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“Deficiency in ELF4, X-Linked”: a Monogenic Disease Entity Resembling Behçet’s Syndrome and Inflammatory Bowel Disease

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Abstract

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet’s- and inflammatory bowel disease (IBD)-like disorder termed “deficiency in ELF4, X-linked” (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

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Acknowledgements

The authors thank the patients and their families for participation in research and all clinical care staff for their contributions. We acknowledge the Yale Cancer Center for support. Figs. 1A, 1B, and 3 were created with BioRender.com.

Funding

C.L.L. is funded by the Mathers Foundation, Rainin Foundation, NIAID/NIH, and Yale University. A.M.M. is funded by a Canada Research Chair (Tier 1) in Paediatric IBD, Canadian Institute of Health Research (CIHR) Foundation Grant, and NIDDK (RC2DK118640) grant and the Leona M. and Harry B. Helmsley Charitable Trust.

Author information

Authors and Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

    Sam J. Olyha, Molly L. Bucklin, Dinesh Babu Uthaya Kumar, Paul M. Tyler, Faiad Alam, Kate M. Jones, Hassan Sheikha & Carrie L. Lucas

  2. Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA

    Shannon K. O’Connor, Hassan Sheikha, Liza Konnikova & Saquib A. Lakhani

  3. Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Shannon K. O’Connor

  4. Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA

    Marat Kribis & Ruth R. Montgomery

  5. Division of Neonatal and Perinatal Medicine, Yale University School of Medicine, New Haven, CT, USA

    Liza Konnikova

  6. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Medical School, New Haven, CT, USA

    Liza Konnikova

  7. Program in Human and Translational Immunology, Yale University School of Medicine, New Haven, CT, USA

    Liza Konnikova & Carrie L. Lucas

  8. Pediatric Genomics Discovery Program, Yale University School of Medicine, New Haven, CT, USA

    Saquib A. Lakhani

  9. Division of Pediatric Allergy and Clinical Immunology, National Jewish Health, Denver, CO, USA

    Jason Catanzaro

  10. National Clinical Research Center for Child Health and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Hongqiang Du

  11. Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Hongqiang Du

  12. Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Hongqiang Du

  13. Department of Rheumatology & Immunology, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Hongqiang Du

  14. Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, USA

    Daniel V. DiGiacomo

  15. Division of Pediatric Rheumatology, MassGeneral for Children, Boston, MA, USA

    Holly Rothermel

  16. Division of Pediatric Gastroenterology, MassGeneral for Children, Boston, MA, USA

    Christopher J. Moran

  17. SickKids Inflammatory Bowel Disease Centre, The Hospital for Sick Children, Toronto, ON, Canada

    Karoline Fiedler & Aleixo M. Muise

  18. Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

    Karoline Fiedler, Neil Warner & Aleixo M. Muise

  19. Department of Pediatric Rheumatology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands

    Esther P.A.H. Hoppenreijs

  20. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands

    Caspar I. van der Made & Alexander Hoischen

  21. Inborn Errors of Immunity Group, Biomedicine Institute of Sevilla (IBiS), CSIC, Seville, Spain

    Peter Olbrich & Olaf Neth

  22. Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Seville, Spain

    Peter Olbrich & Olaf Neth

  23. Departamento de Farmacología, Pediatría y Radiología, Universidad de Sevilla, Seville, Spain

    Peter Olbrich

  24. Pediatric Gastroenterology, Hepatology and Nutrition Unit, Hospital Universitario Virgen del Rocío, Seville, Spain

    Alejandro Rodríguez-Martínez

  25. Unidad de Inmunología, Hospital Universitario Virgen del Rocío, Sevilla, Spain

    José Manuel Lucena Soto

  26. Erasmus MC University Medical Center-Sophia Children’s Hospital, Department of Pediatrics, Division of Infectious Diseases and Immunology, Rotterdam, The Netherlands

    Annemarie M.C. van Rossum

  27. Department of Medical Microbiology and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    Annemarie M.C. van Rossum

  28. Department of Immunology, Laboratory of Medical Immunology, Erasmus University Medical Centre, Rotterdam, The Netherlands

    Virgil A.S.H. Dalm

  29. Department of Internal Medicine, Division of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Virgil A.S.H. Dalm

  30. Academic Center for Rare Immunological Diseases (RIDC), Erasmus University Medical Center, Rotterdam, The Netherlands

    Virgil A.S.H. Dalm

  31. Department of Pediatrics, Institute of Medical Science and Biochemistry, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada

    Aleixo M. Muise

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  1. Sam J. Olyha
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  2. Shannon K. O’Connor
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  3. Marat Kribis
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  4. Molly L. Bucklin
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  6. Paul M. Tyler
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  9. Hassan Sheikha
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  10. Liza Konnikova
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  11. Saquib A. Lakhani
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  12. