MEN 1 and MEN 2

The mutliple endocrine neoplasia syndromes (denoted MEN 1 and MEN 2) are uncommon conditions where patients are at risk of parathyroid, pituitary and pancreatic neoplasms (MEN 1) or medullary thyroid cancer and phaeochromocytoma (MEN 2).

MEN 1

MEN 1 is an autosomal dominant condition caused by a germline defect in the MEN 1 gene. Loss of the remaining MEN 1 gene (two hit hypothesis) leads to loss of production of menin, the gene product. The exact means by which this gene functions as a tumour suppressor is not known. Patients generally develop:

  • Parathyroid adenomas (95%) causing hyperparathyroidism
  • Pituitary adenomas (30%), often prolactinoma
  • Pancreatic neuroendocrine tumours, often gastrinomas, in 40% of patients

Patients are also at increased risk of skin tumours (angiofibromas) and carcinoid tumours of the thymus.

Treatment

Most tumours are benign and can be treated surgically. Patients who are identified as carriers should be screened yearly with calcium levels.

MEN 2

MEN2 is divided into MEN2A and MEN2B; both are related to germline mutation in the RET gene but they have different phenotypes. MEN2B is typically more serious with higher risk thyroid disease.

MEN2A

MEN 2 is an autosomal dominant condition caused by a germline mutation in the RET gene. Patients almost always develop medullary thyroid cancer, and half will develop phaeochromocytoma. Parathyroid adenomas are also more common but not as prevalent as MEN 1. In contrast to MEN 1, preventative surgery (thyroidectomy) is often indicated for at risk patients in childhood (1 - 10 years depending on risk) to prevent the development of medullary thyroid cancer which is potentially fatal.
The risk of MEN 2 depends upon the site of mutation in the RET gene. This can guide the timing of prophylactic thyroidectomy; highest risk patients should undergo thyroidectomy before the age of 1 whereas low risk patients can wait until their age is over 10.

MEN2B

MEN2B is due to more specific mutation in the tyrosine kinase part of the RET gene. This leads to autophosphorylation of the RET gene without a ligand present. MEN2B patients develop multifocal medullary thyroid cancer and phaeochromocytome but do not develop primary hyperparathyroidism.

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