Multiple Endocrine Neoplasias - MEN

Clinical Background

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 additional subtypes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). 

MEN1 (Wermer Syndrome)

Epidemiology

  • Incidence – 1/30,000
  • Age – onset is 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 MEN1 syndrome in a family)
    • Approximately 1-3% of MEN1 mutations are large deletions
  • Variable expressivity
  • Genotype/phenotype associations have not been identified in MEN1
  • 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
  • Gastroenteropancreatic (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
  • Other endocrine tumors
  • Non-endocrine tumors

Treatment

  • Treatment of manifestations dependant on tumor type

MEN2

Epidemiology

  • Incidence – 1/30,000 for MEN2 syndromes
    • MEN2A – 60-90% of cases
    • MEN2B – ~5% of cases
    • FMTC – 5-35% of cases

Inheritance

  • Autosomal dominant – 5% of MEN2A and 50% of MEN2B mutations are de novo
  • Caused by mutation in the RET proto-oncogene 
    • MEN2A – 95% have mutations in exon 10 or 11
    • MEN2B – 95% have a point mutation at codon 918 in exon 16, and 3-4% have a point mutation at codon 883 in exon 15 
      • Rare – mutations in other exons of the RET gene
    • FMTC – ~ 85% have mutations in exon 10 or 11
      • Rare mutations in exons 13, 14 or 15 can also be causative
  • Genotype/phenotype correlations can help predict risk for aggressive MTC
  • Penetrance varies by MEN2 subtype

Clinical Presentation

  • MEN2A
  • MEN2B
    • MTC – onset in early childhood, aggressive
    • Pheochromocytoma – paroxysmal hypertension, palpitations, headaches
    • Marfanoid body type
    • Megacolon
    • Mucosal neuromas
  • FMTC
    • MTC only – onset in middle age

Treatment

  • Prophylactic
    • MEN2A, 2B, and FMTC
      • Thyroidectomy – timing depends on codon position of the identified RET mutation

Diagnosis

MEN1

Indications for Testing

  • Confirm a clinical diagnosis of MEN1 in an individual with ≥2 endocrine tumors (parathyroid, pituitary or GEP)
  • Presymptomatic testing of at-risk family members is advised when a specific MEN1 mutation has been identified in an affected relative

Laboratory Testing

  • Initial biochemical testing can identify tumor presence
    • 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 elevated
    • Anterior pituitary tumor – prolactin and insulin-like growth factor-1 (IGF-1) elevated
    • Pheochromocytoma – metanephrines and genetic testing
    • Medullary thyroid cancer – thyroid stimulating hormone (TSH) and calcitonin
  • Genetic testing
    • Likelihood of detecting a germline MEN1 mutation increases in individuals with more main tumors
    • ~20-55% of families with familial isolated hyperparathyroidism (FIHP) have germline MEN1 mutations
      • Individuals with a single MEN1-related tumor and no family history of the condition rarely have germline MEN1 mutations

Imaging Studies

  • Pancreatic tumors – abdominal MRI/CT
  • Anterior pituitary tumors – cranial MRI

MEN2A and 2B

Indications for Testing

  • Typical tumor presentation and family history

Laboratory Testing

  • RET mutation analysis 
    • Confirms diagnosis
    • Allows for presymptomatic testing of at-risk family members

FMTC

Indications for Testing

  • Family history of MTC in multiple generations without the presence of pheochromocytoma or parathyroid adenoma/hyperplasia

Laboratory Testing

  • RET mutation analysis to confirm a clinical diagnosis and allow for presymptomatic testing of family members

Monitoring

  • MEN1
    • Periodic screening for MEN1-associated endocrine tumors beginning in early childhood and continuing for life
      • Risk for malignant progression of MEN1-associated tumors depends on tumor type
  • MEN2
    • 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

Indications for Laboratory Testing

  • 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

Confirm clinical diagnosis of MEN2

Rule out MEN2 for individuals with MTC and/or other suggestive findings

Mutations in RET gene introns, regulatory regions, and exons not targeted for sequencing are not detected

  
Multiple Endocrine Neoplasia, Type 2B (RET) 2 Mutations 0051492
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Confirm clinical diagnosis of MEN2B

Test pre-symptomatic, at-risk family members when an MEN2B mutation (M918T or A883F) has been previously identified in an affected relative

Mutations other than M918T and A883F will not be detected

 Patients negative for the M918T and A883F mutations should have additional sequencing of RET exons 10-11 and 13-16
Immunohistochemistry Stain Offering arup005
Method: Immunohistochemistry

For fixed tissue samples, consultative services as well as immunohistochemical staining for CAM5, chromogranin A, 2 (LMW), PGP9.5, parathyroid hormone and synaptophysin are available

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

Test pre-symptomatic, 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

For assistance in ordering this test, contact a genetic counselor
Additional Tests Available
 
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Calcitonin 0070006
Method: Chemiluminescent Immunoassay
Calcium, Ionized, Serum 0020135
Method: Ion-Selective Electrode/pH-Electrode
Calcium, Urine 0020472
Method: Spectrophotometry
Calcium, Ionized, Whole Blood 0020140
Method: Ion-Selective Electrode/pH-Electrode
Calcium, Serum or Plasma 0020027
Method: Spectrophotometry
Chromogranin A 0080469
Method: Enzyme Immunoassay
Chromosome FISH, Metaphase 2002299
Method: Fluorescence in situ Hybridization
C-Peptide, 24-Hour Urine 0081121
Method: Chemiluminescent Immunoassay
Gastrin 0070075
Method: Chemiluminescent Immunoassay
Glucagon 0099165
Method: Radioimmunoassay
Glucose, Plasma or Serum 0020024
Method: Enzymatic
IGF-1 (Insulin-Like Growth Factor I) 0070125
Method: Chemiluminescent Immunoassay
Insulin, Free & Total 0070155
Method: Chemiluminescent Immunoassay
Metanephrines, Plasma (Free) 0050184
Method: High Performance Liquid Chromatography
Parathyroid Hormone, Intact with Calcium 0070172
Method: Electrochemiluminescent Immunoassay
Parathyroid Hormone, Intact 0070346
Method: Electrochemiluminescent Immunoassay
Prolactin 0070115
Method: Chemiluminescent Immunoassay
Thyroid Stimulating Hormone 0070145
Method: Electrochemiluminescent Immunoassay