100-Year evolution of precision medicine and surgery for multiple endocrine neoplasia type 2A

To determine whether published disease penetrance estimates of 50% for pheochromocytoma and 20-30% for primary hyperparathyroidism in multiple endocrine neoplasia (MEN 2A), conceivably reflecting overrepresentation of index patients with completely developed MEN 2A, may be too high.

Cross-sectional study of carriers at high risk of MEN 2A from a tertiary referral center.

There were 213 carriers of RET mutations in codon 634, born between 1922 and 2014. Median age of thyroidectomy was 17 years, with MTC being present in 76.5%; pheochromocytoma in 31.0% at a median of 34 years in the first, and in 18.8% at a median of 35 years in the second adrenal; and primary hyperparathyroidism in 10.8% at a median of 39 years. MTC, pheochromocytoma and primary hyperparathyroidism, stratified by year of birth, were diagnosed earlier over time: for MTC from 51 to 4 years; for pheochromocytoma from 51 to 22.5 years in the first, and from 51 to 29.5 years in the second adrenal, and for primary hyperparathyroidism from 46 to 12 years (P ≤ 0.008). This decline in age was paralleled by diminishing tumor diameters, more strongly in the thyroid (from 20 to 1.8 mm; P < 0.001) than in the adrenals (from 43 to 30 mm in the first, and from 20-57.5 to 30.5 mm in the second adrenal; statistically nonsignificant).

The lower disease penetrance estimates and sluggish decline of adrenal tumor diameters call for more widespread adoption of adrenal-sparing and parathyroid preservation surgery based on early and regular biochemical screening.