Although the pathophysiology of CC is hypothesized to be attributable to a sudden, massive release of vasoactive hormones, a prospective study conducted by Condron et al. did not find a statistically significant increase in serotonin, histamine, kallikrein, or bradykinin during the crises, suggesting that CC could be an entirely separate pathophysiologic entity from CS, rather than the extreme end of a spectrum of CS [49]. Here, KLK4 is linked to Cowden syndrome 1.