The most direct link between the iRhom proteins and cancer are mutations in the cytoplasmic domain of iRhom2, which cause a rare familial syndrome, tylosis with oesophageal cancer (TOC), characterised by a very high lifetime risk of developing oesophageal cancer (Blaydon et al., 2012; Ellis et al., 2015; Mokoena et al., 2018; Qu et al., 2019; Saarinen et al., 2012). This evidence concerns the gene RHBDF2 and palmoplantar keratoderma-esophageal carcinoma syndrome.