In addition to proliferative defects, we unexpectedly identified a requirement for WNT10A/β-catenin signalling in permitting regionally restricted, suprabasal differentiation programmes in tongue filiform papillae and palmoplantar epidermis, explaining the smooth tongue and palmoplantar keratoderma phenotypes observed in human patients. Here, WNT10A is linked to hereditary palmoplantar keratoderma.