Recent progress in the genetics of incontinentia pigmenti (Bloch-Sulzberger syndrome)

Incontinentia pigmenti (IP) is a rare disorder which affects organs and tis sues of ectodermal and mesodermal origin. It is characterized by swirled pa tterns of hyperpigmentation. In some cases, the condition is also associate d with malformations of the teeth, nails, skeleton, hair, eyes, and the cen tral nervous system. The disorder is inherited as an X-linked dominant trai t and mostly affects females, However, there have been several cases of IP in males that survived to birth. While IP in females could be caused by a s kewed pattern of X-inactivation, three mechanisms: namely, the half-chromat id hypothesis, unstable premutation, and a higher rate of de-novo germline mutations, have been proposed to explain the survival of affected male pati ents. Cytogenetic studies in several sporadic cases with signs similar to I P exhibited an X/autosomal translocation involving a breakpoint at Xp11, su ggesting a gene locus on Xp11 (IP1). Linkage analysis of familial IF, on th e other hand, has identified a second locus, in the Xq28 region (IP2), Mole cular genetic analysis of two candidate genes located at Xp11 and Xq28, as well as the human homologue of the murine Str gene, failed to reveal any di sease-causing mutations. Although heterozygous female mice deficient for th e IKK gamma /NEMO gene exhibited dermatopathy similar to that in human IP, studies of the gene in human IP have not yet been available. In an effort t o isolate the genes causing IP, cosmid clones containing the translocation breakpoint located at Xp11 and the transcriptional map of the Xq28 region w ere constructed. These maps could be invaluable tools in the identification of genes in the near future.