Wurth Rachel, Jha Abhishek, Kamilaris Crystal, Gill Anthony J, Poplawski Nicola, Xekouki Paraskevi, Quezado Martha M, Pacak Karel, Stratakis Constantine A, Hannah-Shmouni Fady
Section on Endocrinology and Genetics, National Institutes of Health, Bethesda, Maryland, USA.
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Endocrinol Diabetes Metab Case Rep. 2021 Mar 28;2021. doi: 10.1530/EDM-20-0170.
Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC.
The succinate dehydrogenase enzyme is encoded by four subunit genes (SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes. Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs. Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants. Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.
琥珀酸脱氢酶缺乏症与多种肿瘤形成有关，包括肾细胞癌（RCC）以及与遗传性副神经节瘤（PGL）/嗜铬细胞瘤（PHEO）综合征、卡尼二联征和卡尼三联征相关的肿瘤。卡尼三联征是一种罕见的多肿瘤综合征，其特征为并存副神经节瘤、胃肠道间质瘤（GIST）和肺软骨瘤（CHO）。我们报告一例57岁男性患者，其表现为主动脉旁和胃食管肿块以及右肾上级病变，手术切除后病理检查分别诊断为多发副神经节瘤、胃肠道间质瘤和透明细胞肾细胞癌。此外，影像学诊断为肺软骨瘤，但未进行活检。确诊为卡尼三联征。副神经节瘤和胃肠道间质瘤的SDHB免疫组化染色均为阴性，提示琥珀酸脱氢酶缺乏。有趣的是，肾细胞癌的SDHB和SDHA染色均为阳性。随后对琥珀酸脱氢酶亚基基因进行基因筛查，发现一个种系失活杂合SDHA致病变异（c.91 C>T，p.R31X）。在肾细胞癌的肿瘤水平未检测到杂合性缺失，这可能表明SDHA变异不是肾细胞癌的病因，但仍可能易患肿瘤形成。据作者所知，这是首例报道的卡尼三联征合并肾细胞癌患者存在SDHA致病变异的病例。
琥珀酸脱氢酶由四个亚基基因（SDHA、SDHB、SDHC和SDHD；统称为SDHx）编码，这些基因与多种肿瘤形成有关，被归类为肿瘤抑制基因。卡尼三联征是一种罕见的多肿瘤综合征，表现为副神经节瘤、胃肠道间质瘤和肺软骨瘤的联合。如肿瘤组织所示，卡尼三联征最常与SDHC的高甲基化相关，但约10%的病例是由致病的SDHx变异引起。虽然SDHB致病变异在琥珀酸脱氢酶缺乏的肾细胞癌中最常被报道，但罕见情况下也有SDHA致病变异的报道。
