Succinate dehydrogenase (SDHB, SDHC, SDHD) gene variants significantly modify clinical outcomes in paraganglioma-pheochromocytoma but have a limited impact on head and neck paraganglioma

Purpose Succinate dehydrogenase (SDH) gene variant types differentially influence risk for thoracic-abdominal paraganglioma-pheochromocytoma (PPGL) and head and neck paraganglioma (HNPGL), but quantitative correlations are lacking. Methods In this genotype-phenotype study of 2706 patients with PPGL-HNPGL and SDH variants from 57 centres worldwide, we analysed correlations of SDHB, SDHC and SDHD variants with tumour incidence, age of diagnosis, risk of metastasis and other clinical characteristics. Results SDH variant types (missense variants vs. protein truncating variants (PTVs)) had a major differential impact on PPGLs, but little effect on HNPGLs. Combined PPGL and HNPGL (sPP&pHNPGL) was significantly more common in patients with SDHD variants, especially PTVs. Compared to PTVs, SDH missense variants showed broader clinical variability. Common vs. rare variants appeared to differentially impact clinical outcomes, including metastasis. Furthermore, specific SDH variants exhibited distinct clinical profiles. Regarding novel general findings, patients with SDHB (but not SDHC or SDHD) variants were diagnosed with PPGLs significantly earlier than HNPGLs, and paediatric cases with HNPGL showed elevated risk for metastasis and sPP&pHNPGL. We also observed an elevated risk for sPP&pHNPGL in males. Conclusion SDH variant types exhibit tissue-specific clinical differences, significantly influencing PPGL but not HNPGL clinical outcomes and underlining biological differences between precursor tissues.