NEMO gene rearrangement (exon 4–10 deletion) and genotype–phenotype relationship in Japanese patients with incontinentia pigmenti and review of published work in Japanese patients

Abstract

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis caused by mutations of the NEMO gene, which is required for activation of the nuclear factor-κB signaling pathway. NEMO gene rearrangement, exon 4-10 deletion, is the most common mutation with a frequency of 60-80%. Only four case reports about NEMO rearrangement in Japanese IP cases have been published. In our study, NEMO gene rearrangement was examined in 10 Japanese IP patients and their mothers and was revealed in five of 10 patients and three of their mothers. Interestingly, NEMO gene rearrangement was confirmed in the mothers of two patients without clinical symptoms; thus, NEMO mutation analysis is helpful to detect subclinical IP patients. The clinical symptoms of recently diagnosed Japanese IP patients were summarized for examination of the phenotype-genotype relationship and for comparison between those with and without NEMO gene rearrangement. Results revealed no definite difference in extracutaneous manifestations between the patients with NEMO rearrangement in our study and in other Japanese IP patients previously reported in both Japanese and English-language published work. However, there is higher frequency of ocular manifestation in our study than in other reports. Furthermore, evaluation of dental and nail abnormalities was difficult because most of our patients were observed for 1 year only. Long-term observation is needed for proper evaluation of the clinical status and phenotype-genotype relationship in IP patients.

Dental treatment considerations for a pediatric patient with incontinentia pigmenti (Bloch-Sulzberger syndrome)

“…Only few reports related to East Asian population have been published including Korea,[5] Japan,[6] China, and Taiwan. [7] From those researches, the frequency of NEMO mutation and the susceptibility to IP of Asian populations are similar to those in Western populations.…”

Questionnaire survey on association between preeclampsia and incontinentia pigmenti

“…Schematic representation of relationship between preeclampsia, incontinentia pigmenti and NEMO/IKBKG gene. : * : This article; Ref …”

“…IP is usually lethal for males, but affected females can survive with the mutant X chromosome selectively inactivated. Mutations in the NEMO/IKBKG gene located at Xq28 have been found to cause expression of the disease . There is accumulating evidence that IP might be accompanied by dysfunctions or abnormalities of the immune system.…”

“…Likewise, a negative reproductive history related to male fetus may be shared by both PE and IP. Owing to functional mosaicism from X inactivation, IP is generally lethal in males, but heterozygous females survive . Many studies had pointed out that PE is inherited through maternal lineage, and mothers with male fetuses are more likely to suffer from PE .…”

“…The 23‐kb gene contains 10 exons, with three alternative non‐coding first exons. A large deletion of NEMO/IKBKG exons 4–10 is found in approximately 80% of IP patients, whereas other mutations such as small nucleotide substitution, deletion and insertion account for a small proportion of patients …”