First-positive surveillance screening in an asymptomatic SDHA germline mutation carrier

Abstract

Summary At least 40% of phaeochromocytomas and paraganglioma’s (PPGLs) are associated with an underlying genetic mutation. The understanding of the genetic landscape of these tumours has rapidly evolved, with 18 associated genes now identified. Among these, mutations in the subunits of succinate dehydrogenase complex (SDH) are the most common, causing around half of familial PPGL cases. Occurrence of PPGLs in carriers of SDHB, SDHC and SDHD subunit mutations has been long reported, but it is only recently that variants in the SDHA subunit have been linked to PPGL formation. Previously documented cases have, to our knowledge, only been found in isolated cases where pathogenic SDHA variants were identified retrospectively. We report the case of an asymptomatic suspected carotid body tumour found during surveillance screening in a 72-year-old female who is a known carrier of a germline SDHA pathogenic variant. To our knowledge, this is the first screen that detected PPGL found in a previously identified SDHA pathogenic variant carrier, during surveillance imaging. This finding supports the use of cascade genetic testing and surveillance screening in all carriers of a pathogenic SDHA variant. Learning points: SDH mutations are important causes of PPGL disease. SDHA is much rarer compared to SDHB and SDHD mutations. Pathogenicity and penetrance are yet to be fully determined in cases of SDHA-related PPGL. Surveillance screening should be used for SDHA PPGL cases to identify recurrence, metastasis or metachronous disease. Surveillance screening for SDH-related disease should be performed in identified carriers of a pathogenic SDHA variant.

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

“…SDHC, SDHD, MTCO3, and NDUFV3 were identified as being possible candidates. Succinate dehydrogenase as a key component of the mitochondrial respiratory chain (RC) of all living organisms ( 22 ), SDH mutation frequently occurred in cancer ( 23 – 25 ). SDHC has a higher mutation rate compared with SDHD ( 26 ).…”

UK recommendations forSDHAgermline genetic testing and surveillance in clinical practice

“…As for many other cancer predisposition syndromes, comprehensive data regarding the clinical utility of surveillance are limited in SDHA PGV carriers. However, it is recognised that patients can present at a young age with metastatic disease and cases of positive surveillance have been reported 9 23. There is controversy both over whether surveillance should be offered and if it is, the extent of the surveillance.…”

“…However, it is recognised that patients can present at a young age with metastatic disease and cases of positive surveillance have been reported. 9 23 There is controversy both over whether surveillance should be offered and if it is, the extent of the surveillance. Surveillance with plasma metanephrines alone may not detect the non-secretory head and neck PGL and therefore, if surveillance is recommended it should comprise both biochemical studies and imaging including neck, thorax, abdomen and pelvis.…”

“…8 As for many other rare cancer predisposition genes, there is sparse information available on the effectiveness of surveillance in SDHA PGV carriers and the impact of early detection on clinical outcomes. 9 At the UKCGG (UK Cancer Genetics Group) Consensus meeting in Cambridge in Spring 2019 (https://www.ukcgg.org/information-education/ ukcgg-consensus-meetings/), a surveillance protocol for SDHA PGV carriers was agreed consisting of annual clinical review and biochemistry with abdominal imaging and MRI neck, thorax, abdomen and pelvis at baseline, followed by 3-5 yearly imaging, based on published recommendations and expert opinion. 10 11 Since that meeting, questions regarding the utility of predictive testing and surveillance for a on March…”

“…In addition to malignant wtGIST, SDHA PGV carriers may also develop malignant PGL 8. As for many other rare cancer predisposition genes, there is sparse information available on the effectiveness of surveillance in SDHA PGV carriers and the impact of early detection on clinical outcomes 9…”