CHU Lille, Laboratoire de Biochimie-Hormonologie, Métabolisme, Nutrition, Oncologie, Centre de Biologie Pathologie, F.59037 Lille Cedex, France.
CHU Lille, Service d'Anatomie Pathologique, Centre de Biologie Pathologie, F-59037 Lille Cedex, France.
J Clin Endocrinol Metab. 2023 Aug 18;108(9):2343-2352. doi: 10.1210/clinem/dgad109.
Pheochromocytomas and paragangliomas (PPGLs) with SDHx pathogenic variants (PVs) are characterized by a higher intratissular succinate/fumarate ratio (RS/F) than non-SDHx-mutated ones. Also, an increase in serum succinate levels has been reported in patients with germline SDHB or SDHD PV.
To assess whether measurement of serum succinate, fumarate levels, and RS/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.
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 RS/F was calculated to assess SDH enzymatic function. Diagnostic performance was assessed by receiver operating characteristic analysis.
RS/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 RS/F differed between asymptomatic SDHB/SDHD PV/LPV carriers and SDHB/SDHD-linked patients with PPGL. Finally RS/F could be helpful to easily evaluate the functional impact of VUS in SDHx.
Measurement of serum RS/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 RS/F for SDHx VUS reclassification needs to be evaluated further.
携带有 SDHx 种系致病性变异（PV）的嗜铬细胞瘤和副神经节瘤（PPGL）的组织内琥珀酸/富马酸比值（RS/F）高于非 SDHx 突变型。此外，已有报道称，SDHB 或 SDHD 种系 PV 患者的血清琥珀酸水平升高。
评估测量血清琥珀酸、富马酸水平和 RS/F 是否有助于识别 PPGL 患者或无症状亲属中的 SDHx 种系 PV/可能致病性变异（LPV）；并指导通过下一代测序识别 SDHx 中的意义不明变异（VUS）中的 PV/LPV。
这项前瞻性单中心研究纳入了 93 名前往内分泌肿瘤遗传单位进行基因检测的患者。通过气相色谱-质谱联用技术测量血清中的琥珀酸和富马酸。计算 RS/F 以评估 SDH 酶活性。通过接受者操作特征分析评估诊断性能。
与单独测量琥珀酸相比，RS/F 具有更高的鉴别能力，可用于识别 PPGL 患者中的 SDHx PV/LPV。然而，SDHD PV/LPV 经常被遗漏。仅在无症状的 SDHB/SDHD PV/LPV 携带者和 SDHB/SDHD 相关的 PPGL 患者之间 RS/F 存在差异。最后，RS/F 有助于轻松评估 SDHx 中 VUS 的功能影响。
在 PPGL 患者和无症状亲属中测量血清 RS/F 是一种有价值的初始检查工具，可用于检测携带 SDHx 种系 PV/LPV 的个体。其鉴别能力与单独测量琥珀酸相当或更优。这些生化工具较少识别 SDHD PV/LPV。需要进一步评估 RS/F 用于 SDHx VUS 再分类的作用。
