Gain-of-function (GOF) mutations in the human rhomboid 5 homolog 2 (RHBDF2) gene constitutively activate epidermal growth factor receptor (EGFR) signaling to cause tylosis with esophageal cancer syndrome (TOC; OMIM: 148500) (Blaydon et al., 2012; Saarinen et al., 2012; Mokoena et al., 2018). Here, RHBDF2 is linked to palmoplantar keratoderma-esophageal carcinoma syndrome.