The strongest and most direct evidence for the involvement of iRhom2 in human cancer is in the case of a rare inherited syndrome called tylosis with oesophageal cancer (TOC), which is caused by mutations in a small and highly conserved region within the cytoplasmic N-terminal domain of iRhom2 (Fig. 3A) (Blaydon et al., 2012). Here, RHBDF2 is linked to Non-epidermolytic palmoplantar keratoderma.