title: Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes.
abstract: 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.
authors.affiliation: Clinical Neurocardiology Section and Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. ge@box-g.nih.gov
authors.forename: G
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: M M
authors.initials: MM
authors.lastname: Walther
authors.forename: T T
authors.initials: TT
authors.lastname: Huynh
authors.forename: S T
authors.initials: ST
authors.lastname: Li
authors.forename: S R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: A
authors.initials: A
authors.lastname: Vortmeyer
authors.forename: M
authors.initials: M
authors.lastname: Mannelli
authors.forename: D S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: W M
authors.initials: WM
authors.lastname: Linehan
authors.forename: J W
authors.initials: JW
authors.lastname: Lenders
authors.forename: K
authors.initials: K
authors.lastname: Pacak
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D002395:Catecholamines / Q000097:blood; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008676:Metanephrine / Q000097:blood; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010625:Phenylethanolamine N-Methyltransferase / Q000235:genetics; D010673:Pheochromocytoma / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D006623:von Hippel-Lindau Disease / Q000378:metabolism* / Q000473:pathology
chemical_list: D002395:Catecholamines; D012333:RNA, Messenger; D008676:Metanephrine; D014446:Tyrosine 3-Monooxygenase; D010625:Phenylethanolamine N-Methyltransferase