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 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
- VIPoma (~2%) – Verner-Morrison syndrome
- Watery diarrhea, hypokalemia, achlorhydria
- Glucagonoma (rare) – hyperglycemia, skin rash, anorexia, diarrhea
- Anterior pituitary tumors
- Develop in 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%)
- 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
Treatment
- Treatment of manifestations dependant on tumor type
MEN2
Epidemiology
- Incidence – 1/30,000 for MEN2 syndromes
- MEN2A – 70-80% 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 and 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; and 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)
- 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
- MEN2A, 2B, and FMTC
- Thyroidectomy – timing depends on codon position of identified RET mutation
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