How has genetics changed the diagnosis and care of multiple endocrine neoplasia type 2? The merits and pitfalls of a genetic-based diagnostic and therapeutic approach.

The discovery of RET as the primary driver of hereditary medullary thyroid cancer in multiple endocrine neoplasia syndrome drastically changed the diagnosis, management, and prognosis of patients with this rare endocrine tumor. First, from a diagnostic viewpoint, RET testing within families became possible, ruling out unnecessary follow-up for negative patients and proposing an adapted surveillance protocol for positive patients. Second, large-scale epidemiological studies paved the way for early "prophylactic" thyroidectomy, rendering a historically fatal disease curable. RET identification also allowed for proper screening of pheochromocytoma and primary hyperparathyroidism. Lastly, RET identification enabled the synthesis of new, highly effective, and well-tolerated specific inhibitors, which changed the outcome for patients with metastatic disease. The RET discovery is thus a perfect example of how gene discovery can transform the fate of a rare syndrome, and this is what will be described in this short review.