Multiple Endocrine Neoplasias - MEN

Diagnosis

Multiple Endocrine Neoplasia 1 (MEN1)

Indications for Testing

  • Diagnostic testing for patients with clinical or biochemical evidence diagnosis of MEN1
  • 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
    • Carcinoid tumor – testing depends on tumor location
      • ACTH, gastrin, βhCG, somatostatin, pancreatic polypeptide, serotonin, histamine, tachykinins
    • Parathyroid tumor – calcium and parathyroid hormone (PTH)
    • Gastrinoma tumor – gastrin and gastric acid output measures
    • Insulinoma and other pancreatic tumors – chromogranin A, glucagon, serum insulin, and C-peptide levels
    • Anterior pituitary tumor – prolactin and insulin-like growth factor-1 (IGF-1); additional anterior pituitary testing based on symptoms
    • Pheochromocytoma – metanephrines
    • VIPoma – vasoactive intestinal peptide
  • Genetic testing
    • Confirms MEN1 
    • Likelihood of detecting a germline MEN1 mutation increases in proportion to the number of main tumors found in patient
      • MEN1 mutation seldom found in patient with no family history and single MEN1-associated tumor
    • ~20-55% of families with familial isolated hyperparathyroidism (FIHP) have germline MEN1 mutations
    • If the specific familial mutation has already been identified in a relative, testing can be performed on at-risk family members using familial mutation targeted sequencing

MEN2A and 2B

Indications for Testing

  • Typical tumor presentation (MTC or pheochromocytoma) and family history

Laboratory Testing

  • Biochemical testing
  • Genetic testing
    • RET mutation analysis 
      • Confirms presence of mutation in patient with MTC or pheochromocytoma
      • Presymptomatic testing of at-risk family members
      • For additional RET information, please refer to ARUP's MEN2 and RET database, which documents RET sequence changes relevant to MEN2 syndromes

Familial Medullary Thyroid Carcinoma (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

Multiple Endocrine Neoplasia 1 (MEN1)

  • Periodic screening for MEN1-associated endocrine tumors beginning in early childhood and continuing for life (NCCN, 2014)
    • Consider annual testing for the following
      • Parathyroid tumor
      • Pancreatic neuroendocrine tumor
      • Bronchial carcinoid/thymic carcinoid previously
        • Chest imaging at 1-3 years
      • Pituitary
        • Previous pituitary – MRI at 3-5 years
        • No previous pituitary
          • IGF-1
        • Prolactin
  • Risk for malignant progression of MEN1-associated tumors depends on tumor type
    • Malignancy uncommon before early adulthood

Multiple Endocrine Neoplasia 2 (MEN2)

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 the 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 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 above 95% by 40 years
  • Genotype/phenotype associations have not been identified in MEN1

Clinical Presentation

  • Parathyroid tumors
    • Primary hyperparathyroidism develops in >98% of patients
    • 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 (3%) – carcinoid syndrome
        • Flushing, wheezing, diarrhea, carcinoid heart disease
      • VIPoma (~2%) – Verner-Morrison syndrome
        • Watery diarrhea, hypokalemia, achlorhydria
      • Glucagonoma (rare)
        • Hyperglycemia, skin rash, anorexia, diarrhea
  • Anterior pituitary tumors
    • Develop in ~35% 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
  • Non-endocrine 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
    • 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 MTC
  • Penetrance – varies by MEN2 subtype
    • Nearly 100% for MTC

Clinical Presentation

  • MEN2A (Sipple syndrome)
    • MTC (~90%) – early onset; usually <35years 
    • Pheochromocytoma (~50%) – paroxysmal hypertension, palpitations, headaches
      • Usually bilateral
    • Parathyroid tumors (~25%) – adenoma, hyperplasia
    • Lichen planus amyloidosis
  • MEN2B
    • MTC – childhood onset; aggressive
    • Pheochromocytoma ~50%) – paroxysmal hypertension, palpitations, headaches
    • Skeletal deformities (eg, Marfaniod body type)
    • Eye abnormalities (eg, corneal thickening)
    • Mucosal and intestinal ganglioneuromatosis
  • FMTC
    • MTC only – onset in middle age
    • Considered a variant of MEN2 with decreased penetrance

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

Diagnosis and presymptomatic identification of MEN1

Regulatory region mutations, deep intronic mutations, breakpoints of large deletions/duplications, and mutations in genes other than MEN1 are not evaluated

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
Diagnosis and presymptomatic identification of MEN2

Regulatory region mutations, deep intronic mutations, large deletions/duplications, and RET exons other than 5, 8, 10, 11, 13-16 are not evaluated

Diagnostic errors can occur due to rare sequence variations

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

Use for testing presymptomatic, at-risk family members when a specific RET mutation has been identified in an affected relative

Familial mutation is the only mutation 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
Adrenocorticotropic Hormone 0070010
Method: Quantitative Chemiluminescent Immunoassay
Beta-hCG, Serum Quantitative 0070025
Method: Chemiluminescent Immunoassay
Calcitonin 0070006
Method: Quantitative Chemiluminescent Immunoassay
Calcium, Ionized, Serum 0020135
Method: Ion-Selective Electrode/pH Electrode
Calcium, Serum or Plasma 0020027
Method: Quantitative Spectrophotometry
Chromogranin A 0080469
Method: Quantitative Enzyme Immunoassay
Chromosome FISH, Metaphase 2002299
Method: Fluorescence in situ Hybridization
C-Peptide, Serum or Plasma 0070103
Method: Quantitative Chemiluminescent Immunoassay
Electrolytes, Urine 0020498
Method: Quantitative Ion-Selective Electrode
Gastrin 0070075
Method: Quantitative Chemiluminescent Immunoassay
Glucagon 0099165
Method: Quantitative Radioimmunoassay
Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic
IGF-1 (Insulin-Like Growth Factor 1) 0070125
Method: Quantitative Chemiluminescent Immunoassay
Insulin, Fasting 0070063
Method: Quantitative Chemiluminescent Immunoassay
Metanephrines, Plasma (Free) 0050184
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Parathyroid Hormone, Intact with Calcium 0070172
Method: Quantitative Electrochemiluminescent Immunoassay
Lipid Panel 0020421
Method: Quantitative Enzymatic
Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay
Renal Function Panel 0020144
Method: Quantitative Chemiluminescent Immunoassay/Quantitative Enzyme-Linked Immunosorbent Assay
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay
Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay
Somatostatin Quantitative, Plasma 2010001
Method: Quantitative Extraction/Immunoassay
Pancreatic Polypeptide 0099436
Method: Quantitative Radioimmunoassay
Histamine, Plasma 0070036
Method: Quantitative Enzyme-Linked Immunosorbent Assay
Serotonin, Serum 0080397
Method: Quantitative High Performance Liquid Chromatography
Vasoactive Intestinal Peptide 0099435
Method: Quantitative Radioimmunoassay
Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing 2005359
Method: Polymerase Chain Reaction/Sequencing
Multiple Endocrine Neoplasia Type 1 (MEN1) Deletion/Duplication 2005346
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification