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An Atypical Incontinentia Pigmenti Female with Persistent Mucocutaneous Hyperinflammation and Immunodeficiency Caused by a Novel Germline IKBKG Missense Mutation

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Abstract

While most missense mutations of the IKBKG gene typically result in Ectodermal Dysplasia with Immunodeficiency, there have been rare reported instances of missense mutations of the IKBKG gene causing both Incontinentia Pigmenti (IP) and immunodeficiency in female patients. In this study, we described an atypical IP case in a 19-year-old girl, characterized by hyperpigmented and verrucous skin areas over the entire body. Remarkably, she experienced recurrent red papules whenever she had a feverish upper respiratory tract infection. Immunohistochemical staining unveiled a substantial accumulation of CD68+ macrophages alongside the TNF-α positive cells in the dermis tissue of new pustules, with increased apoptotic basal keratinocytes in the epidermis tissue of these lesions. Starting from the age of 8 years old, the patient suffered from severe and sustained chronic respiratory mucous membrane scar hyperplasia and occluded subglottic lumen. In addition to elevated erythrocyte sedimentation rate values, inflammatory cells were observed in the pathologic lesions of endobronchial biopsies and Bronchoalveolar Lavage Fluid (BALF) smear. Further histological analysis revealed a destructive bronchus epithelium integrity with extensive necrosis. Simultaneously, the patient experienced recurrent incomplete intestinal obstructions and lips contracture. The patient’s BALF sample displayed an augmented profile of proinflammatory cytokines and chemokines, suggesting a potential link to systemic hyperinflammation, possibly underlying the pathogenic injuries affecting the subglottic, respiratory, and digestive systems. Furthermore, the patient presented with recurrent pneumonias and multiple warts accompanied by a T+BlowNKlow immunophenotype. Next generation sequencing showed that the patient carried a novel de novo germline heterozygous missense mutation in the IKBKG gene (c. 821T>C, p. L274P), located in the highly conserved CC2 domain. TA-cloning sequencing of patient’s cDNA yielded 30 mutant transcripts out of 44 clones. In silico analysis indicated that the hydrogen bond present between Ala270 and Leu274 in the wild-type NEMO was disrupted by the Leu274Pro mutation. However, this mutation did not affect NEMO expression in peripheral blood mononuclear cells (PBMCs). Moreover, patient PBMCs exhibited significantly impaired TNF-α production following Lipopolysaccharide (LPS) stimulation. X-chromosome inactivation in T cells and neutrophils were not severely skewed. Reduced levels of IκBα phosphorylation and degradation in patient's PBMCs were observed. The NF-κB luciferase reporter assay conducted using IKBKG-deficient HEK293T cells revealed a significant reduction in NF-kB activity upon LPS stimulation. These findings adds to the ever-growing knowledge on female IP that might contribute to the better understanding of this challenging disorder.

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Funding

This study was supported by grants from National Natural Science Foundation of China (No. 82173084, 82002129) and the fourth batch of public welfare and development from Beijing Municipal Health Commission (No. 2021-9).

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Authors and Affiliations

  1. Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China

    Wenjun Mou & Jingang Gui

  2. Department of Pulmonology, Beijing Children’s Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children’s Health, Beijing, 100045, China

    Zhipeng Zhao, Liwei Gao, Yan Guo, Lanqin Chen, Hao Wang, Jun Liu, Qiang Qin, Baoping Xu, Xiuyun Liu & Jianxin He

  3. Department of Pathology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China

    Libing Fu

  4. Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Jia Li

  5. Department of Interventional Pulmonology, Beijing Children’s Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children’s Health, Beijing, 100045, China

    Anxia Jiao

  6. Department of Radiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, China

    Yun Peng & Tong Yu

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  1. Wenjun Mou
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Contributions

WM, JH, JG, and XL designed most of the studies. WM carried out much of the work together with JH, ZZ, LG, LF, JL, AJ, YP, TY, YG, LC, HW, JL, QQ, and BX. WM, JH, JG, and XL analyzed the data. WM drafted the manuscript and all authors approved the final manuscript.

Corresponding authors

Correspondence to Xiuyun Liu, Jianxin He or Jingang Gui.

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Ethics Approval

The studies involving human participants were reviewed and approved by Medical Ethics Committee of Beijing Children’s Hospital.

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Clinical information and blood samples were collected from the patient, the parents, and controls, all of whom had given their prior informed consent to participation in the study. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

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Supplementary Information

ESM 1

Supplementary Figure 1. Persistent microcytic hypochromic anemia. (A-B) Air-conduction (AC) and bone-conduction (BC) pure tone averages (PTA) were calculated based on four-point values at 500, 1000, 2000, and 3000 Hz in accordance with the American Academy of Otolaryngology-Head and Neck Surgery Hearing Committee minimal reporting standards. The AC-PTA and BC-PTA of left ear (A) was 120 and 67.5 dB, respectively while the AC-PTA and BC-PTA of right ear (B) was 115 and 67.5 dB, respectively. (C) Blood HGB value during therapy. (D) Blood MCHC value during therapy. (E) Blood MCV value during therapy.

ESM 2

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Mou, W., Zhao, Z., Gao, L. et al. An Atypical Incontinentia Pigmenti Female with Persistent Mucocutaneous Hyperinflammation and Immunodeficiency Caused by a Novel Germline IKBKG Missense Mutation. J Clin Immunol 43, 2165–2180 (2023). https://doi.org/10.1007/s10875-023-01564-x

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