期刊
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
卷 -, 期 -, 页码 -出版社
ENDOCRINE SOC
DOI: 10.1210/clinem/dgad109
关键词
paraganglioma; pheochromocytoma; SDH; succinate; fumarate; enzyme deficiency
This study aimed to evaluate the role of measuring serum succinate and fumarate levels, as well as the succinate/fumarate ratio, in detecting pathogenic variants in SDHx genes in PPGL patients. The results showed that the succinate/fumarate ratio had a better discriminative power in identifying patients with SDHx pathogenic variants compared to succinate and fumarate levels alone. However, these biochemical markers were less effective in identifying SDHD gene mutations.
Context Pheochromocytomas and paragangliomas (PPGLs) with SDHx pathogenic variants (PVs) are characterized by a higher intratissular succinate/fumarate ratio (R-S/F) than non-SDHx-mutated ones. Also, an increase in serum succinate levels has been reported in patients with germline SDHB or SDHD PV. Objective To assess whether measurement of serum succinate, fumarate levels, and R-S/F might aid identification of an SDHx germline PV/likely pathogenic variant (LPV) in patients with PPGL or in asymptomatic relatives; and to guide identification of a PV/LPV among the variants of unknown significance (VUS) identified in SDHx by next-generation sequencing. Methods This prospective monocentric study included 93 patients attending an endocrine oncogenetic unit for genetic testing. Succinate and fumarate were measured in serum by gas chromatography coupled to mass spectrometry. The R-S/F was calculated to assess SDH enzymatic function. Diagnostic performance was assessed by receiver operating characteristic analysis. Results R-S/F had a higher discriminant power than succinate alone to identify an SDHx PV/LPV in patients with PPGL. However, SDHD PVs/LPVs are frequently missed. Only R-S/F differed between asymptomatic SDHB/SDHD PV/LPV carriers and SDHB/SDHD-linked patients with PPGL. Finally R-S/F could be helpful to easily evaluate the functional impact of VUS in SDHx. Conclusion Measurement of serum R-S/F in patients with PPGL and in asymptomatic relatives is a valuable initial workup tool to detect those carrying a germline PV/LPV in SDHx. Its discriminative power is equal or superior to those of succinate measured alone. SDHD PVs/LPVs are less frequently identified by these biochemical tools. Use of R-S/F for SDHx VUS reclassification needs to be evaluated further.
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