Can subunit‐specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?

Abstract

Objective: With the discovery that familial phaeochromocytoma and paraganglioma syndrome can be caused by mutations in each subunit of the succinate dehydrogenase enzyme (SDH), has come the recognition that mutations in the individual subunits have their own distinct natural histories. Increased genetic screening is leading to the identification of increasing numbers of, mostly asymptomatic, gene mutation carriers and the implementation of screening strategies for these individuals. Yet there is, to date, no international consensus regarding screening strategies for asymptomatic carriers.Design: A comprehensive PubMed search from 1/1/2000 to 28/2/2018 was undertaken using multiple search terms and subsequently a manual review of references in identified papers to identify all clinically relevant cases and cohorts. In this review, the accumulated, published experience of phenotype and malignancy risks of individual SDH subunits is analysed. Where possible screening results for asymptomatic SDH mutation carriers have been analysed separately to define the penetrance in asymptomatic carriers (asymptomatic penetrance). Results:The combined data confirms that "asymptomatic penetrance" is highest for SDHD and when there is penetrance, the most likely site to develop a PGL is head and neck (SDHD) and extra-adrenal abdominal (SDHB). However, the risk in SDHB carriers of developing HNPGL is also high (35.5%) and a PCC is low (15.1%), and in SDHD carriers there is a high risk of developing a PCC (35.8%) or abdominal PGL (9.4%) and a small, but significant risk at other sympathetic sites. The data suggest that the risk of malignant transformation is the same for both PCC and extra-adrenal abdominal PGLs (30%-35%) in SDHB carriers. In SDHD carriers, the risk of malignant transformation was highest in HNPGLs (7.5%) and similar for sympathetic sites (3.8%-5.2%). Conclusions:Using this data, we suggest surveillance screening of asymptomatic carriers can be tailored to the underlying SDH subunit and review possible surveillance programmes. K E Y W O R D S imaging, MRI, paraganglioma, phaeochromocytoma, screening, SDH, succinate dehydrogenase, surveillance S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Tufton N, Sahdev A, Drake WM, Akker SA. Can subunit-specific phenotypes guide surveillance imaging decisions in asymptomatic SDH mutation carriers?. Clin Endocrinol. 2019;90:31-46. https://doi.

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

“…Although different SDHx mutations occur in genes encoding for a single enzyme, the clinical picture for each subunit differs with regard to penetrance, manifestations and rate of malignancy. International guidelines advice to screen all germline mutation carriers, however with different screenings strategies for different SDHx mutation carriers . Screenings advices do not only differ between the different mutations, but also over time, because studies on penetrance differ over time regarding the population studied (index included or not), the imaging methods used and the duration of follow‐up.…”

“…Mutations in the SDHB gene are those most frequently found in PGL and account for about 10% of all cases of PGL . Most common manifestations are sympathetic PGLs (50%), whereas PCC and HNPGL occur less often (20%‐25% and 20%‐30%, respectively) . Bilateral PCCs appear to be rare in SDHB mutation carriers.…”

“…In a meta‐analysis including 12 studies comprising both asymptomatic SDHB carriers and carriers with manifest non‐metastatic disease, van Hulsteijn et al reported a metastatic rate of 17% . The risk of metastasis in HNPGL in SDHB mutation carriers appears to be lower compared to PGL developing at other sites . In a recent meta‐analysis of the outcomes of metastatic PGL and PCC, Hamidi et al found that the overall mortality in SDHB mutation carriers ranged from 35% to 55% (n = 96) compared to an overall mortality of 53% (95% confidence interval 43%‐63%) in the whole group of PGL/PCC .…”

“…International guidelines advice to screen all germline mutation carriers, however with different screenings strategies for different SDHx mutation carriers. 15 Screenings advices do not only differ between the different mutations, but also over time, because studies on penetrance differ over time regarding the population studied (index included or not), the imaging methods used and the duration of follow-up. Adherence to screening, leads to the detection of smaller PCC/PGL and might even lead to an improved survival for patients who develop metastases, although this is based on only few patients.…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…For example, a diagnosis of MEN1 in a patient may lead to the early detection of otherwise asymptomatic tumours through the implementation of surveillance screening programmes . Genetic testing may guide patient follow‐up; for example, patients with PPGL due to SDHB mutations are at a higher risk of metastatic or recurrent disease . In some instances, a genetic diagnosis may guide therapy; for example, children with infantile hypophosphatasia (ie due to bi‐allelic TNSALP mutations) may benefit from enzyme replacement therapy with alfotase‐alpha .…”