Wermer Syndrome (MEN Type 1) 

  • Author: Irina Lendel, MD; Chief Editor: George T Griffing, MD   more...
 
Updated: Oct 8, 2010
 

Background

Multiple endocrine neoplasia (MEN) syndromes consist of 2 categories, MEN 1 and MEN 2. Since 1975, MEN 2 (Sipple syndrome) has been subcategorized into MEN 2a and MEN 2b.

The combination of parathyroid tumors, pancreatic islet cell tumors, and pituitary hyperplasia or tumor formation (see the images below) is called MEN 1. It is an autosomal dominant disorder, but it may also occur sporadically as a result of new mutations.

In 1954, Wermer was the first to describe the syndrome as a distinct clinical entity.

Sagittal (left image) and coronal (right image), TSagittal (left image) and coronal (right image), T1-weighted magnetic resonance images of the brain in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1). These images show a pituitary macroadenoma (arrows). Indium-111 (111In) octreotide scan in a patient wiIndium-111 (111In) octreotide scan in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1). These nuclear images demonstrate abnormal activity in the pituitary macroadenoma (curved arrow), parathyroid adenoma (straight arrow), and gastrinoma metastases throughout the abdomen (arrowheads).
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Pathophysiology

Parathyroid tumors

Hyperparathyroidism is the most common manifestation of MEN 1, caused by hyperplasia of multiple parathyroid glands (see image below). Penetrance is almost 100% by age 50 years.

Technetium-99m sestamibi scan (99mTc MIBI) in a paTechnetium-99m sestamibi scan (99mTc MIBI) in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1). These images demonstrate persistent abnormal activity of the inferior right parathyroid gland that is consistent with an adenoma.

Clinical manifestations include urolithiasis, bone abnormalities, and, in severe cases, generalized weakness and mental or cognitive dysfunction.

Hyperparathyroidism in MEN 1 differs from sporadic cases by earlier age at presentation, involvement of multiple glands, and high recurrence rate postoperatively (50% by 8-12 y after surgery).[1]

Enteropancreatic tumors

Pancreatic islet cell tumors represent the second most common manifestation of MEN 1 and occur in 80% of patients. Tumors are often multicentric and may undergo malignant transformation. Often, they produce multiple peptides and biogenic amines.

Nonfunctioning pancreatic endocrine tumors are the most common pancreatic tumors, occurring in 80-100% of cases. However, the name is a misnomer because most of them produce pancreatic polypeptide. The tumor mass, even at an advanced stage, may not cause a clinical syndrome outside of its mass effect. Although they may be malignant, tumors less than 2 cm in size have low risk of metastasis or death. Average life expectancy of patients with nonfunctioning pancreatic endocrine tumors is decreased when compared to MEN 1 patients who do not have them.

Gastrinomas, seen in the image below, are the most common cause of symptomatic disease and are found in approximately 60% of patients with MEN 1. Compared with the sporadic form of gastrinomas in Zollinger-Ellison syndrome (ZES), tumors in MEN 1 are more often duodenal, small, and multicentric, thus diminishing the probability of surgical cure. The features predictive of poor prognosis include pancreatic location of lesions, metastases, ectopic Cushing syndrome, and height of gastrin levels. Development of gastrinomas is preceded by multifocal hyperplasia of the gastrin-producing cells. Long-standing MEN 1/ZES may lead to development of gastric carcinoid tumors that might be aggressive.[2]

Computed tomography (CT) scan of the pancreas in aComputed tomography (CT) scan of the pancreas in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1) and a gastrinoma. This image shows a pancreatic head mass (large, white arrow), as well as a low-attenuating lesion in the liver (small, black arrowhead) that indicates metastases. Note the calcifications of the right renal medullary pyramids (medullary nephrocalcinosis; black arrows) in this nonenhanced CT scan.

Insulinomas (see the images below) account for approximately 20-35% of functional pancreatic islet cell tumors. Similar to gastrinomas, they can be multicentric (10-20%), where 25% metastasize either to regional lymph nodes or to the liver.

Endoscopic ultrasonogram in a patient with an insuEndoscopic ultrasonogram in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV). (From: Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. Jun 25 1992;326(26):1721-6.) Computed tomography (CT) scan image with oral and Computed tomography (CT) scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (From: Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St. Louis, Mo: Mosby-Year Book; 1993: 272.)

Glucagonomas occur in 3% of patients with MEN 1 and are silent or present with hyperglycemia. Only a few patients show the typical skin lesions known as necrolytic migratory erythema.

The occurrence of the watery diarrhea, hypokalemia, hypochlorhydria, and acidosis (WDHA) syndrome (incidence approximately 1%) may be due either to either a pancreatic islet cell or to a carcinoid tumor.

