<i>SDHB</i> -Associated Paraganglioma in Saudi Arabia: High Metastatic Risk Linked to a Likely Founder Truncating Mutation

Abstract Context SDHB-related pheochromocytoma and paraganglioma (PPGL) are associated with a high risk of metastasis. Minimal data are available on these genetically-based tumors from the Middle East. Objective To characterize the phenotype, genotype, and outcomes of SDHB-associated PPGLs from Saudi Arabia. Methods We retrospectively reviewed a cohort of 37 patients with SDHB-associated PPGL. DNA was isolated from peripheral blood samples, and genetic testing was performed using whole-exome sequencing (WES) and confirmed by Sanger sequencing. Results We identified 37 patients with SDHB mutations, including 14 (37.8%) females and 23 males (62.2%), with a median age at diagnosis of 28 years (range 6-49). Nineteen patients (51.4%) had a positive family history of PPGL, and 18 (48.6%) were apparently sporadic but tested positive for SDHB mutations. The most common presentation was hyperadrenergic symptoms (54 %) and the most common tumor location was the upper abdomen (45.9 %). The most common SDHB mutation (likely a founder mutation) was the truncating mutation c.268T&amp;gt;C (p.R90*), which occurred in 23/37 patients (62%). This mutation was associated with high rates of locally invasive or distant metastasis (56.5%) and mortality (21.7%). At a median follow-up of 7 years, only ten patients (27%) achieved remission, seven (18.9%) died due to PPGL, one died due to leukemia, and 19 patients (51.4%) continued to have evidence of localized or metastatic disease. Conclusion In this Middle Eastern cohort, SDHB-associated PPGL were characterized by high rates of locally invasive or metastatic disease, frequently associated with a possible founder mutation (p.R90*) and substantial mortality.