Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome

Incontinentia pigmenti (IP), or "Bloch-Sulzberger syndrome," is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. I P results from mutations in the gene for NF-kappaB essential modulator (NEM O), with deletion of exons 4-10 of NEMO accounting for >80% of new mutation s. Male fetuses inheriting this mutation and other "null" mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male p atients with skin, dental, and ocular abnormalities typical of those seen i n female patients with IP (without immunodeficiency) are rare. We investiga ted four male patients with clinical hallmarks of IP. All four were found t o carry the deletion normally associated with male lethality in utero. Surv ival in one patient is explained by a 47, XXY karyotype and skewed X inacti vation. Three other patients possess a normal 46, XY karyotype. We demonstr ate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repea t-mediated rearrangement leading to the common deletion does not require me iotic division. Hypomorphic alleles, a 47, XXY karyotype, and somatic mosai cism therefore represent three mechanisms for survival of males carrying a NEMO mutation.