Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-gamma)

Familial incontinentia pigmenti (IP [MIM 308310]), or Bloch-Sulzberger synd rome, is an X-linked dominant and male-lethal disorder. We recently demonst rated that mutations in NEMO (IKK-gamma), which encodes a critical componen t of the NF-kappaB signaling pathway, were responsible for IP. Virtually al l mutations eliminate the production of NEMO, causing the typical skewing o f X inactivation in female individuals and lethality in male individuals, p ossibly through enhanced sensitivity to apoptosis. Most mutations also give rise to classic signs of IP, but, in this report, we describe two mutation s in families with atypical phenotypes. Remarkably, each family included a male individual with unusual signs, including postnatal survival and either immune dysfunction or hematopoietic disturbance. We found two duplication mutations in these families, at a cytosine tract in exon 10 of NEMO, both o f which remove the zinc (Zn) finger at the C-terminus of the protein. Two d eletion mutations were also identified in the same tract in additional fami lies. However, only the duplication mutations allowed male individuals to s urvive, and affected female individuals with duplication mutations demonstr ated random or slight skewing of X inactivation. Similarly, NF-kappaB activ ation was diminished in the presence of duplication mutations and was compl etely absent in cells with deletion mutations. These results strongly indic ate that male individuals can also suffer from IP caused by NEMO mutations, and we therefore urge a reevaluation of the diagnostic criteria.