AREG and palmoplantar keratoderma-esophageal carcinoma syndrome: Together, these data suggest that, analogous to the phenomena in human TOC mutations, Rhbdf2P159L/P159L is a GOF mutation in the mouse Rhbdf2 gene, and that these GOF mutations enhance secretion of AREG and lead to constitutive activation of EGFR signaling to cause TOC.