Multiple Endocrine Adenomatosis, Type 2

 The type A variant of multiple endocrine neoplasia, type 2 (MEN2A), is an autosomal dominant disorder characterized by a high incidence of medullary carcinoma of the thyroid that is often but not always associated with pheochromocytoma, benign parathyroid adenomas, or both. Patients with the rarer type B variant (MEN2B) have, in addition to younger age of onset of the tumors seen in patients with MEN2A, thickening of nerves and the benign neural tumors, known as neuromas, on the mucosal surface of the mouth and lips and along the gastrointestinal tract.

The pathogenic variants responsible for MEN2 are in the RET oncogene. Individuals who inherit an activating variant in RET have a greater than 60% chance of developing medullary thyroid carcinoma. Blood tests for thyrocalcitonin or urinary catecholamines synthesized by pheochromocytomas are abnormal in over 90% of individuals with MEN2.

RET encodes a cell- surface protein that contains an extracellular domain that can bind signaling molecules and a cytoplasmic tyrosine kinase domain. Tyrosine kinases are a class of enzymes that phosphorylate tyro sines in proteins. Tyrosine phosphorylation initiates a signaling cascade of changes in protein- protein and DNA- protein interactions and in the enzymatic activity of many proteins (Fig. 1). Normally, tyrosine kinase receptors must bind specific signaling molecules to undergo the conformational change that makes them enzymatically active and able to phosphorylate other cellular proteins. The pathogenic variants in RET that cause MEN2 increase its kinase activity even in the absence of its ligand (a state referred to as constitutive activation).

Fig1. Schematic diagram of the function of the Ret receptor, the product of the RET proto- oncogene. Upon binding of a ligand (L), such as glial- derived growth factor or neurturin, to the extracellular domain, the protein dimerizes and activates its intracellular kinase domain to autophosphorylate specific tyrosine residues. These then bind the SHC adaptor protein, which sets off multiple cascades of complex protein interactions involving other serine- threonine and phosphatidylinositol kinases and small G proteins, which in turn activate other proteins, ultimately activating certain transcription factors that suppress apoptosis and stimulate cellular proliferation. Pathogenic variants in RET that result in the type A variant of multiple endocrine neoplasia, type 2 (MEN2A), cause inappropriate dimerization and activation of its own intrinsic kinase without ligand binding.

The RET gene is expressed in many tissues of the body and is required for normal embryonic development of autonomic ganglia and the kidney. It is unclear why germline activating mutations in this proto- oncogene result in particular cancers of distinct histologic types restricted to specific tissues, whereas other tissues in which the oncogene is expressed do not develop tumors. Interestingly, RET is also implicated in some cases of Hirschsprung disease, although the associated pathogenic variants are usually loss of function, not activating. There are, however, some families in which the same pathogenic variant in RET can act as an activated oncogene in some tissues (such as thyroid) and cause MEN2A, and not have sufficient function in other tissues such as the developing enteric neurons of the gastrointestinal tract, resulting in Hirschsprung dis ease. Thus even the identical variant can have different effects on different tissues.

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