Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.

Summary We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCC/PGLs), a rare tumor type. Multi-platform integration revealed that PCC/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically-mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, NF1). We also discovered fusion genes in PCC/PGL, involving MAML3, BRAF, NGFR and NF1. Integrated analysis classified PCC/PGLs into four molecularly-defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCC/PGL included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.

Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.