Multiple Endocrine Neoplasia (MEN) Syndromes

Basics

  • Multiple endocrine neoplasia (MEN) syndromes are autosomal dominant disorders that predispose individuals to the development of neoplasms, usually benign but sometimes malignant, in characteristic clusters of endocrine tissues.
  • The classic syndromes are MEN1 and MEN2A and MEN2B.
  • Also considered as closely related disorders: MEN4 (MEN1-like phenotype), von Hippel-Lindau syndrome (produces norepinephrine, not epinephrine), Cowden syndrome, Carney complex, and familial paragangliomas

Description

  • Three main subtypes:
    • MEN1: parathyroid hyperplasia or adenoma (90% penetrance at age 50 years), anterior pituitary adenomas (prolactinoma most commonly), and tumors of the endocrine pancreas (gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor [VIPoma]). A mnemonic commonly used to remember this is the 3Ps. Combinations of >20 different types of tumors are described in these patients, but the above three are considered characteristic (1)[A].
    • MEN2A: medullary thyroid carcinoma (90%), pheochromocytoma (50%), and parathyroid hyperplasia or single adenoma (20–30%) (2)[A]
    • MEN2B: medullary thyroid carcinoma (90%), pheochromocytoma, and mucosal and GI ganglioneuromatosis; marfanoid habitus (2)[A]
  • MEN4: bilateral pheochromocytomas, hyperparathyroidism/parathyroid adenoma, paraganglioma, C-cell (multifocal thyroid) hyperplasia, neuroendocrine carcinoid tumor, and hyperplasia of the endocrine pancreas. MEN4 has a variable age of onset with parathyroid and pituitary manifestations in the 4th and 3rd decades of life, respectively (3)[B].
  • Synonym(s): multiple endocrine adenomatosis (MEA); Wermer syndrome (MEN1); Sipple syndrome (MEN2); Wagenmann-Froboese syndrome

Epidemiology

  • MEN1: prevalence estimated to be 1:30,000; 10% of cases are sporadic (90% familial); male = female; clinical manifestations occur by the 5th decade in 95% of cases, with most diagnosed in early adulthood. Hyperparathyroidism is the most frequent and earliest manifestation (4).
  • MEN2: prevalence estimated at 1:30,000 individuals:
    • MEN2A: most common subtype (>80% of MEN2 cases); the typical age at onset of symptoms is 5 to 25 years (4).

Etiology and Pathophysiology

Genetics

  • Autosomal dominant
  • MEN1: results from mutation causing the loss of function of tumor suppressor gene MEN1 located on chromosome 11q13, encoding the nuclear protein menin; patients have germline mutations and develop tumors when a “second hit” occurs to the other allele. The exact action of menin not known, but it appears to be involved in the cell cycle and in DNA transcription and replication. 10% of mutations arise de novo; no mutation is identified in 10–20% of cases.
  • MEN2: results from mutation causing gain of function of proto-oncogene RET (also called MEN2 gene) located on chromosome 10q11.2, encoding the protein RET, which is a membrane tyrosine kinase receptor; 5% of MEN2A and 50% of MEN2B cases are secondary to de novo mutations; no mutation is identified in 5% of cases. There is a significant genotype–phenotype correlation.
  • MEN4: results from germline mutation causing inactivation of the cyclin-dependent kinase inhibitor 1B (CDKN1B); negative MEN1

Risk Factors

Significant family history

Commonly Associated Conditions

In addition to the defining MEN-associated tumors, other associated conditions include:

  • MEN1: adrenal cortical tumors (nonfunctioning or causing hypercortisolemia); thyroid tumors including carcinoma, adenoma, or colloid goiters; carcinoid tumors; facial angiofibromas; facial collagenomas; lipomas; meningiomas
  • MEN2A: Rare variants exist, including MEN2A with cutaneous lichen amyloidosis and with Hirschsprung disease.
  • MEN2B: developmental abnormalities including marfanoid habitus or skeletal deformities

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