Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes

This study examined the mechanisms linking different biochemical and clinic al phenotypes of pheochromocytoma in multiple endocrine neoplasia type 2 (M EN 2) and von Hippel-Lindau (VHL) syndrome to underlying differences in the expression of tyrosine hydroxylase (TR), the rate-limiting enzyme in catec holamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT), t he enzyme that converts norepinephrine to epinephrine. Signs and symptoms o f pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 pat ients and 30 VHL patients with adrenal pheochromocytomas. MEN 2 patients we re more symptomatic and had a higher incidence of hypertension (mainly paro xysmal) and higher plasma concentrations of metanephrines, but paradoxicall y lower total plasma concentrations of catecholamines, than VHL patients. M EN 2 patients all had elevated plasma concentrations of the epinephrine met abolite, metanephrine, whereas VHL patients showed specific increases in th e norepinephrine metabolite, normetanephrine. The above differences in clin ical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine an d expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients . Thus, mutation-dependent differences in the expression of genes controlli ng catecholamine synthesis represent molecular mechanisms linking the under lying mutation to differences in clinical presentation of pheochromocytoma in patients with MEN 2 and the VHL syndrome.