Early-Onset Renal Cell Carcinoma as a Novel Extraparaganglial Component of SDHB-Associated Heritable Paraganglioma

Abstract

Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.

Dopamine-secreting Carotid Body Paragangliomas-Biochemical Control with Radiotherapy

“…According to the genetic testing algorithm recommended by experts at the First International Symposium on Pheochromocytoma (26), testing for SDHB and SDHD mutations is suggested for patients who present with bilateral extra-adrenal tumors. SDHB mutations have been associated with malignant disease (27), extra-adrenal paragangliomas (28), and other extra-paraganglial tumors, for example renal cell carcinoma (29). A preponderance of head and neck paragangliomas and multifocal disease has been reported in SDHD mutations (23,25), as in the present patient.…”

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…An increasing number of genes can be responsible for development of both tumour types individually or in association, which suggests a closer connection than previously appreciated [86][87][88][89] . In addition to VHL, SDH 90,91 , FH 92 and TMEM127 (REFS 93,94), genes can also be mutated in renal carcinomas either with or without co-occurrence of PPGL. The MET gene, previously known to cause hereditary papillary renal cancer 95 , was also found to be mutated in PPGLs 14,96 .…”

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…SDH mutations have been involved in the etiopathogeny of pheochromocytomas (PCCs), paragangliomas (PGLs), gastrointestinal stromal tumors (GISTs), renal-cell carcinomas (RCCs), and pituitary adenomas (PAs). 1,2,[4][5][6][7][8][9] In addition, mutations in fumarate hydratase (FH), another member of the TCA cycle and which catalyzes the hydration of fumarate to malate, predispose to tumor formation, including RCCs, cutaneous and uterine leiomyomas, and PCCs/PGLs. 10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas.…”