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

  • MEN 3 (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%)

  • 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 develop adenomas of the pituitary, parathyroid glands, and neuroendocrine tumors (NETs) of the pancreas.

  • This makes them appear to have MEN 1, but they have no mutation in the menin gene

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

OTHER SYNDROMES RELATED To MEN

  • Carney complex

    • Tumors develop in the adrenal cortex, pituitary, thyroid, and gonads

    • Cardiac myxomas

    • Hyperpigmentation

  • 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

    • Associated with pheochromocytomas, pancreatic/duodenal somatostatinomas

    • Erythrocytosis

    • Retinal abnormalities

  • Neurofibromatosis type 1 (NF1)

    • Associated with pheochromocytomas and pancreatic/duodenal somatostatinomas as well as neurofibromas and hypothalamic hamartomas

Clinical Findings

Symptoms and Signs

MEN 1

  • Tumors ...

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