New Insights into the Clinical Characterization of SDHAF2-related Familial Paraganglioma Syndrome

The clinical characterization of SDHAF2-related familial paraganglioma syndrome remains elusive. The aim of this study is to contribute to the knowledge of this syndrome with valuable new information.

A total of 56 individuals with the p.(Gly78Arg) variant in the SDHAF2 gene were prospectively evaluated. Of the 33 subjects who developed paragangliomas (PGLs)/pheochromocytomas (PCs) throughout follow-up, clinical, biochemical, and imaging data were collected. [68Ga]Ga-DOTA-TOC and [18F]DOPA positron emission tomography/computed tomography (PET/CT) scans were carried out on a subset of 22 patients with PGLs/PCs to compare their accuracy; surgical specimens (n = 13) were microscopically evaluated to elucidate their potential malignant behavior.

Of the 33 patients (58.9%) with SDHAF2-related tumors, 17 (51.5%) were women, with a mean age at diagnosis of 38.6 ± 17.2 years. Tumor development was found to be inherited paternally in all subjects. All the patients evaluated except 1 showed head and neck PGLs. Eleven patients (33.3%) showed mediastinal and abdominal extra-adrenal PGLs and 2 patients presented PCs. Multifocality was observed in 26 subjects (78.8%). Sixteen patients (48.5%) were asymptomatic at diagnosis. Only 4 patients with PGLs/PCs showed normetanephrine or 3-methoxytyramine secretion. Metastatic disease was observed in 2 patients (6.1%). Grading System for Adrenal Pheochromocytoma and Paraganglioma score was ≥3 in 84.6% of tumors and Pheochromocytoma of the Adrenal Gland Scaled Score was ≥4 in 69.2%. [68Ga]Ga-DOTA-TOC PET/CT showed a greater detection rate (95.7%) of multifocal PGLs and metastatic lesions than [18F]DOPA PET/CT (79.3%), as well as higher mean maximum standardized uptake value.

The current study offers new insights into the phenotypic characterization of SDHAF2-related paraganglioma syndrome including the development of extra-cervical PGLs and metastatic transformation.