A novel X-linked disorder of immune deficiency and hypohidrotic ectodermaldysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO)

Hypohidrotic ectodermal dysplasia (HED), a congenital disorder of teeth, ha ir, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant and recessive forms exist. We hav e studied males from four families with HED and immunodeficiency (HED-ID), in which the disorder segregates as an X-linked recessive trait. Affected m ales manifest dysgammaglobulinemia and, despite therapy, have significant m orbidity and mortality from recurrent infections. Recently, mutations in IK K-gamma (NEMO) have been shown to cause familial incontinentia pigmenti (LP ). Unlike HED-ID, IP affects females and, with few exceptions, causes male prenatal lethality. Wt-gamma is required for the activation of the transcri ption factor known as "nuclear factor kappa B" and plays an important role in T and B cell function. We hypothesize that "milder" mutations at this lo cus may cause HED-ID. In all four families, sequence analysis reveals exon 10 mutations affecting the carboxy-terminal end of the IKK-gamma protein, a domain believed to connect the IKK signalsome complex to upstream activato rs. The findings define a new X-linked recessive immunodeficiency syndrome, distinct from other types of HED and immunodeficiency syndromes. The data provide further evidence that the development of ectodermal appendages is m ediated through a tumor necrosis factor/tumor necrosis factor receptor-like signaling pathway, with the IKK signalsome complex playing a significant r ole.