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Disease Categories > Endocrine Disease

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Multiple Endocrine Neoplasias - MEN

Multiple Endocrine Neoplasia (MEN) syndromes are characterized by tumors involving multiple endocrine glands
Subtypes are distinguished by clinical features and/or molecular testing
- MEN 1
- MEN 2 – 2A, 2B, Familial Medullary Thyroid Carcinoma (FMTC)

MEN 1 (Wermer Syndrome)

Epidemiology
- Incidence – 1/30,000
- Age of onset – 20-45 years
Inheritance
- Autosomal dominant – 10% of mutations are de novo
- Germline mutations in the MEN1 gene on 11q13 are causative
  - Sequence analysis of MEN1 detects a germline mutation in 80-90% of familial cases and 65% of simplex patients (ie. a single occurrence of MEN 1 syndrome in a family)
  - Approximately 1-3% of MEN1 mutations are large deletions
- Variable expressivity
- Genotype/phenotype associations have not been identified in MEN 1
- Penetrance for clinical features is age-related; 50% by age 20 and above 95% by age 40
Clinical Presentation
- Parathyroid tumors
  - Develop in 90-95% of patients; primary hyperparathyroidism is the first clinical manifestation in 90% of individuals
  - Typically involves all four parathyroid glands (unlike sporadic disease)
  - Signs – hypercalcemia, hyperparathyroidism
  - Symptoms – fatigue, anorexia, polydipsia, polyuria, bone lesions, abdominal pain, kidney stones
- Gastro-entero-pancreatic (GEP) tumors
  - Develop in 30-80% of patients
  - Symptoms depend on specific tumor type
    - Gastrinoma (Zollinger Ellison syndrome) – peptic ulcer disease, recurrent diarrhea, abdominal pain
    - Insulinoma – hypoglycemia and related symptoms
    - Glucagonoma – hyperglycemia, skin rash, anorexia, diarrhea
    - VIPoma (Verner Morrison syndrome) – watery diarrhea, hypokalemia, achlorhydria
- Anterior pituitary tumors
  - Develop in 10-60% of patients
  - Symptoms depend on the pituitary hormone produced
    - Amenorrhea and galactorrhea occur in females with prolactin-secreting tumors
    - Reduction of libido or impotence occurs in males with prolactin-secreting tumors
    - Gigantism and acromegaly occur in children and adults, respectively, with growth hormone-secreting tumors
    - Hypercortisolism occurs in ACTH-secreting tumors
- Other endocrine tumors
  - Adrenal cortical adenomas, 5-40% of patients
  - Carcinoid tumors, 3% of patients
  - Thyroid neoplasms, 8-25% of patients
  - Pheochromocytoma, 0.5% of patients
- Non-endocrine tumors
  - Collagenomas and facial angiofibromas, 70-85% of patients
  - Lipomas, 30% of patients
  - Central nervous system meningiomas or ependymomas
  - Leiomyomas
  - Malignant melanoma
Diagnosis
- Laboratory testing
  - Goal is to identify the presence of multiple endocrine tumors using biochemical testing initially
  - Parathyroid tumor – calcium and parathyroid hormone (PTH), elevated
  - Gastrinoma tumor – Gastrin and gastric acid output measures, elevated
  - Insulinoma and other pancreatic tumors– Chromogranin A, glucagon, serum insulin and C-peptide levels, all elevated
  - Anterior pituitary tumor – prolactin and insulin-like growth factor-1 (IGF-1), elevated
- Imaging studies
  - Pancreatic tumors – abdominal MRI/CT
  - Anterior pituitary tumors – cranial MRI
- Indications for genetic testing
  - Confirm a clinical diagnosis of MEN 1 in an individual with at least two of the three following endocrine tumors: parathyroid, pituitary, GEP
    - The likelihood of detecting a germline MEN1 mutation increases in individuals with more main tumors
    - Individuals with a single MEN 1 related tumor, without family history of the condition, rarely have germline MEN1 mutations
    - Approximately 20-55% of families with familial isolated hyperparathyroidism (FIHP) have a germline MEN1 mutation
  - Presymptomatic testing of at-risk family members when a specific MEN1 mutation has been identified in an affected relative
Disease Monitoring/Treatment
- Periodic screening for MEN 1 associated endocrine tumors beginning in early childhood and continuing for life
- Risk for malignant progression of MEN 1 associated tumors depends on tumor type
- Treatment of manifestations dependant on tumor type

