We identified a novel de novo variant (c.1234C > A, p.His412Asn) in KLF4, which is located within the first zinc finger motifs of KLF4, in a patient with progressive symmetric erythrokeratodermia. By dual-luciferase reporter assay, quantitative reverse transcriptase-polymerase chain reaction and immunofluorescence, we demonstrated that the KLF4 variant is a loss-of-function mutation, and the expression of SLURP1 and DSG1, both of which are transcriptionally regulated by KLF4, was downregulated.