Pituitary tumors

These often-multicentric tumors occur in more than 50% of patients and are clinically apparent in up to 20% of patients. These tumors tend to be larger and more aggressive than those not associated with MEN 1.

Prolactinomas are the most common pituitary tumor in patients with MEN 1.

Growth hormone–producing tumors account for 25% of these adenomas. Growth hormone levels rise due to autonomous secretion from the pituitary tumor or, less commonly, by production of growth hormone–releasing factor by a pancreatic or other endocrine tumor.

A pituitary tumor or carcinoid tumor that produces corticotropin can cause Cushing syndrome in patients with MEN 1. Ectopic production of corticotropin-releasing factor from a pancreatic islet cell tumor also has been described.

Other tumors associated with MEN 1

Carcinoid tumors occur occasionally in patients with MEN 1, usually in the foregut (eg, thymus, lungs, stomach, duodenum). In men, especially smokers, the thymus is most often affected. Thymic carcinoids[3] associated with MEN 1 are often nonfunctional and aggressive. In women, the lung is affected most often. Carcinoids may release ectopic adrenocorticotropic hormone.

Cutaneous tumors include angiofibromas (occurring in 40-80% of patients) and collagenomas. They are often multifocal. Finding of more than 3 angiofibromas and any collagenomas has a sensitivity of 75% and specificity of 95% for diagnosis of MEN 1. This criterion has greater sensitivity than pituitary or adrenal disease and comparable to hyperparathyroidism in some studies.

Lipomas, subcutaneous and visceral, are found in one third of patients. They have loss of heterozygosity for chromosome band 11q12-12 and are associated with defective globular (G) protein function.

Adrenal tumors are most often benign and consist of nonfunctional cortical adenomas or diffuse or nodular hyperplasia. They occur in 20-40% of patients. Adrenal cortical carcinomas are rare.

Thyroid adenomas (5-30% of patients) have little clinical significance.

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Epidemiology

Frequency

United States

The estimated prevalence is 0.02-0.2 cases per 1000 population.

Mortality/Morbidity

Patients with MEN 1 have a decreased life expectancy, with a 50% probability of death by age 50 years.

  • Half of the deaths result directly from a malignant process or a sequela of the endocrine disease.
  • ZES is the major cause of morbidity and mortality in patients with MEN 1.
  • In a series of 103 patients with MEN 1, 46% died from causes related to their endocrine tumors at a median age of 47 years.

Race

No racial differences exist.

Sex

There is about equal female-to-male ratio.

Age

The peak incidence of symptoms is during the third decade of life in women and during the fourth decade of life in men.

  • Hyperparathyroidism, the most common abnormality in MEN 1, develops in patients aged 20-40 years, but it may appear in individuals as young as 17 years.
  • In related individuals, occult MEN 1 can be detected with screening (more effectively in persons >18 y).
  • The degree of penetrance at age 20 years is approximately 43%, at age 35 years is approximately 85%, and at age 50 years is 94%.
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Contributor Information and Disclosures
Author

Irina Lendel, MD  Clinical Instructor in Endocrinology, Division of Endocrinology, Diabetes, and Metabolism, Milton S Hershey Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

James M Hammond, MD  Distinguished Professor of Medicine, Penn State University College of Medicine, Milton S Hershey Medical Center

James M Hammond, MD is a member of the following medical societies: Alpha Omega Alpha, American Diabetes Association, American Federation for Clinical Research, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Phi Beta Kappa, and Society for the Study of Reproduction

Disclosure: Nothing to disclose.

Klaus Radebold, MD, PhD  Research Associate, Department of Surgery, Yale University School of Medicine

Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences

Disclosure: Nothing to disclose.

Specialty Editor Board

Frederick H Ziel, MD  Associate Professor of Medicine, David Geffen School of Medicine at UCLA; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, and International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS  Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, American Society of Law, Medicine & Ethics, Endocrine Society, and International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Mark Cooper, MBBS, PhD, FRACP  Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD  Professor of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

References

  1. Eller-Vainicher C, Chiodini I, Battista C, et al. Sporadic and MEN 1 related primary hyperparathyroidism: differences in clinical expression and severity. J Bone Miner Res. Mar 23 2009;[Medline].

  2. Anlauf M, Perren A, Meyer CL, et al. Precursor lesions in patients with multiple endocrine neoplasia type 1-associated duodenal gastrinomas. Gastroenterology. May 2005;128(5):1187-98. [Medline].

  3. Ferolla P, Falchetti A, Filosso P, et al. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. J Clin Endocrinol Metab. May 2005;90(5):2603-9. [Medline]. [Full Text].

  4. Yip L, Ogilvie JB, Challinor SM, et al. Identification of multiple endocrine neoplasia type 1 in patients with apparent sporadic primary hyperparathyroidism. Surgery. Dec 2008;144(6):1002-6; discussion 1006-7. [Medline].

