogle Scholar
  218. 218.
    Fleming JB, Lee JE, Bouvet M, et al. Surgical strategy for the treatment of medullary thyroid carcinoma. Ann Surg. 1999;230(5):697–707.PubMedCentralPubMedGoogle Scholar
  219. 219.
    Massoll N, Mazzaferri EL. Diagnosis and management of medullary thyroid carcinoma. Clin Lab Med. 2004;24(1):49–83.PubMedGoogle Scholar
  220. 220.
    Gottlieb JA, Hill Jr CS. Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients. N Engl J Med. 1974;290(4):193–7.PubMedGoogle Scholar
  221. 221.
    Martinez SR, Beal SH, Chen A, Chen SL, Schneider PD. Adjuvant external beam radiation for medullary thyroid carcinoma. J Surg Oncol. 2010;102(2):175–8.PubMedCentralPubMedGoogle Scholar
  222. 222.
    Gild ML, Bullock M, Robinson BG, Clifton-Bligh R. Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinol. 2011;7(10):617–24.PubMedGoogle Scholar
  223. 223.
    Wells Jr SA, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134–41.PubMedCentralPubMedGoogle Scholar
  224. 224.
    Schoffski PER, Müller S, Brose MS, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline [abstract]. J Clin Oncol. 2012;30.Google Scholar
  225. 225.
    Smit J. Treatment of advanced medullary thyroid cancer. Thyroid Res. 2013;6 Suppl 1:S7.PubMedCentralPubMedGoogle Scholar
  226. 226.
    Bargellini T, Cantelli G, Bruscino A, et al. Left laparoscopic adrenalectomy for pheochromocytoma in MEN 2B: case report. G Chir. 2011;32(3):132–4.PubMedGoogle Scholar
  227. 227.
    Fassbender WJ, Krohn-Grimberghe B, Gortz B, et al. Multiple endocrine neoplasia (MEN)–an overview and case report–patient with sporadic bilateral pheochromocytoma, hyperparathyroidism and marfanoid habitus. Anticancer Res. 2000;20(6C):4877–87.PubMedGoogle Scholar
  228. 228.
    Nguyen L, Niccoli-Sire P, Caron P, et al. Pheochromocytoma in multiple endocrine neoplasia type 2: a prospective study. Eur J Endocrinol. 2001;144(1):37–44.PubMedGoogle Scholar
  229. 229.
    Eisenhofer G, Rivers G, Rosas AL, et al. Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management. Drug Saf. 2007;30(11):1031–62.PubMedGoogle Scholar
  230. 230.
    Bilezikian JP, Khan AA, Potts Jr JT. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94(2):335–9.PubMedCentralPubMedGoogle Scholar
  231. 231.
    Twigt BA, Scholten A, Valk GD, Rinkes IH, Vriens MR. Differences between sporadic and MEN related primary hyperparathyroidism; clinical expression, preoperative workup, operative strategy and follow-up. Orphanet J Rare Dis. 2013;8:50.PubMedCentralPubMedGoogle Scholar
  232. 232.
    Moley JF, Debenedetti MK, Dilley WG, Tisell LE, Wells SA. Surgical management of patients with persistent or recurrent medullary thyroid cancer. J Intern Med. 1998;243(6):521–6.PubMedGoogle Scholar
  233. 233.
    Kahraman T, de Groot JW, Rouwe C, et al. Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a. Eur J Surg Oncol. 2003;29(4):331–5.PubMedGoogle Scholar
  234. 234.
    Szinnai G, Meier C, Komminoth P, Zumsteg UW. Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis. Pediatrics. 2003;111(2):E132–9.PubMedGoogle Scholar
  235. 235.
    Hansford JR, Mulligan LM. Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis. J Med Genet. 2000;37(11):817–27.PubMedCentralPubMedGoogle Scholar
  236. 236.
    Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346(19):1459–66.PubMedGoogle Scholar
  237. 237.
    Gimenez-Roqueplo AP, Lehnert H, Mannelli M, et al. Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf). 2006;65(6):699–705.Google Scholar
  238. 238.
    Erlic Z, Rybicki L, Peczkowska M, et al. Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res. 2009;15(20):6378–85.PubMedGoogle Scholar
  239. 239.
    Punales MK, Graf H, Gross JL, Maia AL. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003;88(6):2644–9.PubMedGoogle Scholar
  240. 240.
    Gimm O, Neuberg DS, Marsh DJ, et al. Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene. 1999;18(6):1369–73.PubMedGoogle Scholar
  241. 241.
    Romeo G, Ceccherini I, Celli J, et al. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med. 1998;243(6):515–20.PubMedGoogle Scholar
  242. 242.
    Aiello A, Cioni K, Gobbo M, et al. The familial medullary thyroid carcinoma-associated RET E768D mutation in a multiple endocrine neoplasia type 2A case. Surgery. 2005;137(5):574–6.PubMedGoogle Scholar
  243. 243.
    Jimenez C, Habra MA, Huang SC, et al. Pheochromocytoma and medullary thyroid carcinoma: a new genotype-phenotype correlation of the RET protooncogene 891 germline mutation. J Clin Endocrinol Metab. 2004;89(8):4142–5.PubMedGoogle Scholar
  244. 244.
    Gibelin H, Bezieau S, Misso C, Bouin-Pineau MH, Marechaud R, Kraimps JL. Germline RET V804M mutation associated with multiple endocrine neoplasia type 2A. Br J Surg. 2004;91(11):1458–9.PubMedGoogle Scholar
  245. 245.
    Feldman GL, Edmonds MW, Ainsworth PJ, et al. Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG→ATG) mutation. Surgery. 2000;128(1):93–8.PubMedGoogle Scholar
  246. 246.
    Frohnauer MK, Decker RA. Update on the MEN 2A c804 RET mutation: is prophylactic thyroidectomy indicated? Surgery. 2000;128(6):1052–7; discussion 57–58.PubMedGoogle Scholar
  247. 247.
    Rothberg AE, Raymond VM, Gruber SB, Sisson J. Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. Thyroid. 2009;19(6):651–5.PubMedGoogle Scholar
  248. 248.
    Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med. 2011;13(9):755–64.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Neuroendocrine Tumor Unit, Endocrinology and Metabolism Service, Department of MedicineHadassah-Hebrew University Medical CenterJerusalemIsrael

Personalised recommendations