We report on a family with three stillborn males, three affected males who were small for gestational age and died within 8 months, and one male who died at age 5 years. This boy had cone‐shaped teeth and oligoodontia. He had serious bacterial infections and inflammatory bowel disease. Mutations in the NF‐κB essential modulator (NEMO) gene have recently been shown to be the cause of a group of ectodermal dysplasia and immunodeficiency disorders (EDA‐ID). Analysis of the NEMO gene revealed a nucleotide change in the consensus sequence of the splicing donor site of exon 6 IVS6 + 5G → A(1027 + 5G → A), which has not previously been described in EDA‐ID. RT‐PCR analysis of fibroblast RNA from an aborted affected male fetus demonstrated a skipping of exons 4, 5, and 6 which resulted in a truncated protein of about 35 kDa revealed by NEMO antibody. The skipping of exons 4, 5, and 6 did not affect the ORF of the C‐terminal of NEMO encoded by exons 7, 8, 9, and 10, which contains a coiled‐coil motif (CC2), a leucin‐zipper (LZ), and a zinc finger motif (ZF) sub‐domains of NEMO. IκBα degradation was strongly impaired in the fetal fibroblasts, suggesting an impaired NF‐κB signaling. One healthy carrier had a completely skewed X‐inactivation pattern with the normal X active, whereas the two other carriers had a random X‐inactivation pattern. This family may represent a new phenotype within the EDA‐ID disorders. From the heterogeneity in X‐inactivation phenotype, we conclude that this mutation is not deleterious enough to be lethal for peripheral blood cells. © 2005 Wiley‐Liss, Inc.