Multiple Endocrine Neoplasias - MEN

Last Literature Review: June 2017 Last Update:

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Mao

Rong Mao, MD, FACMG
Professor of Pathology (Clinical), and Co-Director of Laboratory Genetics and Genomics Fellowship, University of Utah
Medical Director, Molecular Genetics and Genomics, ARUP Laboratories
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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

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)
    • Consider annual testing for the following
      • Parathyroid tumor
        • Calcium (ionized)
        • Electrolytes
        • Parathyroid hormone
      • 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
          • Insulin-like growth factor-1 (IGF-1)
        • Prolactin
  • 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])

References

Additional Resources