MEN 2

Epidemiology
- Medullary thyroid carcinoma (MTC) accounts for approximately 5-10% of all diagnosed thyroid carcinomas; about 25% of these cases are believed to be familial
- Incidence: 1/30,000 for MEN 2 syndromes
  - MEN 2A (60-90% of cases)
  - MEN 2B (~5% of cases)
  - FMTC (5-35% of cases)
Inheritance
- Autosomal dominant; 5% of MEN 2A and 50% of MEN 2B mutations are de novo
- Caused by RET proto-oncogene mutations
  - 95% of MEN 2A have RET mutations in exon 10 or 11
  - MEN 2B is caused by a point mutation at codon 918 in exon 16 in 95% of cases and at codon 883 in exon 15 in 3-4%; rarely, the phenotype results from a mutation in other exons of the RET gene
  - About 85% of FMTC is caused by a RET mutation in exon 10 or 11; although rare mutations in exons 13, 14 or 15 can be causative
- Penetrance varies by MEN 2 subtype
- Genotype/phenotype correlations can help predict risk for aggressive MTC
Clinical Presentation
- MEN 2A
  - MTC – early adulthood onset
  - Pheochromocytoma – paroxysmal hypertension, palpitations, headaches
  - Parathyroid tumors – hypercalcemia
- MEN 2B
  - MTC – early childhood onset, aggressive
  - Pheochromocytoma – paroxysmal hypertension, palpitations, headaches
  - Marfanoid body type
  - Megacolon
  - Mucosal neuromas
- FMTC
  - MTC only – middle age onset
Diagnosis
- MEN 2A and 2B
  - Typical tumor presentation and family history
    - Refer to testing algorithms for pheochromocytoma, hypercalcemia (hyperparathyroidism) and thyroid nodules
  - RET mutation analysis to confirm a clinical diagnosis and allow for presymptomatic testing of family members
- FMTC
  - Established by family history of MTC in multiple generations without presence of pheochromocytoma or parathyroid adenoma/hyperplasia
  - RET mutation analysis to confirm a clinical diagnosis and allow for presymptomatic testing of family members
Disease Monitoring
- Calcitonin stimulation test for residual or recurrent MTC
- PTH for parathyroid tumors and individuals who have undergone thyroidectomy with autotransplantation of parathyroids
- Chromogranin A neuroendocrine marker testing for pheochromocytoma
Prophylactic Treatment
- MEN 2A, 2B, and FMTC
  - Thyroidectomy – timing depends on codon position of the identified RET mutation

Indications for Ordering

Tests generally appear in the order most useful for common clinical situations
Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Recommended Use	Limitations	Follow Up
Multiple Endocrine Neoplasia Type 2 (MEN2), RET Gene Mutations by Sequencing 0051390 Method: Polymerase Chain Reaction/Sequencing	Rule out MEN 2 for individuals with medullary thyroid carcinoma Diagnose MEN 2	Mutations in RET gene introns, regulatory regions, and exons not targeted for sequencing are not detected
Multiple Endocrine Neoplasia Type 2B (MEN2B), RET Gene M918T & A883F Mutations 0051492 Method: Polymerase Chain Reaction/Fluorescence Monitoring	Confirm a clinical diagnosis of MEN 2B Pre-symptomatic testing for at-risk family members when a MEN 2B mutation (M918T or A883F) has been previously identified in an affected relative	Mutations other than M918T and A883F will not be detected	Recommend that patients negative for the M918T and A883F mutations have additional sequencing of exon 10-11, 13-16 of the RET protooncogene
Custom PCR and Sequencing 0050358 Method: Polymerase Chain Reaction*/DNA Sequencing	Pre-symptomatic testing of at-risk family members when a specific RET mutation has been identified in an affected relative	Mutations other than the familial mutation will not be detected

Additional Tests Available

Click on number for test-specific information in the ARUP Laboratory Test Directory