  5. Whitley SA, Moyes VJ, Park KM, et al. The appearance of the adrenal glands on computed tomography in multiple endocrine neoplasia type 1. Eur J Endocrinol. Dec 2008;159(6):819-24. [Medline].

  6. Tsukada T, Nagamura Y, Ohkura N. MEN1 gene and its mutations: basic and clinical implications. Cancer Sci. Dec 8 2008;[Medline].

  7. Waldmann J, Fendrich V, Habbe N, et al. Screening of patients with multiple endocrine neoplasia type 1 (MEN-1): a critical analysis of its value. World J Surg. Jun 2009;33(6):1208-18. [Medline].

  8. Hebert SC. Therapeutic use of calcimimetics. Annu Rev Med. 2006;57:349-64. [Medline].

  9. Tucker ON, Crotty PL, Conlon KC. The management of insulinoma. Br J Surg. Mar 2006;93(3):264-75. [Medline].

  10. Wilson SD, Krzywda EA, Zhu YR, et al. The influence of surgery in MEN-1 syndrome: observations over 150 years. Surgery. Oct 2008;144(4):695-701; discussion 701-2. [Medline].

  11. Hubbard JG, Sebag F, Maweja S, et al. Subtotal parathyroidectomy as an adequate treatment for primary hyperparathyroidism in multiple endocrine neoplasia type 1. Arch Surg. Mar 2006;141(3):235-9. [Medline]. [Full Text].

  12. 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. Nov 2004;89(11):5328-36. [Medline].

  13. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. Dec 2001;86(12):5658-71. [Medline].

  14. Doherty GM, Olson JA, Frisella MM. Lethality of multiple endocrine neoplasia type I. World J Surg. Jun 1998;22(6):581-6; discussion 586-7. [Medline].

  15. Donow C, Pipeleers-Marichal M, Schroder S. Surgical pathology of gastrinoma. Site, size, multicentricity, association with multiple endocrine neoplasia type 1, and malignancy. Cancer. Sep 15 1991;68(6):1329-34. [Medline].

  16. Eriksson B, Bergstrom M, Orlefors H. Use of PET in neuroendocrine tumors. In vivo applications and in vitro studies. Q J Nucl Med. Mar 2000;44(1):68-76. [Medline].

  17. Eriksson B, Oberg K, Stridsberg M. Tumor markers in neuroendocrine tumors. Digestion. 2000;62 Suppl 1:33-8. [Medline].

  18. Granberg D, Stridsberg M, Seensalu R. Plasma chromogranin A in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. Aug 1999;84(8):2712-7. [Medline].

  19. Hausman MS Jr, Thompson NW, Gauger PG, Doherty GM. The surgical management of MEN-1 pancreatoduodenal neuroendocrine disease. Surgery. Dec 2004;136(6):1205-11.

  20. Katai M, Sakurai A, Inaba H, Ikeo Y, Yamauchi K, Hashizume K. Octreotide as a rapid and effective painkiller for metastatic carcinoid tumor. Endocr J. Apr 2005;52(2):277-80.

  21. Lairmore TC, Chen VY, DeBenedetti MK. Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1. Ann Surg. Jun 2000;231(6):909-18. [Medline].

  22. Lairmore TC, Piersall LD, DeBenedetti MK, Dilley WG, Mutch MG, Whelan AJ. Clinical genetic testing and early surgical intervention in patients with multiple endocrine neoplasia type 1 (MEN 1). Ann Surg. May 2004;239(5):637-45; discussion 645-7.

  23. Lambert LA, Shapiro SE, Lee JE, Perrier ND, Truong M, Wallace MJ. Surgical treatment of hyperparathyroidism in patients with multiple endocrine neoplasia type 1. Arch Surg. Apr 2005;140(4):374-82.

  24. Lowney JK, Frisella MM, Lairmore TC. Pancreatic islet cell tumor metastasis in multiple endocrine neoplasia type 1: correlation with primary tumor size. Surgery. Dec 1998;124(6):1043-8, discussion 1048-9. [Medline].

  25. MacFarlane MP, Fraker DL, Alexander HR. Prospective study of surgical resection of duodenal and pancreatic gastrinomas in multiple endocrine neoplasia type 1. Surgery. Dec 1995;118(6):973-9; discussion 979-80. [Medline].

  26. Mailman MD, Muscarella P, Schirmer WJ. Identification of MEN1 mutations in sporadic enteropancreatic neuroendocrine tumors by analysis of paraffin-embedded tissue. Clin Chem. Jan 1999;45(1):29-34. [Medline].

  27. Norton JA, Cornelius MJ, Doppman JL. Effect of parathyroidectomy in patients with hyperparathyroidism, Zollinger-Ellison syndrome, and multiple endocrine neoplasia type I: a prospective study. Surgery. Dec 1987;102(6):958-66. [Medline].

