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
  • Medullary thyroid cancer – thyroid stimulating hormone (TSH) and calcitonin
  • 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)
  • Pheochromocytoma – metanephrines
  • VIPoma – vasoactive intestinal peptide
• Genetic testing
  • Likelihood of detecting a germline MEN1 mutation increases in proportion to the number of main tumors found in patient
  • ~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
  • If the specific familial mutation has already been identified in a relative, testing can be performed on at-risk family members by ordering familial mutation targeted sequencing
  • For additional MEN1 information, please refer to ARUP's MEN1 database, which documents known MEN1 missense variants and associated clinical information from symptomatic patients

Imaging Studies

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

MEN2A and 2B

Indications for Testing

• Typical tumor presentation (MTC or pheochromocytoma) and family history
  • Refer to testing algorithms for pheochromocytoma and thyroid nodules

Laboratory 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

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 – 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
• 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 (~40%) – Zollinger-Ellison syndrome
      • Peptic ulcer disease, recurrent diarrhea, abdominal pain
    • Insulinoma (~10%) – pancreatic islet tumors
      • 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 15-90% 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%)
      • Gigantism in children and acromegaly in adults
    •  Combination – prolactinoma/growth hormone tumor (~5%)
      • Combined symptoms
    •  Adrenal tumors (~2-5%) – most nonfunctioning
      • Hypercortisolism
• Other endocrine tumors
  • Adrenal cortical adenomas – 5-40% of patients
  • Thyroid neoplasms – 8-25% of patients
  • Pheochromocytoma – 0.5% of patients
• Non-endocrine tumors
  • Cutaneous tumors
    • Collagenoma and facial angiofibromas – 70-85% of patients
    • Lipomas – 30% of patients
    • Malignant melanoma
  • Central nervous system tumors
    • Meningiomas
    • Ependymomas
  • Muscle tumors
    • Leiomyomas

Treatment

• Treatment of manifestations dependant on tumor type

MEN2

Epidemiology

• Incidence – 1/30,000
  • MEN2A – 60-90% of cases
  • FMTC – 5-35% 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 
  • MEN2A – 95% have mutations in exon 10 or 11
  • MEN2B – 95% have a point mutation at codon 918 in exon 16; 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 (Sipple syndrome)
  • MTC (~90%) – onset in early adulthood  
  • Pheochromocytoma (~50%) – paroxysmal hypertension, palpitations, headaches
  • Parathyroid tumors (20-30%) – hypercalcemia
  • Lichen planus amyloidosis
• MEN2B
  • MTC – onset in early childhood; aggressive
  • Pheochromocytoma – paroxysmal hypertension, palpitations, headaches
  • Marfanoid body type
  • Megacolon
  • Mucosal and intestinal ganglioneuromatosis
• FMTC
  • MTC only – onset in middle age

Treatment

• Prophylactic
  • Thyroidectomy – timing depends on codon position of identified RET mutation

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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 0098192 Method: Quantitative Extraction/Radioimmunoassay
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

Diagnostic Algorithm

  Hypercalcemia Testing Algorithm

  Pheochromocytoma Testing Algorithm

  Thyroid Nodules Testing Algorithm