Multiple Endocrine Neoplasia (MEN)

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: medullary thyroid cancers, hyperparathyroidism, pheochromocytomas, Hirschsprung disease

• MEN 3: 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

  • Adrenocortical nodular hyperplasia

  • Pituitary adenomas

  • Thyroid tumors

  • Gonadal Sertoli cell tumors

  • Cardiac myxomas

• 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, 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