EDA-ID and IP, Two Faces of the Same Coin: How the Same IKBKG/NEMO Mutation Affecting the NF-κB Pathway Can Cause Immunodeficiency and/or Inflammation

Anhidrotic Ectodermal Dysplasia with ImmunoDeficiency (EDA-ID, OMIM 300291) and Incontinentia Pigmenti (IP, OMIM 308300) are two rare diseases, caused by mutations of the IKBKG/NEMO gene. The protein NEMO/IKK gamma is essential for the NF-kappa B activation pathway, involved in a variety of physiological and cellular processes, such as immunity, inflammation, cell proliferation, and survival. A wide spectrum of IKBKG/NEMO mutations have been identified so far, and, on the basis of their effect on NF-kappa B activation, they are considered hypomorphic or amorphic (loss of function) mutations. IKBKG/NEMO hypomorphic mutations, reducing but not abolishing NF-kappa B activation, have been identified in EDA-ID and IP patients. Instead, the amorphic mutations, abolishing NF-kappa B activation by complete IKBKG/NEMO gene silencing, cause only IP. Here, we present an overview of IKBKG/NEMO mutations in EDA-ID and IP patients and describe similarities and differences between the clinical/immunophenotypic and genetic aspects, high-lighting any T and B lymphocyte defect, and paying particular attention to the cellular and molecular defects that underlie the pathogenesis of both diseases.