Gain-of-function variants in the KDF1 gene cause hidradenitis suppurativa associated with ectodermal dysplasia by stabilizing IκB kinase α

Abstract

Keratinocyte differentiation factor (KDF)1 has been shown to cause ectodermal dysplasia with or without hidradenitis suppurativa in a single family. KDF1 is known to regulate epidermal differentiation through its interaction with IκB kinase (IKK)α. We report a novel de novo KDF1 variant (p.His254Tyr) in a 20-year-old male patient presenting with hidradenitis suppurativa and ectodermal dysplasia. We demonstrate that variants in KDF1 associated with hidradenitis suppurativa actually cause pathogenic gain-of-function of KDF1 through upregulation of IKKα. Ectodermal dysplasia may be present in a subset of individuals with hidradenitis suppurativa and should be investigated. Inhibition of IKKα appears to be a suitable therapeutic target for these individuals.