Mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, 
kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential 
modulator (NEMO), gene are the most common single cause of incontinentia 
pigmenti (IP) in females and anhydrotic ectodermal dysplasia with 
immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 
chromosomal region, encodes for the regulatory subunit of the inhibitor of 
kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB 
pathway. Therefore, the remarkably heterogeneous and often severe clinical 
presentation reported in IP is due to the pleiotropic role of this signaling 
transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG 
gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG 
rearrangement found in IP females (which is lethal in males), a total of 69 
different small mutations (missense, frameshift, nonsense, and splice-site 
mutations) have been reported, including 13 novel ones in this work. The updated 
distribution of all the IP- and EDA-ID-causing mutations along the IKBKG gene 
highlights a secondary hotspot mutation in exon 10, which contains only 11% of 
the protein. Furthermore, familial inheritance analysis revealed an unexpectedly 
high incidence of sporadic cases (>65%). The sum of the observations can aid 
both in determining the molecular basis of IP and EDA-ID allelic diseases, and 
in genetic counseling in affected families.