Pheochromocytomas and
paragangliomas are
catecholamine-secreting
tumors of neural crest origin caused by germline mutations in at least six distinct genes. This genetic heterogeneity has provided a rich source for both the discovery and functional characterization of new
tumor-related genes. However, the genetic repertoire of these
tumors is still not fully known, and current evidence points to the existence of additional
pheochromocytoma susceptibility genes. Here, the unique contributions of three hereditary models of
pheochromocytoma that can advance our knowledge of the disease pathogenesis are presented. The first model, loss of
succinate dehydrogenase (SDH) function, illustrates how SDHB, C, or D mutations, components of the energy metabolism pathway, serve as a unique system to explore the pervasive metabolic shift of
cancer cells towards glycolysis as a source of energy (also known as the Warburg effect) in contrast to the characteristic oxidative phosphorylation of normal cells. In the second model, mechanisms of
tumorigenesis distinct from classical
pheochromocytoma susceptibility genes are discussed in the context of a novel putative suppressor of
neural crest-derived tumors, the KIF1B beta gene. Finally, NF1 loss is highlighted as a valuable study model to investigate the cell lineage selectivity of the Egln3-mediated developmental apoptotic defect of chromaffin precursor cells. Results from these studies may offer clues to understand the tissue specificity of hereditary
pheochromocytoma syndromes. These distinct
hereditary disease models illustrate how genetic-driven progress has the potential to narrow current gaps in our knowledge of
pheochromocytoma and
paraganglioma pathogenesis.