SDHB -associated paraganglioma in Saudi Arabia: High metastatic risk linked to a likely founder 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 outcome of SDHB-associated PPGLs in 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 (62.2%) males, 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>C (p.R90*), which occurred in 23/37 patients (62%). This mutation was associated with high rates of locally invasive and/or distant metastasis (56.5%) and mortality (21.7%). At a median follow-up of 7 years (IQR 3.5-15), only 10 patients (27%) achieved remission, 7 (18.9%) died due to PPGL, one patient died due to leukemia, and 19 patients (51.4%) continued to have evidence of locally invasive or metastatic disease. Conclusion In this Middle Eastern cohort, SDHB-associated PPGLs were characterized by high rates of locally invasive or metastatic disease, frequently associated with a possible founder mutation (p.R90*), and substantial mortality.