Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers

Summary The 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?”.

will reduce the morbidity and mortality associated with SDH deficient tumours, 3 there is at present 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?".

| ME THODS
In order to address this important clinical question, a thorough review of the literature was performed. MEDLINE was searched via PubMed using the following search terms; (a) SDH or succinate de-  A copy number variant was identified in 6 (6.4%) cases (one gene duplication, five exonic deletions and one whole gene deletion).

| What is the prevalence of related disease in childhood
Notably, the frequency of reported truncating variants (nonsense/ frameshift and splice site variants) identified in this paediatric population was 72% compared to a reported frequency of 52% in an adult population presenting with PPGL. 1 The mean age of this cohort was 13.5 years (range 5-18 years).
There was no significant difference in the mean age at presentation with PPGL in those patients with germline SDHB variants  possibility of SDHx mutation penetrance at a young age. However, an appropriate surveillance protocol must balance the occurrence of paediatric tumour development against the increasing evidence that the penetrance of SDHB is lower than originally reported and the potential adverse effects of screening.

| What are the current recommendations for the age at which to commence surveillance for SDHx mutation carriers?
The Endocrine Society recommends that surveillance should comprise annual biochemistry (urinary or plasma metanephrines) and sporadic cross-sectional imaging of the skull base, neck, thorax, abdomen and pelvis (MRI is the preferred radiation sparing imaging modality). 3 There are no recommendations as to the lower age limit of genetic testing of children in SDHx mutation families. In the UK, genetic testing for inherited neoplasia syndromes is usually conducted around the time when clinical, biochemical and radiological surveillance would begin. 53 It is also important to note that as SDHD variants have a preferential paternal transmission pattern of inheritance, clinical surveillance is only recommended for those carriers that inherit an SDHD variant from their father.
To our knowledge, no guidance exists to inform the most appropriate starting age for clinical, biochemical and radiological surveillance in paediatric SDHx mutation carriers. A review of the literature identified 13 manuscripts that attempted to address this issue. Eight studies argued for surveillance to start before or at 10 years including one expert opinion, 54 three case series with less than five patients, 6,55,56 three retrospective studies with 32, 92 and 116 patients, respectively 5,57,58 ), and one case-control study with 241 patients. 59 Three reports recommended starting from the second decade of life (one systematic review of 95 papers suggesting a start age between 11-20 years, one retrospective study with 91 patients suggesting an age of 27.1 years based on HNPGL penetrance calculations and one case series of three families suggested a starting age of 18 years for HNPGL screening). 15,60,61 However, two further studies suggested that the starting age should either be between 5 and 10 years or alternatively a minimum of one decade before the earliest age of disease onset in that kindred (two expert opinions). 62,63 When considering at what age a screening programme should Recent studies, focused on more accurately predicting the clinical penetrance of SDHx genes, have adopted methods to control for ascertainment bias and suggest an estimated clinical penetrance of around 20% by age 50 years for SDHB mutation carriers. 64 In the largest study of SDHB and SDHD mutation carriers yet re-  Table 2). There are some limitations to this analysis. Firstly, the figures include probands who are affected with the disease and therefore will increase penetrance estimates, and therefore, the analysis was also performed with probands excluded (

| What are the controversies and/or risks of early surveillance?
Several factors complicate the decision when surveillance should be commenced in paediatric SDHx mutation carriers. Important considerations include the growing awareness that the lifetime penetrance of SDHB mutations is significantly lower (see above) than that estimated when the gene was first identified (originally estimated at 70%-80%).
In addition, surveillance programmes can be disruptive to patients'

| CON CLUS ION
Despite the occurrence of SDHx driven tumours in children, the majority of these tumours present in adulthood. The absolute risks