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

Background: The clinical characterisation 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.

Methods: 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)/phaeochromocytomas (PCs) throughout follow-up, clinical, biochemical and imaging data were collected. [68Ga]Ga-DOTA-TOC and [18F]DOPA PET/CT scans were carried out on a subset of 22 patients with PGLs/PCs to compare their accuracy and surgical specimens (n=13) were microscopically evaluated to elucidate their potential malignant behaviour.

Results: Of the 33 patients (58.9%) with SDHAF2-related tumours, 17 (51.5%) were women, with a mean age at diagnosis of 38.6±17.2 years. Tumour development was found to be inherited paternally in all subjects. All the patients evaluated except one showed head and neck PGLs. Eleven patients (33.3%) showed mediastinal and abdominal extra-adrenal PGLs and two patients presented PCs. Multifocality was observed in 26 subjects (78.8%). Sixteen patients (48.5%) were asymptomatic at diagnosis. Only four patients with PGLs/PCs showed normetanephrine or 3-methoxytyramine secretion. Metastatic disease was observed in two patients (6.1%). GAPP score was ≥3 in 84.6% of tumours and PASS 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 SUVmax.

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