Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma - PubMed (original) (raw)

Multicenter Study

doi: 10.1373/clinchem.2010.153320. Epub 2011 Jan 24.

Jacques W M Lenders, Henri Timmers, Massimo Mannelli, Stefan K Grebe, Lorenz C Hofbauer, Stefan R Bornstein, Oliver Tiebel, Karen Adams, Gennady Bratslavsky, W Marston Linehan, Karel Pacak

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Multicenter Study

Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma

Graeme Eisenhofer et al. Clin Chem. 2011 Mar.

Abstract

Background: Pheochromocytomas are rare catecholamine-producing tumors derived in more than 30% of cases from mutations in 9 tumor-susceptibility genes identified to date, including von Hippel-Lindau tumor suppressor (VHL); succinate dehydrogenase complex, subunit B, iron sulfur (Ip) (SDHB); and succinate dehydrogenase complex, subunit D, integral membrane protein (SDHD). Testing of multiple genes is often undertaken at considerable expense before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine, and methoxytyramine, the O-methylated metabolites of catecholamines, might help to distinguish different hereditary forms of the tumor.

Methods: Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome, and 59 with mutations of SDHB or SDHD.

Results: In contrast to patients with VHL, SDHB, and SDHD mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDHB and SDHD mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL, SDHB, and SDHD gene mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDHB and SDHD mutations from those with VHL mutations in an additional 78% of cases.

Conclusions: The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily used tool to guide cost-effective genotyping of underlying disease-causing mutations.

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Figures

Fig. 1

Fig. 1

Bar graphs showing tumor tissue contents of norepinephrine (panel A), epinephrine (panel B) and dopamine (panel C) in patients with MEN 2, NF1 and mutations of VHL, SDHB and SDHD genes. Results are expressed as mean (±SEM) percent values of total contents of all three catecholamines. Differences (P<0.05) between groups are indicated by different symbols (* and †), where * indicates significant higher values than † (Tukey-Kramer post-hoc test)

Fig. 2

Fig. 2

Dot plots showing normalized logarithmic distributions of plasma concentrations of catecholamines and the free O-methylated catecholamine metabolites in patients with PPGLs due to VHL syndrome, MEN 2, NF1 and mutations of SDHB and SDHD genes. Plasma concentrations of normetanephrine (panel A) and its catecholamine precursor, norepinephrine (panel B), are shown in the upper panels; those of metanephrine (panel C) and its catecholamine precursor, epinephrine (panel D), in the middle panels; while concentrations of methoxytyramine (panel E) and its catecholamine precursor, dopamine (panel F), are shown in the lower panels. The dashed horizontal lines show the upper limits of reference intervals for each analyte.

Fig. 3

Fig. 3

Principle components analysis scatter plot illustrating clustering of patients with PPGLs due to MEN 2 or NF1 (red dots) compared to patients with VHL (blue dots) and SDH (green dots) mutations according to relationships of plasma concentrations of methoxytyramine (x-axis), metanephrine (y-axis) and normetanephrine (z-axis). Values shown on axes are in units nmol/L.

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References

    1. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366:665–75. - PubMed
    1. Mannelli M, Ercolino T, Giache V, Simi L, Cirami C, Parenti G. Genetic screening for pheochromocytoma: should SDHC gene analysis be included? J Med Genet. 2007;44:586–7. - PMC - PubMed
    1. Bryant J, Farmer J, Kessler LJ, Townsend RR, Nathanson KL. Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Cancer Inst. 2003;95:1196–204. - PubMed
    1. Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol. 2005;23:8812–8. - PubMed
    1. Mannelli M, Castellano M, Schiavi F, Filetti S, Giacche M, Mori L, et al. Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009;94:1541–7. - PubMed

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