Incontinentia pigmenti in a female infant with somatic mosaicism due to the IKBKG variant

概要

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis characterized by typical skin lesions along Blaschko’s lines, affecting the skin and other sites including teeth, nails, hair, eyes, and the nervous system1. It is usually lethal in affected males, but females generally survive because of X-chromosome inactivation. Approximately 80% of female patients with IP carry the IKBKG gene deletion located on chromosome Xq28. In rare cases, male patients with IP could survive if they also have Klinefelter syndrome (47, XXY) or IKBKG somatic mosaicism2 3. A 14-day-old female infant presented with blisters on her right forearm, abdomen, and thigh. She was born at term after 39 weeks and a day of pregnancy as the firstborn, without a family history of skin disorders, weighing 2,824 g, and was born out of a normal pregnancy and delivery. On day 2 after birth, she was noted to have small blisters on her right forearm. On day 4, acyclovir was administered; however, her skin condition did not improve. Physical examination revealed the presence of erythematous vesicular eruptions that were arranged linearly and that followed Blaschko’s lines on her right forearm and right lateral abdomen, with pigmentation on her right groin and thigh, and a keratotic papule on the her nipple (Figs. 1a, 1b). She showed no scalp hair loss and no abnormality in her teeth shape. No neurological or ophthalmic involvement was noted during the first 14 days. The mother was not observed for any mild symptoms that could have been indicative of IP. A skin biopsy of her right forearm revealed abundant eosinophils in intraepidermal vesicles and superficial dermis along with pigment incontinence in the dermis, which suggested IP (Figs. 1c, 1d). After obtaining informed consent from her parents, genomic DNA was extracted from the patient’s peripheral blood. Polymerase chain reaction (PCR) of IKBKG showed no exon 4_10 deletion (Fig. 1e). Multiplex ligation-dependent probe amplification revealed no insert/deletion variants. Sanger sequence analysis detected no common deletions, nucleotide alterations, or copy number variations in IKBKG. Considering the possibility of low-frequency somatic mosaicism, quantitative nested PCR of IKBKG was performed and exon 4_10 deletion was confirmed4 (Fig. 1e). The human androgen receptor (HUMARA) X-chromosome inactivation assay showed no skewed X-chromosome inactivation, suggesting that the patient had somatic mosaicism due to the IKBKG variant in IP. The overall detection of the IKBKG variant has been reported to be relatively low at 77.6% and specifically at 65% for the detection of exon 4_10 deletion because of its complex genomic structure despite IKBKG being the only causative gene for IP5. Although cases of somatic mosaicism of male IP patients have been reported2 3, a female patient with mosaicism of IP, as in our case, should be considered when patients feature much milder clinical symptoms without the detection of pathological variants of IKBKG, which will require a nested PCR study. No skewed inactivation detected in X-chromosome inactivation studies, such as the HUMARA assay for IP, would also be helpful for the consideration of low-frequency mosaicism. 4.

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