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Pheochromocytomas in von Hippel-Lindau Syndrome and Multiple Endocrine Neoplasia Type 2 Display Distinct Biochemical and Clinical Phenotypes

Clinical Neurocardiology Section and Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (G.E., T.-T.H., S.-T.L., A.V., D.S.G.); Urologic Oncology Branch, National Cancer Institute (M.M.W., W.M.L.); and Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development (S.R.B., K.P.), National Institutes of Health, Bethesda, Maryland 20892; Department of Clinical Pathophysiology, University of Florence (M.M.), Florence, Italy; and Department of Internal Medicine, St. Radboud University Hospital (J.W.M.L.), Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Dr. Graeme Eisenhofer, Building 10, Room 6N252, National Institutes of Health, 10 Center Drive, MSC 1620, Bethesda, Maryland 20892-1620. E-mail: ge{at}box-g.nih.gov

This study examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau (VHL) syndrome to underlying differences in the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN 2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN 2 patients all had elevated plasma concentrations of the epinephrine metabolite, metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite, normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis represent molecular mechanisms linking the underlying mutation to differences in clinical presentation of pheochromocytoma in patients with MEN 2 and the VHL syndrome.

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