Adams, Karen T.

Abstract Carney's triad (CTr) is a non-hereditary condition, primarily seen in young women, characterized by gastrointestinal stromal tumors (GIST), extra-adrenal paragangliomas and pulmonary chondromas. Most CTr patients present with GIST and pulmonary chondroma (incomplete CTr). A marked decrease in the enzymatic activity of succinate dehydrogenase (SDH) has been detected in these tumors, but the presence or absence of SDH mutations in CTr is controversial. A related disease, known as Carney-Stratakis Syndrome (CSS), has no female predisposition and presents with extra-adrenal paragangliomas and GIST tumors, without pulmonary chondromas. In distinction to CTr, CSS is hereditary due to germline SDH mutations in the enzyme's subunits (SDHA, SDHB, SDHC and SDHD) with corresponding decreased SDH activity in associated tumors. We have investigated 64 patients with CTr for germline mutations and/or deletions in the SDH subunit genes; four patients were found to have germline mutations in SDHB or SDHC. All four patients had multifocal gastric GIST and pulmonary chondromas at diagnosis; two subsequently developed paragangliomas, confirmed by biopsy. One of the patients with CTr and a SDHB mutation had a nephew with the same mutation and a neuroblastoma, confirming a previously reported association of neuroblastoma with gist (JMG 2009; 46:215, and AJMG 2010; 152A: 1531). We conclude that few CTr patients maybe more correctly classified as having CSS; the genetic distinction of CTr from CSS needs further study. [S.A.B. and P.X. should be regarded as joint first authors.] Citation Format: Sosipatros A. Boikos, Paraskevi Xekouki, Fabio R. Faucz, Karel Pacak, Margarita Raygada, Karen Adams, Evan Szarek, Evan Ball, Su Young Kim, Elena Fumagalli, Lee J. Helman, J Aidan Carney, Constantine A. Stratakis. Few Carney's Triad patients have mutations in two subunits of the succinate dehydrogenase enzyme (SDHB, SDHC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 568. doi:10.1158/1538-7445.AM2014-568

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.