De Novo KRT9 p.Leu458Pro in Infantile-Onset pEDD: Reclassification as Likely Pathogenic

Abstract

KRT9-palmoplantar epidermal differentiation disorder (KRT9-pEDD) is a rare autosomal dominant genodermatosis, characterized by infantile-onset diffuse thickening of the palmoplantar epidermis with sharp erythematous margins and fissuring. This condition is caused by pathogenic variants in KRT9, which encodes keratin 9, a type I keratin filament that plays a role in the structural integrity of terminally differentiated palmoplantar epidermis. We report a patient with infantile-onset clinical pEDD who underwent genetic testing in adulthood, revealing a rare KRT9:c.1373T>C (p.Leu458Pro). To our knowledge, this variant has been reported only once previously in the literature, where it was classified as a variant of uncertain significance. In the present case, application of ACMG criteria supports reclassification of this variant as likely pathogenic. This report expands on the limited data on KRT9-associated pEDD, provides additional clinical evidence supporting pathogenicity of a rare variant, and underscores the importance of retrospective genetic testing as variant databases and classification standards evolve.