Analysis of IKBKG/NEMO gene in five Japanese cases of incontinentia pigmenti with retinopathy: fine genomic assay of a rare male case with mosaicism

Haque, Muhammad Nazmul; Ohtsubo, Masafumi; Nishina, Sachiko; Nakao, Shiro; Yoshida, Kazue; Hosono, Katsuhiro; Kurata, Kentaro; Ohishi, Kentaro; Fukami, Maki; Sato, M.; Hotta, Yoshihiro; Azuma, Noriyuki; Minoshima, Shinsei

doi:10.1038/s10038-020-00836-3

Cited by 8 publications

(10 citation statements)

References 24 publications

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“…This mutation accounts for 70–80% of patients with IP worldwide ( 22 – 24 ). This is found in European ( 25 – 27 ), Chinese ( 24 , 28 ), Japanese ( 29 – 31 ), Korean ( 32 , 33 ), and Indian ( 34 ) populations ( Supplementary Table 1 ). Apart from the 11.7-kb deletion, IP can also arise due to other types of mutations along the IKBKG genes that include single nucleotide substitution, point mutation, and small insertion/deletion (indel).…”

Section: Incontinentia Pigmenti: Genetics and Pathophysiologymentioning

confidence: 82%

“…Both point mutation, as well as indel, may also cause aberrant splicing of the IKBKG mRNA. These mutations can result in the absence of or defective IKBKG protein, which yields a phenotype of IP ( 24 , 28 – 31 ). Other than mutations involving exons, a single nucleotide polymorphism involving intron 8 was also reported by Chinese populations ( 28 ).…”

Section: Incontinentia Pigmenti: Genetics and Pathophysiologymentioning

confidence: 99%

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Uncovering incontinentia pigmenti: From DNA sequence to pathophysiology

et al. 2022

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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.

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Section: Incontinentia Pigmenti: Genetics and Pathophysiologymentioning

confidence: 82%

Section: Incontinentia Pigmenti: Genetics and Pathophysiologymentioning

confidence: 99%

Uncovering incontinentia pigmenti: From DNA sequence to pathophysiology

et al. 2022

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“…Skin lesions change over the years from stage I to IV in the clinical course of IP [ 15 ]; however, his hyperpigmentation started just after his birth as “confetti” splashes and grew into streaks (like stage III lesions in IP)—and continued over eight years, which is not a typical clinical course for IP. Since IP is a disorder of X-linked dominance, a male with a pathogenic variant in the IKBKG gene is embryonically lethal, except for a few cases of male patients with mosaicism of the wild type and a pathogenic IKBKG gene or with Klinefelter syndrome (47, XXY) [ 17 , 18 , 19 , 20 , 21 ]. In this case, the proband’s karyotype was normal by G-banding, and mosaicism was not detected with clinical exome sequencing using peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

A Case of Mucopolysaccharidosis II Caused by a Novel Variant with Skin Linear Hyperpigmented Streaks along Blaschko’s Lines

Sofronova

Gurinova²,

Петухова

et al. 2023

IJMS

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We report a case of an eight-year-old boy with mucopolysaccharidosis (MPS) II with atypical skin lesions of hyperpigmented streaks along Blaschko′s lines. This case presented with mild symptoms of MPS such as hepatosplenomegaly, joint stiffness, and quite mild bone deformity, which was the reason for the delay in diagnosis until the age of seven years. However, he showed an intellectual disability that did not meet the diagnostic criteria for an attenuated form of MPS II. Iduronate 2-sulfatase activity was reduced. Clinical exome sequencing of DNA from peripheral blood revealed a novel pathogenic missense variant (NM_000202.8(IDS_v001):c.703C>A, p.(Pro235Thr)) in the IDS gene, which was confirmed in the mother with a heterozygous state. His brownish skin lesions differed from the Mongolian blue spots or “pebbling” of the skin that are observed in MPS II.

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“…The majority of IP mutations include the deletion of exons 4–10 of IKBKG . These mutations cause either partial or complete loss of function of NFκB, which results in increased susceptibility to apoptosis via activation of tumor necrosis factor α and subsequent cell death [7,8 ▪ ,9]. In males, mutations in IKBKG are typically fatal, and thus males with IP only present in rare cases, such as in Klinefelter syndrome or in cases of mosaicism [8 ▪ ].…”

Section: Pathophysiologymentioning

confidence: 99%

“…These mutations cause either partial or complete loss of function of NFκB, which results in increased susceptibility to apoptosis via activation of tumor necrosis factor α and subsequent cell death [7,8 ▪ ,9]. In males, mutations in IKBKG are typically fatal, and thus males with IP only present in rare cases, such as in Klinefelter syndrome or in cases of mosaicism [8 ▪ ]. Females who present with somatic mosaicism can have a much milder syndrome; in these patients, skin biopsy and genetic testing can help secure the diagnosis [10 ▪ ].…”

Section: Pathophysiologymentioning

confidence: 99%

Incontinentia pigmenti and the eye

Islam

Khurshid

2022

Current Opinion in Ophthalmology

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Purpose of Review:Incontinentia pigmenti (IP) is a rare X-linked dominant phakomatosis that predominately presents with dermatologic manifestations but can also cause central nervous system and ocular abnormalities. Awareness of the ocular complications of IP is crucial to identify ocular abnormalities early and prevent permanent vision loss.Recent Findings:There have been significant recent advances in ocular diagnostic imaging in IP. Optical coherence tomography (OCT) has helped characterize outer plexiform layer abnormalities in the macula, which can help explain central vision loss in IP patients. OCT angiography (OCT-A) also identifies macular vascular changes that induce these foveal structural abnormalities and may supplement fluorescein angiography, the current standard of care to identify peripheral retinal ischemia and neovascularization for infants with IP. Additionally, recent studies have presented excellent anatomic outcomes years after laser photocoagulation to ischemic retina. Early data indicates that antivascular endothelial growth factor therapy can induce retinal revascularization, but runs the risk of late recurrent neovascularization and requires long-term monitoring.Summary:Ophthalmic imaging is evolving in the evaluation of IP and is increasingly guiding treatment modalities. A particular focus on the ocular manifestations of IP has been the ideal treatment for retinopathy in this disorder.

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Analysis of IKBKG/NEMO gene in five Japanese cases of incontinentia pigmenti with retinopathy: fine genomic assay of a rare male case with mosaicism

Cited by 8 publications

References 24 publications

Uncovering incontinentia pigmenti: From DNA sequence to pathophysiology

Uncovering incontinentia pigmenti: From DNA sequence to pathophysiology

A Case of Mucopolysaccharidosis II Caused by a Novel Variant with Skin Linear Hyperpigmented Streaks along Blaschko’s Lines

Incontinentia pigmenti and the eye

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