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

Abstract

Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre we aimed to characterize the genotype-phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n=59) diagnosed with a rare variant in SDHX during a thirteen-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and therefore useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, and forming a basis for larger multi-centre follow up studies.

Clinical presentation of sporadic and hereditary pheochromocytoma/paraganglioma

“…In patients with pathogenic SDHB mutations, PHEO occurrence and abdominal/pelvic PGL (7/8) were more frequently observed, also as previously reported ( Muth et al 2019 ). In contrast to other reports where the malignancy rate was relatively high ( van Hulsteijn et al 2012 , Tufton et al 2017 , Main et al 2020 ), none of these eight patients developed malignant disease, although the median follow-up was only 7 years.…”

“…This high percentage of hereditary PPGL makes genetic testing to identify patients and relatives at risk to (re)develop disease and thus enable tumour screening a key step in the management of these rare diseases. Although algorithms for targeted genetic testing might become redundant due to the increased efficiency and lower cost of next-generation sequencing ( Ben Aim et al 2019 , Lenders et al 2020 ), research on differences in disease presentation between sporadic and hereditary PPGL as well as on possible genotype–phenotype correlations in hereditary PPGL still is important for better surveillance and outcome prediction in patients and thus an important basis for future personalized therapy ( Crona et al 2019 , Main et al 2020 ).…”

Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma

“…All these four cases involved young patients who were not related with each other. Distinct differences were reported in the clinical and histopathological characteristics between genetic variants in SDHB ( 23 ). Our two nonrelated cases had the same novel pathogenic variant (NM_003000.3:c.262A>C) in SDHB gene with different clinical presentations ( Table 1 , cases 14 and 15) ( Figure 1 ).…”

Succinate Mediates Tumorigenic Effects via Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas

“…In addition, surgical complication rate is high, particularly for carotid body location, causing nerve damage in 48% of cases, including 17% with permanent damage (8). Also for SDHA, SDHC, and SDHD mutations, metastatic disease has been reported (9). Treatment options for inoperable cases are extremely limited and prognosis is dismal once metastases are present.…”