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Filaggrin-Associated Atopic Skin, Eye, Airways, and Gut Disease, Modifying the Presentation of X-Linked Reticular Pigmentary Disorder (XLPDR)

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Abstract

Background

X-linked reticular pigmentary disorder (XLPDR) is a rare condition characterized by skin hyperpigmentation, ectodermal features, multiorgan inflammation, and recurrent infections. All probands identified to date share the same intronic hemizygous POLA1 hypomorphic variant (NM_001330360.2(POLA1):c.1393-354A > G) on the X chromosome. Previous studies have supported excessive type 1 interferon (IFN) inflammation and natural killer (NK) cell dysfunction in disease pathogenesis. Common null polymorphisms in filaggrin (FLG) gene underlie ichthyosis vulgaris and atopic predisposition.

Case

A 9-year-old boy born to non-consanguineous parents developed eczema with reticular skin hyperpigmentation in early infancy. He suffered recurrent chest infections with chronic cough, clubbing, and asthma, moderate allergic rhinoconjunctivitis with keratitis, multiple food allergies, and vomiting with growth failure. Imaging demonstrated bronchiectasis, while gastroscopy identified chronic eosinophilic gastroduodenitis. Interestingly, growth failure and bronchiectasis improved over time without specific treatment.

Methods

Whole-genome sequencing (WGS) using Illumina short-read sequencing was followed by both manual and orthogonal automated bioinformatic analyses for single-nucleotide variants, small insertions/deletions (indels), and larger copy number variations. NK cell cytotoxic function was assessed using 51Cr release and degranulation assays. The presence of an interferon signature was investigated using a panel of six interferon-stimulated genes (ISGs) by QPCR.

Results

WGS identified a de novo hemizygous intronic variant in POLA1 (NM_001330360.2(POLA1):c.1393-354A > G) giving a diagnosis of XLPDR, as well as a heterozygous nonsense FLG variant (NM_002016.2(FLG):c.441del, NP_0020.1:p.(Arg151Glyfs*43)). Compared to healthy controls, the IFN signature was elevated although the degree moderated over time with the improvement in his chest disease. NK cell functional studies showed normal cytotoxicity and degranulation.

Conclusion

This patient had multiple atopic manifestations affecting eye, skin, chest, and gut, complicating the presentation of XLPDR. This highlights that common FLG polymorphisms should always be considered when assessing genotype–phenotype correlations of other genetic variation in patients with atopic symptoms. Additionally, while the patient exhibited an enhanced IFN signature, he does not have an NK cell defect, suggesting this may not be a constant feature of XLPDR.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank the patient and his family for participating in this study.

Funding

WGS was performed by the Kinghorn Centre for Clinical Genomics Sequencing Laboratory. This study was supported by the NHMRC of Australia via a Leadership 1 Investigator Grant (2017463) awarded to CSM and Leadership 3 Investigator Grant awarded to SGT. CIRCA investigators are supported by the Jeffrey Modell Foundation and the John Brown Cook Foundation.

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Author notes

  1. Paul E. Gray and Cindy S. Ma contributed equally to this work.

Authors and Affiliations

  1. Department of Allergy and Immunology, Sydney Children’s Hospital, Sydney, Australia

    Margaret W. Y. Li & Paul E. Gray

  2. School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, Australia

    Margaret W. Y. Li, Artiene Tatian, Stuart G. Tangye & Cindy S. Ma

  3. Garvan Institute of Medical Research, Sydney, Australia

    Leslie Burnett, Pei Dai, Danielle T. Avery, Stuart G. Tangye & Cindy S. Ma

  4. Clinical Immunogenomics Research Consortium Australasia (CIRCA), Sydney, Australia

    Leslie Burnett, Pei Dai, Stuart G. Tangye, Paul E. Gray & Cindy S. Ma

  5. School of Clinical Medicine, Faculty of Medicine and Health, St Vincent’s Healthcare Clinical Campus, UNSW Sydney, Sydney, Australia

    Leslie Burnett

  6. Peter MacCallum Cancer Centre, Melbourne, Australia

    Tahereh Noori & Ilia Voskoboinik

  7. Department of Ophthalmology, Sydney Children’s Hospital, Sydney, Australia

    Parth R. Shah

  8. Department of Dermatology, Sydney Children’s Hospital, Sydney, Australia

    Artiene Tatian

  9. School of Medicine, Western Sydney University, Sydney, Australia

    Paul E. Gray

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Contributions

P.E.G., M.W.Y.L., and C.S.M. designed the study and co-wrote the manuscript; all authors contributed to the revision of the final version of the manuscript and approved the final version submitted. P.E.G., M.W.Y.L., A.T., and P.S. assessed and treated the patient; L.B. and P.D. performed genomic analysis; I.V., D.T.A., and T.N. conducted experiments.

Corresponding authors

Correspondence to Margaret W. Y. Li or Paul E. Gray.

Ethics declarations

Ethics Approval

This study was carried out in accordance with the recommendations of Sydney Children’s Hospital ethics committee with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved for CIRCA—investigation of primary immunodeficiencies, by the Sydney Children’s Hospital.

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The authors affirm that human research participants provided written informed consent for participation in this study in accordance with Sydney Children’s Hospital Ethics Committee and the Declaration of Helsinki.

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The authors affirm that human research participants provided informed consent for publication, including publication of the images in Figs. 1, 2, and 3.

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The authors declare no competing interests.

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Li, M.W.Y., Burnett, L., Dai, P. et al. Filaggrin-Associated Atopic Skin, Eye, Airways, and Gut Disease, Modifying the Presentation of X-Linked Reticular Pigmentary Disorder (XLPDR). J Clin Immunol 44, 38 (2024). https://doi.org/10.1007/s10875-023-01637-x

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