What causes Multiple Endocrine Neoplasia?

The MEN syndromes are all caused by genetic mutations in special genes that normally act to regulate the normal controlled cell division that occurs during development. The mutations result in cell division in the affected tissues to become uncontrolled producing tumours. The specific genes are beginning to become understood.

MEN 1

The gene responsible is on the long arm of chromosome 11. It normally produces menin, a tumour suppressor protein (acting to slow down cell division). When mutated unregulated cell division causes excess growth and the formation of tumours.

MEN 2a

This is caused by mutation of the RET gene on long arm of chromosome 10. This gene normally produces a receptor that a molecule called glial cell-derived neurotropic factor (GDNF) binds to. When mutated it becomes constantly active, causing the affected cells to divide autonomously, resulting in tumour formation.

Diagram to show RET mutation - click to enlarge

Genes like RET are known as 'proto-oncogenes' - genes that when mutated promote tumour development by increasing cell division.

MEN2b

This is caused by a mutation in the same RET proto-oncogene that causes MEN2a. However a slightly different type of mutation seems to be responsible.

The reason so many different tissues are affected is that the mutations affect cells in the embryo which act as a common source for all these tissues. Hence, later in development, when the cells have migrated to different parts of the body from a common origin, it appears the tumours are not closely related anatomically. Embryologically however, they are.