Increased Mortality in SDHB but Not in SDHD Pathogenic Variant Carriers.

Johannes Rijken,Michiel Kerstens,Leonie Van Hulsteijn,Marieke Van Dooren,Olaf Dekkers,Henricus Kunst,Anouk Van Berkel,Koen Dreijerink,Peter Bisschop,Nicolasine Niemeijer,Erik Hensen,Eleonora Corssmit,Frederik Hes,Anouk Van Der Horst-Schrivers,Karin Eijkelenkamp,C Leemans,Henri Timmers,Jeroen Jansen

doi:10.3390/cancers11010103

Abstract

Germline mutations in succinate dehydrogenase subunit B and D (SDHB and SDHD) are predisposed to hereditary paraganglioma (PGL) and pheochromocytoma (PHEO). The phenotype of pathogenic variants varies according to the causative gene. In this retrospective study, we estimate the mortality of a nationwide cohort of SDHB variant carriers and that of a large cohort of SDHD variant carriers and compare it to the mortality of a matched cohort of the general Dutch population. A total of 192 SDHB variant carriers and 232 SDHD variant carriers were included in this study. The Standard Mortality Ratio (SMR) for SDHB mutation carriers was 1.89, increasing to 2.88 in carriers affected by PGL. For SDHD variant carriers the SMR was 0.93 and 1.06 in affected carriers. Compared to the general population, mortality seems to be increased in SDHB variant carriers, especially in those affected by PGL. In SDHD variant carriers, the mortality is comparable to that of the general Dutch population, even if they are affected by PGL. This insight emphasizes the significance of DNA-testing in all PGL and PHEO patients, since different clinical risks may warrant gene-specific management strategies.

Highlights

Paragangliomas (PGL) are rare tumors that originate from cells of neural crest origin in the paraganglia associated with the autonomic nervous system
The mortality of this nationwide SDHB-linked cohort was compared with the mortality of the general Dutch population and with the mortality of an updated cohort of SDHD variant carriers, which has been described previously [12]
192 SDHB variant carriers and 232 SDHD variant carriers were included in this study

Summary

Introduction

Paragangliomas (PGL) are rare tumors that originate from cells of neural crest origin in the paraganglia associated with the autonomic nervous system. An increasing number of genes are associated with hereditary PGL/PHEO. Hereditary PGL syndrome is caused by genes encoding subunits or cofactors of succinate dehydrogenase (SDH), such as SDHA/B/C/D/AF2. Other associated genes are RET, NF1, VHL, HIF2A, FH, TMEM127, and MAX [1,2]. In the Netherlands, pathogenic variants in SDHD are the most prevalent cause of PGL syndrome, followed by variants in SDHB and SDHA [3,4]. All SDHx genes encode subunits of the same SDH complex and pathogenic variants all disrupt its enzymatic function, different genes are associated with different phenotypes

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Discussion

Conclusion