Aplasia Cutis Congenita Pathomechanisms Reveal Key Regulators of Skin and Skin Appendage Morphogenesis

Aplasia cutis congenita (ACC) manifests at birth as a defect of the scalp skin. New findings answer 2 longstanding questions: why ACC forms and why it affects mainly the midline scalp skin. Dominant-negative mutations in the genes KCTD1 or KCTD15 cause ACC owing to loss of function of KCTD1/KCTD15 complexes in cranial neural crest cells (NCCs), which normally form midline cranial suture mesenchymal cells that express keratinocyte growth factors. Loss of KCTD1/KCTD15 function in NCCs impairs the formation of normal midline cranial sutures and, consequently, the overlying skin, resulting in ACC. Moreover, KCTD1/KCTD15 complexes in keratinocytes regulate skin appendage morphogenesis.