Test Name and Number	Comments
Calcitonin 0070006 Method: Chemiluminescent Immunoassay
Calcium, Ionized, Serum 0020135 Method: Ion-Selective Electrode/pH-Electrode
Calcium, Urine 0020472 Method: Spectrophotometry
Parathyroid Hormone, Intact with Calcium 0070172 Method: Electrochemiluminescent Immunoassay
Calcium, Ionized, Whole Blood 0020140 Method: Ion-Selective Electrode/pH-Electrode
Calcium, Serum or Plasma 0020027 Method: Spectrophotometry
Parathyroid Hormone, CAP 0095611 Method: Immunoradiometric Assay
Parathyroid Hormone, Intact 0070346 Method: Electrochemiluminescent Immunoassay
Parathyroid Hormone-Related Peptide (PTHrP) 0093014 Method: Immunoradiometric Assay

Additional Information

Click here for laboratories performing MEN 1 testing

Click here for ARUP MEN disease database for sequence variations within the RET proto-oncogene relevant to MEN2 syndromes

General References

Anlauf M, Perren A, Kloppel G. Endocrine precursor lesions and microadenomas of the duodenum and pancreas with and without MEN1: criteria, molecular concepts and clinical significance. Pathobiology. 2007;74(5):279-284. (Link to PubMed)

Blackburn M, Diamond T. Primary hyperparathyroidism and familial hyperparathyroid syndromes. Aust Fam Physician. 2007;36(12):1029-1033. (Link to PubMed)

Boikos SA, Stratakis CA. Molecular mechanisms of medullary thyroid carcinoma: current approaches in diagnosis and treatment. Histol Histopathol. 2008;23(1):109-116. (Link to PubMed)

Bordi C. Multiple endocrine neoplasia (MEN)-associated tumours. Dig Liver Dis. 2004;36 Suppl 1:S31-S34. (Link to PubMed)

Busygina V, Bale AE. Multiple endocrine neoplasia type 1 (MEN1) as a cancer predisposition syndrome: clues into the mechanisms of MEN1-related carcinogenesis. Yale J Biol Med. 2006;79(3-4):105-114. (Link to PubMed)

Doherty GM. Multiple endocrine neoplasia type 1. J Surg Oncol. 2005;89(3):143-150. (Link to PubMed)

Duerr EM, Chung DC. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab. 2007;21(1):1-14. (Link to PubMed)

GeneTests: Multiple Endocrine Neoplasia. (Accessed 25 Feb 2008) (Link to resource)

Kouvaraki MA, Shapiro SE, Cote GJ, Lee JE, Yao JC, Waguespack SG, Gagel RF, Evans DB, Perrier ND. Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World J Surg. 2006;30(5):643-653. (Link to PubMed)

Lakhani VT, You YN, Wells SA. The multiple endocrine neoplasia syndromes. Annu Rev Med. 2007;58:253-265. (Link to PubMed)

Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Tognarini I, Luzi E, Brandi ML. Multiple endocrine neoplasia type 2. Orphanet J Rare Dis. 2006;1:45-. (Link to PubMed)

Neumann HP, Vortmeyer A, Schmidt D, Werner M, Erlic Z, Cascon A, Bausch B, Januszewicz A, Eng C. Evidence of MEN-2 in the original description of classic pheochromocytoma. N Engl J Med. 2007;357(13):1311-1315. (Link to PubMed)

Peczkowska M, Januszewicz A. Multiple endocrine neoplasia type 2. Fam Cancer. 2005;4(1):25-36. (Link to PubMed)

References from the ARUP Institute for Clinical and Experimental Pathology®

Margraf RL, Mao R, Highsmith WE, Holtegaard LM, Wittwer CT. RET proto-oncogene genotyping using unlabeled probes, the masking technique, and amplicon high-resolution melting analysis. J Mol Diagn. 2007;9(2):184-196. (Link to PubMed)

Reviewed by

Lyon, Elaine, Ph.D. Medical Director, Molecular Genetics at ARUP Laboratories; Associate Professor, Pathology, University of Utah

Mao, Rong , M.D. Co-Medical Director, Molecular Genetics at ARUP Laboratories; Assistant Professor, Pathology, University of Utah

Meikle, A. Wayne, M.D. Medical Director, RIA and Endocrinology at ARUP Laboratories; Professor of Internal Medicine and Pathology, University of Utah

Roberts, William L. , M.D., Ph.D. Medical Director, Automated Core Laboratory at ARUP Laboratories; Professor, Pathology, University of Utah

Comprehensive Review: May 2008
Last Update: July 2008