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For further information, see CMDT Part 26-27: MEN Types 1–4

Key Features

Essentials of Diagnosis

  • MEN 1: tumors of the parathyroid glands, endocrine pancreas and duodenum, anterior pituitary, adrenal, thyroid; carcinoid tumors; lipomas and facial angiofibromas

  • MEN 2 (formerly MEN 2A): medullary thyroid cancers, hyperparathyroidism, pheochromocytomas, Hirschsprung disease

  • MEN 3 (formerly MEN 2B): medullary thyroid cancers, pheochromocytomas, Marfan-like habitus, mucosal neuromas, intestinal ganglioneuroma, delayed puberty

  • MEN 4: tumors of the parathyroid glands, anterior pituitary gland, adrenal gland, ovary, testicle, kidney

General Considerations

MULTIPLE ENDOCRINE NEOPLASIA (MEN) 1 (WERMER SYNDROME)

  • Parathyroid, enteropancreatic, and pituitary tumors

  • Nonendocrine tumors

    • Small head-neck angiofibromas (85%)

    • Lipomas (30%)

    • Collagenomas (70%)

  • Incidental adrenal nodules are found in about 50% of affected patients but are rarely secretory

  • Mutations in the menin gene (11q13) detectable in 60–95% of cases

  • Variants of MEN 1 occur, eg, kindreds with MEN 1 Burin have a high prevalence of prolactinomas, late-onset hyperparathyroidism, and carcinoid tumors, but rarely enteropancreatic tumors

  • In patients with MEN 1 gastrinomas, depending on the kindred, hepatic metastases tend to be less aggressive than in those with sporadic gastrinomas

MEN 2 (FORMERLY MEN 2A; SIPPLE SYNDROME)

  • Medullary thyroid carcinoma, hyperparathyroidism, pheochromocytomas

  • Nonendocrine: Hirschsprung disease

  • Caused by a mutation of the ret proto-oncogene (RET) on chromosome 10 (95%)

  • Each kindred has a certain ret codon mutation that correlates with the particular variation in the MEN 2 syndrome, such as the age of onset and aggressiveness of medullary thyroid cancer

MEN 3 (FORMERLY MEN 2B)

  • Adrenal pheochromocytomas, medullary thyroid carcinoma, mucosal neuromas

  • Nonendocrine manifestations

    • Intestinal ganglioneuromas

    • Marfan-like habitus

    • Skeletal abnormalities

    • Delayed puberty

MEN 4

  • Rare autosomal-dominant familial tumor syndrome caused by germline mutations in the gene CDKN1B

  • Affected patients are particularly prone to parathyroid adenomas (80%), pituitary adenomas (less aggressive than those seen with MEN 1), pancreatic neuroendocrine tumors, and adrenal tumors

  • They also appear to be prone to adrenal tumors, renal tumors, testicular cancer, neuroendocrine cervical carcinoma, and primary ovarian failure

OTHER SYNDROMES RELATED To MEN

  • Carney complex

    • Adrenocortical nodular hyperplasia that can produce skin abnormalities

    • Cushing syndrome

    • GH-secreting pituitary adenomas or hyperplasia with acromegaly

    • Thyroid tumors

    • Gonadal Sertoli cell tumors

    • Myxomas of heart and breast

    • Other malignancies

  • McCune-Albright syndrome:

    • Precocious puberty (particularly girls) due to gonadal hypersecretion

    • Cushing syndrome caused by multiple adrenal nodules

    • Hyperthyroidism from functioning thyroid nodules

    • Acromegaly caused by GH-secreting pituitary tumors may develop

    • Fibrous dysplasia of bones and hypophosphatemia, and bone fractures are common

    • Sudden death has been reported

  • Type 2 von Hippel Lindau (VHL) syndrome

    • Associated with pheochromocytomas, pancreatic/duodenal neuroendocrine tumors, hyperparathyroidism, and pituitary tumors

    • Hemangiomas and renal cell carcinomas

  • Hypoxia Inducible Factor 2A (HIF2A) germline mutations predispose to

    • Pheochromocytomas, ...

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