Skip to main content

Advertisement

SpringerLink
Log in

OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Here, we describe an adult female with severe fasciitis and skin necrosis who carried a private, predicted deleterious missense mutation in OTULIN in heterozygosity. OTULIN is a cellular regulator of deubiquitination that has been shown to play a key role in intrinsic immunity against staphylococcal α-toxin. The patient was treated with broad-spectrum antibiotics, and multiple surgical explorations were conducted without clinical response. Since autoinflammation was the predominant clinical feature, TNF inhibition was started with a good clinical response. We show that excessive inflammation in OTULIN haploinsufficiency can be effectively treated by TNF inhibition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data Availability

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

References

  1. Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB, Kulathu Y, et al. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell. 2013;153(6):1312–26. https://doi.org/10.1016/j.cell.2013.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rivkin E, Almeida SM, Ceccarelli DF, Juang YC, MacLean TA, Srikumar T, et al. The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature. 2013;498(7454):318–24. https://doi.org/10.1038/nature12296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Damgaard RB, Walker JA, Marco-Casanova P, Morgan NV, Titheradge HL, Elliott PR, et al. The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell. 2016;166(5):1215-30.e20. https://doi.org/10.1016/j.cell.2016.07.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Verboom L, Hoste E, van Loo G. OTULIN in NF-κB signaling, cell death, and disease. Trends Immunol. 2021;42(7):590–603. https://doi.org/10.1016/j.it.2021.05.003.

    Article  CAS  PubMed  Google Scholar 

  5. Clague MJ, Urbé S, Komander D. Breaking the chains: deubiquitylating enzyme specificity begets function. Nat Rev Mol Cell Biol. 2019;20(6):338–52. https://doi.org/10.1038/s41580-019-0099-1.

    Article  CAS  PubMed  Google Scholar 

  6. Lork M, Verhelst K, Beyaert R. CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different. Cell Death Differ. 2017;24(7):1172–83. https://doi.org/10.1038/cdd.2017.46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nabavi M, Shahrooei M, Rokni-Zadeh H, Vrancken J, Changi-Ashtiani M, Darabi K, et al. Auto-inflammation in a patient with a novel homozygous OTULIN mutation. J Clin Immunol. 2019;39(2):138–41. https://doi.org/10.1007/s10875-019-00599-3.

    Article  CAS  PubMed  Google Scholar 

  8. Zhou Q, Yu X, Demirkaya E, Deuitch N, Stone D, Tsai WL, et al. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci U S A. 2016;113(36):10127–32. https://doi.org/10.1073/pnas.1612594113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Spaan AN, Neehus AL, Laplantine E, Staels F, Ogishi M, Seeleuthner Y, et al. Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin. Science. 2022;376(6599):eabm6380. https://doi.org/10.1126/science.abm6380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Arts P, Simons A, AlZahrani MS, Yilmaz E, AlIdrissi E, van Aerde KJ, et al. Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies. Genome Med. 2019;11(1):38. https://doi.org/10.1186/s13073-019-0649-3.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bousfiha A, Moundir A, Tangye SG, Picard C, Jeddane L, Al-Herz W, et al. The 2022 update of IUIS phenotypical classification for human inborn errors of immunity. J Clin Immunol. 2022;42(7):1508–20. https://doi.org/10.1007/s10875-022-01352-z.

    Article  PubMed  Google Scholar 

  12. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016;99(4):877–85. https://doi.org/10.1016/j.ajhg.2016.08.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5. https://doi.org/10.1038/ng.2892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43. https://doi.org/10.1038/s41586-020-2308-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. https://doi.org/10.1038/gim.2015.30.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wallis YL, Payne SJ, Mcanulty C, Bodmer D, Sister-mans E, Robertson K, et al. Practice guidelines for the evaluation of pathogenicity and the reporting of sequence variants in clinical molecular genetics. 2013.

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Radboud Institute of Molecular Life Sciences (RIMLS) and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands

    Rob J. W. Arts, Caspar I. van der Made, Marianne M. C. Hendriks, Wouter A. van der Heijden, Quirijn de Mast, Catharina M. Mulders-Manders & Frank L. van de Veerdonk

  2. Department of Medicine (463), Radboud University Nijmegen Medical Center, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, Netherlands

    Rob J. W. Arts, Marianne M. C. Hendriks, Quirijn de Mast, Catharina M. Mulders-Manders & Frank L. van de Veerdonk

  3. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 CX, Utrecht, Netherlands

    Tristan J. van der Linden & András N. Spaan

  4. Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands

    Caspar I. van der Made, Janneke H. M. Schuurs-Hoeijmakers & Annet Simons

Authors
  1. Rob J. W. Arts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tristan J. van der Linden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caspar I. van der Made
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marianne M. C. Hendriks
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wouter A. van der Heijden
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Quirijn de Mast
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Janneke H. M. Schuurs-Hoeijmakers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Annet Simons
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. András N. Spaan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Catharina M. Mulders-Manders
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Frank L. van de Veerdonk
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. All authors took part in the clinical care and diagnosis and treatment of the patient, except for T.J.v.d.L. and A.N.S. who did the functional analysis and measurement of α-toxin antibodies. The first draft of the manuscript was written by R.J.W.A., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Rob J. W. Arts.

Ethics declarations

Ethics Approval

This is an observational study, so no ethical approval is required.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Consent for Publication

The authors affirm that the patient provided informed consent for publication of the images in Fig. 1.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arts, R.J.W., van der Linden, T.J., van der Made, C.I. et al. OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition. J Clin Immunol 44, 10 (2024). https://doi.org/10.1007/s10875-023-01630-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10875-023-01630-4

Keywords

Search

Navigation