Skewed X-inactivation in Incontinentia Pigmenti (IP2). A. Smahi, S. Heuertz, J.P. Bonnefont, A. Delanay, P. Vabres, A. Munnich. Genetique INSERM U393, Hopital Necker, Paris, France.

   Incontinentia Pigmenti (IP2) or Bloch-Sulzberger syndrome is a rare neurocutaneous syndrome characterized by developmental abnormalities of the tissues and organs derived from the embryonic neuroectoderm. The mode of inheritance is X-linked, dominant, with male lethality. Highly skewed X-inactivation has been observed in peripheral blood leukocytes and fibroblasts of IP2 patients (Migeon B.R., et al., 1989; Harris A., et al., 1992; Parrish et al., 1996). We analyzed the pattern of X-inactivation in blood leukocytes of a cohort of 49 sporadic and 70 familial cases of IP2. A total of 98.5% of affected females showed a non-random X-inactivation. Otherwise, a random X-inactivation was observed at the vesicular stage of the disease in two one-year-old girls. These results suggested that the apparent skewed X-inactivation is the result of selection occurring in the early postnatal development against cells expressing the mutated IP2 gene on the active X-chromosome. The study of X-inactivation allowed us to determine the parental origin of the mutant allele in sporadic cases. In 71% of sporadic cases, the paternal X-chromosome was inactivated, suggesting that the IP2 mutation occurred in the father's germline. The remaining 29% were shown to inactivate their maternal X-chromosome. Gonadal and somatic mosaicism were also occasionally noticed. These data indicate that highly skewed X-inactivation is a hallmark for IP2 and is therefore of considerable help in establishing diagnosis in "mild" IP2 phenotype. Thus, combining the X-inactivation test and linkage analysis is required for accurate genetic counseling in IP2.