Multiple Endocrine Neoplasia (MEN) Syndromes

• Multiple Endocrine Neoplasia (MEN) syndromes are inherited in an autosomal dominant pattern.
• These syndromes involve hyperplastic or neoplastic proliferation in multiple endocrine glands.
• Classic forms include MEN 1 and MEN 2, but VHL, Cowden syndrome, Carney complex, and other familial endocrine neoplasia syndromes also belong to this category.

MEN Type 1 (Werner Syndrome)

• Involves the anterior pituitary gland (adenomas), pancreas (PanNETs), and parathyroid glands (chief cell hyperplasia).
• Caused by inactivating mutations in the MEN1 gene on chromosome 11q13.
• Approximately 40% of patients develop gastrinomas, 10% insulinomas, and less than 5% other functional PanNETs.
• Main clinical signs are primary hyperparathyroidism, Zollinger-Ellison syndrome, and acromegaly or hypopituitarism.
• Nonfunctional PanNETs are common.
• Less common abnormalities include those of the adrenal cortex and thyroid gland (nodular hyperplasia/adenomas).
• Carcinoid tumors can arise in various locations, mainly in foregut derivatives (lung, thymus, gastrointestinal tract).
• Other possible issues are soft tissue lipomas, leiomyomas, and Ménétrier disease of the stomach.

MEN Type 2

• Includes three variants: MEN 2a, MEN 2b, and familial medullary thyroid carcinoma (FMTC).
• All are caused by germline mutations in the RET proto-oncogene on chromosome 10q11.2.
• All variants include medullary thyroid carcinoma.
• The RET oncogene is also commonly mutated in Hirschsprung disease and rearranged in papillary thyroid carcinoma.

MEN 2a (Sipple Syndrome)

• Characterized by C-cell hyperplasia and medullary carcinoma of the thyroid gland (often multiple/bilateral).
• Also includes pheochromocytoma of the adrenal glands (often bilateral, with adrenal medullary hyperplasia).
• Primary hyperparathyroidism.
• Parathyroid involvement is the overlap between MEN 1 and MEN 2a, with similar morphology and function.

MEN 2b (Gorlin Syndrome)

• Includes medullary carcinoma of the thyroid and adrenal pheochromocytoma (similar to MEN 2a).
• Also includes mucosal neuromas (hypertrophied corneal nerves, bumpy lips, enlarged nodular tongue).
• Skeletal abnormalities and a marfanoid habitus also occur.
• Mucosal neuromas (or ganglioneuromas/ganglioneuromatosis) are a constant feature.
• Extensive ganglioneuromatosis of the digestive tract can cause constipation, diarrhea, or megacolon.
• Gastrointestinal signs can be the initial presentation.
• Adenomatous polyposis coli has been reported rarely in MEN 2b patients.
• Parathyroid disease is distinctly unusual in MEN 2b.
• Older reports referred to MEN 2b (IIB) as MEN III.

FMTC

• Characterized by medullary thyroid carcinoma in at least four family members.
• Patients do not have other endocrinopathies.
• Other combinations of endocrinopathy have been described, suggesting additional types/varieties of MEN.