SDHA related phaeochromocytoma and paraganglioma: review and clinical management

Phaeochromocytomas and paragangliomas (collectively termed PPGLs) are rare yet highly heritable neuroendocrine tumours, with over one third of cases associated with germline pathogenic variants (PVs) in numerous genes. PVs in succinate dehydrogenase subunit-A gene ( SDHA ) were initially implicated in hereditary PPGL in 2010 and SDHA has since become an important susceptibility gene accounting for up to 2.8 % of cases. However, it remains poorly understood, particularly regarding the clinical nature of SDHA PPGL, rates of recurrence and metastasis, and nature of metastatic disease. We present a narrative review of SDHA -related PPGL, covering pathophysiology, relevance to current clinical practice, and considerations for clinical genetics. We analyse a pool of 107 previously reported cases of SDHA -associated PPGL to highlight the spectrum of SDHA -related PPGL. Our analysis demonstrates SDHA PPGL occurs across a wide age-range (11-81 y) and affects men and women equally. SDHA PPGL typically present as single tumours (91%), usually occurring in the head and neck (46%) or abdomen (43%, including 15% with phaeochromocytomas). Metastatic disease was reported in 25.5% cases with bone (82%) and lymph nodes (71%) being the most common sites of metastasis, often identified many years after initial diagnosis. Family history of SDHA -related neoplasia was rare, reported in only 4% of cases. Understanding the clinical nature and risks associated with SDHA PVs is essential for facilitating optimal management of patients and their families.