  28. Norton JA, Melcher ML, Gibril F, Jensen RT. Gastric carcinoid tumors in multiple endocrine neoplasia-1 patients with Zollinger-Ellison syndrome can be symptomatic, demonstrate aggressive growth, and require surgical treatment. Surgery. Dec 2004;136(6):1267-74.

  29. Oberg K. Interferon in the management of neuroendocrine GEP-tumors. a review. Digestion. 2000;62 Suppl 1:92-7. [Medline].

  30. Phan GQ, Yeo CJ, Hruban RH. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg. Sep-Oct 1998;2(5):472-82. [Medline].

  31. Proye CA, Nguyen HH. Current perspectives in the surgery of multiple endocrine neoplasias. Aust N Z J Surg. Feb 1999;69(2):106-16. [Medline].

  32. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. Jun 25 1992;326(26):1721-6. [Medline].

  33. Ruszniewski P, Podevin P, Cadiot G. Clinical, anatomical, and evolutive features of patients with the Zollinger-Ellison syndrome combined with type I multiple endocrine neoplasia. Pancreas. May 1993;8(3):295-304. [Medline].

  34. Shan L, Nakamura Y, Nakamura M. Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Lab Invest. Apr 1998;78(4):471-5. [Medline].

  35. Silverberg SJ, Bone HG 3rd, Marriott TB, Locker FG, Thys-Jacobs S, Dziem G. Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism. N Engl J Med. Nov 20 1997;337(21):1506-10. [Medline].

  36. Skogseid B, Doherty GM. Multiple endocrine neoplasia type 1: clinical and genetic features. Ital J Gastroenterol Hepatol. Oct 1999;31 Suppl 2:S131-4. [Medline].

  37. Thompson NW. Current concepts in the surgical management of multiple endocrine neoplasia type 1 pancreatic-duodenal disease. Results in the treatment of 40 patients with Zollinger-Ellison syndrome, hypoglycaemia or both. J Intern Med. Jun 1998;243(6):495-500. [Medline].

  38. Thompson NW. Management of pancreatic endocrine tumors in patients with multiple endocrine neoplasia type 1. Surg Oncol Clin N Am. Oct 1998;7(4):881-91. [Medline].

  39. 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. Feb 2006;243(2):265-72. [Medline].

  40. Wang EH, Ebrahimi SA, Wu AY. Mutation of the MENIN gene in sporadic pancreatic endocrine tumors. Cancer Res. Oct 1 1998;58(19):4417-20. [Medline].

  41. Yano M, Fukai I, Kobayashi Y, et al. ACTH-secreting thymic carcinoid associated with multiple endocrine neoplasia type 1. Ann Thorac Surg. Jan 2006;81(1):366-8. [Medline].

  42. Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St Louis, Mo: Mosby-Year Book; 1993:272.

  43. Yim JH, Siegel BA, DeBenedetti MK. Prospective study of the utility of somatostatin-receptor scintigraphy in the evaluation of patients with multiple endocrine neoplasia type 1. Surgery. Dec 1998;124(6):1037-42. [Medline].

 
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Sagittal (left image) and coronal (right image), T1-weighted magnetic resonance images of the brain in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1). These images show a pituitary macroadenoma (arrows).
Indium-111 (111In) octreotide scan in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1). These nuclear images demonstrate abnormal activity in the pituitary macroadenoma (curved arrow), parathyroid adenoma (straight arrow), and gastrinoma metastases throughout the abdomen (arrowheads).
Technetium-99m sestamibi scan (99mTc MIBI) in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1). These images demonstrate persistent abnormal activity of the inferior right parathyroid gland that is consistent with an adenoma.
Computed tomography (CT) scan of the pancreas in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1) and a gastrinoma. This image shows a pancreatic head mass (large, white arrow), as well as a low-attenuating lesion in the liver (small, black arrowhead) that indicates metastases. Note the calcifications of the right renal medullary pyramids (medullary nephrocalcinosis; black arrows) in this nonenhanced CT scan.
Endoscopic ultrasonogram in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV). (From: Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. Jun 25 1992;326(26):1721-6.)
Computed tomography (CT) scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (From: Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St. Louis, Mo: Mosby-Year Book; 1993: 272.)
Anteroposterior radiographic view of the right hand in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1) and primary hyperparathyroidism. This image shows subperiosteal bone resorption along the radial aspects of the middle phalanges (arrows).
Bilateral, anteroposterior radiographic views of the hands in a patient with multiple endocrine neoplasia syndrome type 1 (MEN 1) and primary hyperparathyroidism. These images show subperiosteal bone resorption along the radial aspects of the middle phalanges.
 
 
 
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