Hereditary PGL/PCC Syndromes (SDHB, SDHD Mutations) ? Paraganglioma

Hereditary paraganglioma-pheochromocytoma syndromes (PGL/PCC) are genetic disorders caused by mutations in genes encoding subunits of the succinate dehydrogenase (SDH) enzyme complex, primarily SDHB and SDHD. These syndromes predispose individuals to develop paragangliomas—tumors arising from neuroendocrine cells in the autonomic nervous system that can occur in various body sites, including the head and neck, abdomen, and thorax.

SDHB mutations especially associate with a higher risk of malignant, metastatic paragangliomas often located extra-adrenally, such as in the abdomen. Conversely, SDHD mutations typically present with multiple tumors chiefly in the head and neck and tend to be less malignant. Both are inherited in an autosomal dominant pattern with variable penetrance.

The SDH enzyme links the citric acid cycle and oxidative phosphorylation pathways; mutations cause SDH dysfunction, leading to accumulation of succinate and activation of hypoxia-related pathways that promote tumorigenesis. SDHB mutation carriers often show early-onset and aggressive disease with metastatic potential and require careful genetic testing and surveillance. SDHD mutation carriers frequently develop tumors in the parasympathetic nervous system region. Management chiefly involves surgical tumor removal, while earlier detection through genetic screening can improve outcomes. Research continues to characterize specific mutation variants and their clinical implications to tailor patient care better.