Abstract
SummaryThe succinate dehydrogenase (SDH) enzyme complex functions as a key enzyme coupling the oxidation of succinate to fumarate in the citric acid cycle. Inactivation of this enzyme complex results in the cellular accumulation of the oncometabolite succinate, which is postulated to be a key driver in tumorigenesis. Succinate accumulation inhibits 2‐oxoglutarate‐dependent dioxygenases, including DNA and histone demethylase enzymes and hypoxic gene response regulators. Biallelic inactivation (typically resulting from one inherited and one somatic event) at one of the four genes encoding the SDH complex (SDHA/B/C/D) is the most common cause for SDH deficient (dSDH) tumours. Germline mutations in the SDHx genes predispose to a spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), wild type gastrointestinal stromal tumours (wtGIST) and, less commonly, renal cell carcinoma and pituitary tumours. Furthermore, mutations in the SDHx genes, particularly SDHB, predispose to a higher risk of malignant PPGL, which is associated with a 5‐year mortality of 50%. There is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with dSDH tumours. However, there is no consensus on when and how surveillance should be performed in children and young adults. Here, we address the question: “What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?”.
Highlights
Prior to the turn of this century, it was commonly considered that 10% of phaeochromocytomas and paragangliomas (PPGLs) were fa‐ milial
| 503 of a “clinical PPGL” in the paediatric age group are estimated to exceed 1% and 5% at ages 10 years and 16 years in SDHB mutation carriers and ages 16 and 18 years in SDHD carriers, respectively.[65]. Reviewing those paediatric index cases with SDHx variants re‐ ported in the literature, 9.5% (10/105) of cases presented before the age of 10 years and 70% of those cases were SDHB gene mu‐ tation carriers
In cases for which detailed pheno‐ typic data on paediatric index cases were available (Table 1 and Supporting Information Table S1), 86.3% (63/73) of tumours re‐ ported were secretory and could be diagnosed on bio‐ chemical screening. This data would suggest that the approach to clinical surveillance should be tailored to the SDHx subunit gene affected, as recent studies would suggest a higher risk of PPGL with SDHB gene mutations
Summary
Prior to the turn of this century, it was commonly considered that 10% of phaeochromocytomas and paragangliomas (PPGLs) were fa‐ milial. An understanding that PPGL have a rich hereditary background, as 30% of PPGL are known to be familial.[1] Germline mutations in the SDHx genes account for 30‐40% of hereditary PPGL cases and mutations in the SDHB gene in particular predict a higher risk of malignant potential.[2] there is is general agreement that biochemical and imaging surveillance should be offered to asymp‐ tomatic carriers of SDHx gene mutations in the expectation that this. | 500 will reduce the morbidity and mortality associated with SDH defi‐ cient tumours,[3] there is at present no consensus on when and how surveillance should be performed in children and young adults. We address the question: "What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?"
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