Multiple Endocrine Neoplasia (MEN) Syndromes

Multiple endocrine neoplastic (MEN) syndromes represent primarily autosomal dominant inherited disorders characterized by hyperplastic or neoplastic proliferations of more than one endocrine gland and include:

• MEN type 1

• MEN type 2 further divided into:

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    MEN-2A

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    MEN-2B

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    Familial medullary carcinoma (FMTC)

Autosomal dominant disease:

• May occur sporadically:

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    De novo mutations appear in 10% of all patients with MEN-1.

Characterized by combined occurrence of two or more tumors involving:

• Parathyroid glands

• Pancreas

• Anterior pituitary gland

MEN-1 gene (MEN-1) is located on chromosome 11q13:

• Composed of 10 exons that encode a 610 amino acid protein called menin

• Menin interacts with several different proteins and plays an important role in regulation of cell growth, cell cycle, genome stability, and synapse plasticity.

Tumors caused by a heterozygous germline-inactivating mutation in the MEN-1 gene (first hit) followed by somatic inactivating mutation or loss of the normal copy of the gene (second hit) leading to complete loss of function of encoded protein menin

Familiar MEN-1 has high degree of penetrance with clinical or biochemical manifestations of disease in 80% and 98%, respectively, by the fifth decade.

Clinical manifestations related to tumor localizations and their secretory products:

• Parathyroid glands:

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    Most common, occurring in 95% of MEN-1 patients

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    Chief cell hyperplasia

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    Clinically results in primary hyperparathyroidism

• Pancreatic tumors

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    Occur in 40% to 70% of MEN-1 patients:

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    Tumors include:

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      Gastrinoma (G-cell tumors)

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        Most common pancreaticoduodenal tumor in MEN-1 (50%): approximately 20% of gastrinomas occur in MEN-1 patients; 20% to 60% of MEN-1 patients develop gastrinomas

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        Not always located in pancreas: significant proportion primarily arise in duodenum; other primary sites may include stomach, jejunum, bile ducts

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        Results in Zollinger-Ellison syndrome: clinical signs and symptoms related to gastric acid hypersecretion including: peptic ulcer disease; diarrhea; esophageal reflux disease

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      Insulinoma (beta cell tumors):

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        Occur in approximately 30% of MEN-1 patients

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        Clinical signs and symptoms related to insulin hypersecretion include hypoglycemic symptoms (hyperinsulinemic hypo­glycemia); visual disturbances (blurred vision, diplopia); mental status changes including confusion, amnesia, behavioral changes.

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        Secondary effects of catecholamine release include hunger, weakness, nausea, palpitations, anxiety, perspiration.

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        Symptoms of Whipple triad include: hypoglycemia, low blood glucose levels, symptomatic relief with glucose administration.

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      Vasoactive intestinal peptide (VIP) cell tumors (VIPoma):

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        Occur in approximately 12% of MEN-1 patients

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        Clinical signs and symptoms related to VIP hypersecretion include watery diarrhea associated with hypokalemia and achlorhydria (Verner-Morrison syndrome; pancreatic cholera; WDHA).

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      Glucagonoma (alpha cell tumors):

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        Occur in less than 5% of MEN-1 patients

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        Clinical signs and symptoms related to glucagon hypersecretion include dermatitis (necrolytic migratory erythema), which is most common and usually found intertriginous and periorificial, especially groin and buttocks; diabetes mellitus and glucose intolerance; weight loss; anemia; hypoaminoacidemia.

• Pituitary tumors

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    Occur in 30% to 40% of MEN-1 patients

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    Anterior pituitary adenoma

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    Clinically results in acromegaly or hypopituitarism

• Other tumors described, including:

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    Adrenal cortical tumors

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    Carcinoid tumors (foregut, primarily thymus, and lung)

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    Nonendocrine tumors, including:

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      Lipomas, angiofibromas, collagenomas, and meningiomas

Correlation between genotype and phenotype not found:

• Combinations of tumors may be different in members of same family.

Treatment for each type of endocrine tumor:

• Generally similar as in non-MEN-1-associated tumors

• Results are less successful owing to:

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    Multiplicity of tumors

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    Higher metastatic disease

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    Larger and more aggressive tumors

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    More resistant to treatment

Untreated patients:

• Have decreased life expectancy with 50% probability of death by the age of 50 years

• Cause of death mostly directly related to MEN-1 is malignant pancreatic neuroendocrine tumors (NET) and thymic carcinoids

Prognosis might improve by preclinical tumor diagnosis and appropriate treatment.