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

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?”.

Genotype–phenotype associations in PPGLs in 59 patients with variants in SDHX genes

“…Paragangliomas (PGLs) arising from the parasympathetic nervous system are often non-secreting tumours located in the head and neck region (termed head and neck paragangliomas (HNPGLs)) ( 1 ). Because of the strong heritability, genetic testing is recommended in all patients with PPGLs and, when a variant is detected, also screening of their family members ( 1 , 2 , 3 , 4 , 5 ). Markers of poor prognosis in PPGLs have been identified in different studies, including tumour size >5 cm, vascular invasion, SDHB variants and norepinephrine secretion ( 6 ).…”

Metabolic Drivers in Hereditary Cancer Syndromes

“…For instance, immunostaining of SDHX-related tumors usually shows loss of SDHB expression irrespective of the subunit harboring the germline mutation (Papathomas et al 2015, and all SDHX-mutated tumors are characterized by succinate accumulation. However, despite these shared features, there are also important clinical differences associated with germline mutations in specific subunits, implying that the clinical management of individual families should be tailored toward the specific SDHX gene involved (Wong et al 2019). Thus, while germline SDHAF2 and SDHD mutations display a similar parent-of-origin inheritance pattern, germline mutations in SDHB, SDHC, and SDHA are all associated with no parent-of-origin effects, following a conventional autosomal dominant tumor predisposition inheritance pattern (Baysal & Maher 2015, Wong et al 2019.…”

Catecholamine-Secreting Tumors in Pediatric Patients With Cyanotic Congenital Heart Disease

“…In 2018, Wong et al [46] published practice guidelines on the surveillance of PPGL among patients carrying an SDHx ( SDHA , SDHB , SDHC , or SDHD ) variant mutation who are at an increased risk of developing these tumors. The age at presentation varied depending upon the specific mutation, with the SDHB mutation carriers presenting at younger ages.…”

“…However, the mean age of presentation in patients carrying any of the SDHx mutations was 13.5 years. Wong et al [46] recommended screening with an annual physical examination, including blood pressure, as well as biochemical testing for all high-risk patients. However, guidelines for the age at initiation of screening were different for SDHB mutation carriers as compared with SDHA , SDHC , or SDHD .…”

“…Screening was recommended starting at 5 years of age for SDHB mutation carriers and at 10 years of age for patients carrying a mutation in SDHA , SDHC , or SDHD . Radiologic surveillance using MRI every 2 to 3 years was also recommended, starting at age 10 years for SDHB and 15 years for patients in whom biochemical screening was unremarkable [46].…”