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).

Quick Answers for Clinicians

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

  • Genetic testing
    • MEN1 mutation analysis
      • 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
    • For patients with overlap symptoms or MEN1 presentation without MEN1 gene, consider testing for CDKN1B (MEN4)
  • 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
    • Vasoactive intestinal polypeptide secreting tumor (VIPoma) – vasoactive intestinal peptide 

MEN2A and MEN2B

Indications for Testing

  • Typical tumor presentation (familial medullary thyroid carcinoma [FMTC] or pheochromocytoma) and family history

Laboratory Testing

  • Genetic testing
    • RET mutation analysis
      • Confirms presence of mutation in patient with FMTC 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
  • Biochemical testing

Familial Medullary Thyroid Carcinoma (FMTC)

Indications for Testing

  • Family history of FMTC 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 Multiple Endocrine Neoplasia 1 (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

MEN2 

Background

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])

ARUP Lab Tests

Preferred initial test to confirm diagnosis of MEN1

Clinical sensitivity: combined testing ~94%

  • 90% sequencing
  • 4% deletion/duplication

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

Diagnostic and predictive test for MEN2A and MEN2B

Clinical sensitivity

  • MEN2A: 95%
  • MEN2B: 98%

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

Useful when a pathogenic familial variant identifiable by sequencing is known

Consultation with a genetics counselor is advised

Related Tests

Aid in diagnosis of adrenal insufficiency and determining the presence of anterior pituitary tumors

Diagnose and monitor familial medullary thyroid carcinoma (FMTC)

Secondary test to assist in diagnosing multiple endocrine neoplasia type 2 (MEN2)and FMTC

Assay aids in monitoring but is not recommended for diagnosis of carcinoid tumors

May be useful in monitoring nonsecretory sympathetic and parasympathetic neuroendocrine tumors

FISH probes for specific microdeletion/microduplication syndromes must be specified; if no specific syndrome is in question, genomic microarray should be ordered instead of screening multiple loci by FISH

Aid in detection of insulinoma

Aid in diagnosis of carcinoid and gastrinoma tumors

Aid in diagnosis and monitoring of glucagonoma

Use to diagnose and manage diabetes mellitus (DM) and other carbohydrate metabolism disorders

Aid in evaluation of patient with allergic signs and symptoms, such as anaphylaxis; may assist in diagnosing and monitoring of mast-cell activation disorders

Aid in diagnosis of growth hormone excess or deficiency disorders

Aid in detection of insulinoma

Use to assess cardiovascular disease risk and guide therapy

Panel includes cholesterol, triglycerides, HDL cholesterol, LDL cholesterol (calculated), non-HDL cholesterol, VLDL cholesterol (calculated), appearance chemistry

First-line test in suspected pheochromocytoma

Acceptable initial test to confirm diagnosis of MEN1 but does not detect deletions/duplications

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

Diagnostic errors can occur due to rare sequence variations

Clinical sensitivity: 90%

Aid in diagnosis and monitoring of pancreatic neuroendocrine tumors

Use to evaluate calcium dysregulation

Screening for anterior pituitary tumor

Evaluate for kidney dysfunction in patients with known risk factors (eg, hypertension, diabetes, obesity, family history of kidney disease)

Panel includes albumin, calcium, carbon dioxide, creatinine, chloride, glucose, phosphorous, potassium, sodium, and blood urea nitrogen (BUN) and a calculated anion gap value

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Reflex pattern: if the thyroid stimulating hormone is outside the reference interval, then thyroxine, free (free T4) testing will be added

Preferred test for screening and monitoring of thyroid function

Preferred serotonin test when diagnosing carcinoid tumors is whole blood

Aid in diagnosis of VIPoma

Aid in the detection of insulinoma

May aid in distinguishing type 1 from type 2 diabetes mellitus (DM) in ambiguous cases

Do not use to diagnose DM

Medical Experts

Contributor

Best

Hunter Best, PhD, FACMG
Associate Professor of Clinical Pathology, University of Utah
Scientific Director, NGS and Biocomputing; Medical Director, Molecular Genetics and Genomics, ARUP Laboratories
Contributor

Mao

Rong Mao, MD, FACMG
Professor of Clinical Pathology; Adjunct Associate Professor, Pediatrics; and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah
Section Chief, Molecular Genetics and Genomics, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®