Uncovering incontinentia pigmenti: From DNA sequence to pathophysiology

Abstract

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis. The disease is known to be caused by recurrent deletion of exons 4–10 of the Inhibitor Of Nuclear Factor Kappa B Kinase Regulatory Subunit Gamma (IKBKG) gene located at the Xq28 chromosomal region, which encodes for NEMO/IKKgamma, a regulatory protein involved in the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays a prominent role in the modulation of cellular proliferation, apoptosis, and inflammation. IKBKG mutation that results in a loss-of-function or dysregulated NF-κB pathway contributes to the pathophysiology of IP. Aside from typical skin characteristics such as blistering rash and wart-like skin growth presented in IP patients, other clinical manifestations like central nervous system (CNS) and ocular anomalies have also been detected. To date, the clinical genotype-phenotype correlation remains unclear due to its highly variable phenotypic expressivity. Thus, genetic findings remain an essential tool in diagnosing IP, and understanding its genetic profile allows a greater possibility for personalized treatment. IP is slowly and gradually gaining attention in research, but there is much that remains to be understood. This review highlights the progress that has been made in IP including the different types of mutations detected in various populations, current diagnostic strategies, IKBKG pathophysiology, genotype-phenotype correlation, and treatment strategies, which provide insights into understanding this rare mendelian disorder.

Central nervous system anomalies in 41 Chinese children incontinentia pigmenti

“…Mutations in the IKBKG (formerly known as NEMO/IKKγ ) gene located at Xq28 have been found to cause the disease expression [ 4 , 6 ]. The most common genetic mutation in IP is an approximately 11.7-kb deletion in the IKBKG gene that removes exons 4 through 10.…”

Incorporating Nanopore Sequencing into a Diverse Diagnostic Toolkit for Incontinentia Pigmenti

“…Furthermore, studies on genotype-phenotype correlations are very rare and suggest that variant type, affected domain, status of XCI and genomic background may all contribute to the high phenotypic variability reported in IP patients ranging from mild skin alterations to severe central nervous system (CNS) abnormalities 7 . Interestingly, loss-of-function variants have been shown to coincide a higher likelihood of skewed or extremely skewed XCI 26 and skewing seems to negatively correlate with disease severity and CNS involvement 27 .…”

“…The former is surprising, since hyperpigmented areas of the skin develop in as much as 98% of affected females and can persist up to the fourth decade of life 25 , while hypopigmented skin areas have been suggested to be dramatically underreported in the past 24 . Furthermore, studies on genotype-phenotype correlations are very rare and suggest that variant type, affected domain, status of XCI and genomic background may all contribute to the high phenotypic variability reported in IP patients ranging from mild skin alterations to severe central nervous system (CNS) abnormalities 7 . Interestingly, loss-of-function variants have been shown to coincide a higher likelihood of skewed or extremely skewed XCI 26 and skewing seems to negatively correlate with disease severity and CNS involvement 27 .…”

“…This elimination of mutant allele-expressing cells is due to the vital role of IKBKG in the activation of NF-kB pathways that are crucial for many physiological functions, such as immune, inflammatory, anti-apoptotic and developmental pathways 6 . Cells lacking the IKBKG -encoded NEMO/IKKγ protein due to loss-of-function variants show increased sensitivity to pro-apoptotic stimuli 7 hence driving skewing of XCI. Traditionally, this can be investigated through analysis of methylation status on CpG sites of two polymorphic X-chromosomal repetitive elements near the AR and the RP2 locus, that can be used for separation of the parental alleles 8,9 .…”

Incontinentia Pigmenti: A Case Report of Early Clinical Symptoms in a Lack of Family Inheritance Positive Result

“…Previous reports have shown that incontinentia pigmenti (IP; OMIM 308300) is a very rare genetic disease with skin lesions as a typical feature, accompanied by multisystem developmental disorders, and can involve teeth, eyes, the central nervous system and other organs. 1 , 2 The incidence of this disease is 1.2 per 100,000 births. Because male patients often die in the uterus, the incidence of pigment incontinence is concentrated in female patients.…”