Multiple Endocrine Neoplasias - MEN

Diagnosis

Multiple Endocrine Neoplasia 1 (MEN1)

MEN2A and MEN2B

Indications for Testing

• Typical tumor presentation (familial medullary thyroid carcinoma [FMTC] or pheochromocytoma) and family history
  • Refer to testing algorithms for pheochromocytoma and thyroid nodules

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
  • Pheochromocytoma and medullary thyroid cancer evaluation prior to genetic 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
      • Chromogranin A
      • Other hormone testing based on syndrome presentation
        • Gastrin
        • Glucagon
        • Pancreatic polypeptide
        • Vasoactive intestinal peptide (VIP)
        • Glucose/insulin
    • 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 

• See Pheochromocytoma and Thyroid Cancer

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%)
      • 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 – 20-40% of patients
  • Thyroid neoplasms – 8-25% of patients
  • Pheochromocytoma – <1% of patients
• Nonendocrine 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

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])