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. Here, RHBDF2 is linked to palmoplantar keratoderma-esophageal carcinoma syndrome.