Intriguingly, both RSPO1, FOXL2 and PIS mutations are also associated with failure of epithelium differentiation at different specific position, palmoplantar hyperkeratosis in RSPO1-/- patients, eyelids malformation in FOXL2+/- patients and hornless in PIS-/- goats. The gene discussed is RSPO1; the disease is Palmoplantar hyperkeratosis.