Multiple Endocrine Neoplasias - MEN

Multiple endocrine neoplasia (MEN) syndromes are characterized by tumors involving multiple endocrine glands. Subtypes MEN1 and MEN2 are distinguished by clinical features and molecular testing. MEN2 includes the additional subtypes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC).

  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Multiple Endocrine Neoplasia 1 (MEN1)

  • Periodic screening for MEN1-associated endocrine tumors beginning in early childhood and continuing for life (NCCN, 2017)
  • Risk for malignant progression of MEN1-associated tumors depends on tumor type
    • Malignancy uncommon before early adulthood

Multiple Endocrine Neoplasia 2 (MEN2)

Multiple endocrine neoplasia 1 (MEN1) (Wermer Syndrome)

Epidemiology

  • Incidence – 1/30,000
  • Age – onset is 20-45 years

Inheritance

  • Autosomal dominant inheritance – ~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 MEN1 syndrome in a family)
    • Approximately 1-4% of MEN1 mutations are large deletions
  • Variable expressivity
    • Penetrance for clinical features is age-related – ~50% by 20 years and >95% by 40 years
  • Genotype/phenotype associations have not been identified in MEN1

Clinical Presentation

  • Parathyroid tumors
    • Primary hyperparathyroidism develops in ~100% of patients by age 50
    • Typically involves all four parathyroid glands (unlike sporadic disease)
    • Signs – hypercalcemia, hyperparathyroidism
    • Symptoms – fatigue, anorexia, polydipsia, polyuria, bone lesions, abdominal pain, kidney stones
  • Gastroenteropancreatic (GEP) tumors
    • Develop in 20-55% of patients
    • Some are nonfunctional tumors
    • If functional tumor, symptoms depend on specific tumor type
      • Gastrinoma (~40%) – Zollinger-Ellison syndrome
        • Peptic ulcer disease, recurrent diarrhea, abdominal pain
      • Insulinoma (~10%) – pancreatic islet tumors; usually multiple
        • Hypoglycemia and related symptoms
      • Carcinoid tumors (~10%) – carcinoid syndrome
        • Flushing, wheezing, diarrhea, carcinoid heart disease
      • Vasoactive intestinal polypeptide secreting tumor (VIPoma) (~2%) – Verner-Morrison syndrome
        • Watery diarrhea, hypokalemia, achlorhydria
      • Glucagonoma (~2%)
        • Hyperglycemia, skin rash, anorexia, diarrhea
  • Anterior pituitary tumors
    • 10-60% of patients; symptoms depend on the pituitary hormone produced
      • Prolactinoma (~20%) – most common
        • Females – amenorrhea and galactorrhea
        • Males – impotence or reduced libido
      •  Growth hormone tumor (~5%)
      •  Combination – prolactinoma/growth hormone tumor (~5%)
        • Combined symptoms
      •  Adrenal tumors (~2-5%) – most nonfunctioning
  • Other endocrine tumors
  • Nonendocrine tumors
    • Cutaneous tumors
      • Collagenoma and facial angiofibromas – 70-85% of patients
      • Lipomas – 30% of patients
      • Malignant melanoma
    • Central nervous system tumors
    • Muscle tumors
      • Leiomyomas

MEN2

Epidemiology

  • Incidence – 1/35,000
    • MEN2A – 70-80% of cases
    • Familial medullary thyroid carcinoma (FMTC) – 10-20% of cases
    • MEN2B – ~5% of cases

Inheritance

  • Autosomal dominant – 5% of MEN2A and 50% of MEN2B mutations are de novo
  • Caused by mutation in the RET proto-oncogene – refer to ARUP's MEN2 and RET database
  • Genotype/phenotype correlations – can help predict risk for aggressive FMTC
  • Penetrance – varies by MEN2 subtype
    • MEN2A – 95%
    • MEN2B and FMTC – nearly 100%

Clinical Presentation

  • MEN2A (Sipple syndrome)
    • FMTC (~95%) – early onset; usually <35years
    • Pheochromocytoma (~50%) – paroxysmal hypertension, palpitations, headaches
      • Usually bilateral
    • Parathyroid tumors (~20-30%) – adenoma, hyperplasia
    • Lichen planus amyloidosis
  • MEN2B
    • FMTC – childhood onset; aggressive; 100% of patients
    • Pheochromocytoma (~50%) – paroxysmal hypertension, palpitations, headaches
      • Multiple and often bilateral
    • Skeletal deformities (eg, Marfanoid body type)
    • Eye abnormalities (eg, corneal thickening)
    • Mucosal and intestinal ganglioneuromatosis
    • Parathyroid tumors – uncommon
  • FMTC
    • FMTC only – onset in middle age; 100% of patients
    • Considered a variant of MEN2 with decreased penetrance

MEN4

Epidemiology

  • Incidence – unknown, but rare
  • Inheritance
    • Autosomal recessive
    • Caused by CDKN1B mutation
      • Presents as phenocopy of MEN1 but lacks MEN1 gene
  • Penetrance – unknown

Clinical Presentation

  • Parathyroid tumors
  • Pituitary adenomas
  • Other MEN1 tumors are possible (eg, pancreatic neuroendocrine tumors [PanNETs])

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.

Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing and Deletion/Duplication 2005360
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Not evaluated – regulatory region variants, deep intronic variants, breakpoints of large deletions/duplications, and variants in genes other than MEN1

Diagnostic errors can occur due to rare sequence variations

Multiple Endocrine Neoplasia Type 2 (MEN2), RET Gene Mutations by Sequencing 0051390
Method: Polymerase Chain Reaction/Sequencing

Limitations 

Not evaluated – regulatory region variants, deep intronic variants, large deletions/duplications, and RET exons other than 5, 8, 10, 11, 13-16 

Diagnostic errors can occur due to rare sequence variations

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Guidelines

Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA, Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001; 86(12): 5658-71. PubMed

NCCN Clinical Practice Guidelines in Oncology, Neuroendocrine Tumors. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Aug 2017]

Protocol for the Examination of Specimens from Patients with Carcinomas of the Thyroid Gland. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Revised: Jan 2016; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Appendix. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Jan 2016. College of American Pathologists (CAP) . Northfield, IL [Revised : Oct 2013; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Small Intestine and Ampulla. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised : Oct 2013; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Stomach. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised: Jun 2014; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Primary Carcinoma of the Colon and Rectum. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised: Jan 2016; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Tumors of the Brain/Spinal Cord. No AJCC/UICC TNM Staging System. Protocol web posting date: Dec 2014. College of American Pathologists (CAP). Northfield, IL [Last Modified: Nov 2017; Accessed: Jan 2018]

Protocol for the Examination of Specimens from Patients with Tumors of the Endocrine Pancreas. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Revised : Aug 2016; Accessed: Jun 2017]

Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML, Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012; 97(9): 2990-3011. PubMed

General References

Almeida MQ, Stratakis CA. Solid tumors associated with multiple endocrine neoplasias. Cancer Genet Cytogenet. 2010; 203(1): 30-6. PubMed

DeLellis RA. Parathyroid tumors and related disorders. Mod Pathol. 2011; 24 Suppl 2: S78-93. PubMed

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

Giusti F, Marini F, Brandi M. Multiple Endocrine Neoplasia Type 1. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated: Feb 2015; Accessed: Nov 2015]

Marquard J, Eng C. Multiple Endocrine Neoplasia Type 2. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated: Jun 2015; Accessed: Nov 2015]

Marsh DJ, Gimm O. Multiple endocrine neoplasia: types 1 and 2. Adv Otorhinolaryngol. 2011; 70: 84-90. PubMed

Nosé V. Familial thyroid cancer: a review. Mod Pathol. 2011; 24 Suppl 2: S19-33. PubMed

Raue F, Frank-Raue K. Update multiple endocrine neoplasia type 2. Fam Cancer. 2010; 9(3): 449-57. PubMed

Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014; 386(1-2): 2-15. PubMed

Walls GV. Multiple endocrine neoplasia (MEN) syndromes. Semin Pediatr Surg. 2014; 23(2): 96-101. PubMed

Zhang Y, Nosé V. Endocrine tumors as part of inherited tumor syndromes. Adv Anat Pathol. 2011; 18(3): 206-18. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Agarwal AM, Bentz JS, Hungerford R, Abraham D. Parathyroid fine-needle aspiration cytology in the evaluation of parathyroid adenoma: cytologic findings from 53 patients. Diagn Cytopathol. 2009; 37(6): 407-10. PubMed

Margraf RL, Calderon FR, Mao R, Wittwer CT. RET mutation scanning update: exon 15. Clin Chem. 2009; 55(11): 2059-61. PubMed

Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Calderon FR, Wittwer CT, Mao R. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat. 2009; 30(4): 548-56. PubMed

Margraf RL, Durtschi JD, Stephens JE, Perez M, Voelkerding KV. Determination of RET Sequence Variation in an MEN2 Unaffected Cohort Using Multiple-Sample Pooling and Next-Generation Sequencing. J Thyroid Res. 2012; 2012: 318232. PubMed

Margraf RL, Mao R, Highsmith E, 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): 184-96. PubMed

Margraf RL, Mao R, Wittwer CT. Rapid diagnosis of MEN2B using unlabeled probe melting analysis and the LightCycler 480 instrument. J Mol Diagn. 2008; 10(2): 123-8. PubMed

Medical Reviewers

Content Reviewed: 
June 2017

Last Update: November 2017