In a male infant (patient IP85) with ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291), The International Incontinentia Pigmenti Consortium (2000) identified a hemizygous c.1259A-G transition in exon 10 of the IKBKG gene, resulting in a stop420-to-trp (X420W) substitution. This change results in the addition of 27 residues to the C terminus of the mature protein. The mutation was also found in heterozygous state in his mother, who had incontinentia pigmenti (IP; 308300). In addition to recurrent infections, the boy also had osteopetrosis and lymphedema. He died at age 2.5 years from a tuberculosis infection.
Doffinger et al. (2001) studied patient IP85 reported by The International Incontinentia Pigmenti Consortium (2000) as well as another boy, of French descent, with the hemizygous X420W mutation and classified both as having anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema (OLEDAID; see 300291), which is within the phenotypic spectrum of EDAID1. Infections in the French boy, who died at the age of 1.5 years, included atypical mycobacteria and pneumococcus; he also had osteopetrosis and lymphedema, indicating that these additional features are associated with this specific mutation. His mother, who carried the mutation in heterozygous state, had mild IP. Detailed in vitro functional expression studies showed that the X420W mutation resulted in a 50 to 60% reduction of NF-kappa-B activation. Cells from both male patients with this mutation showed impaired cellular responses to LPS, IL1B, and TNFA. The findings indicated that the X420W mutation impairs, but does not abolish, NFKB activation, consistent with a hypomorphic allele and postnatal survival of the boys.
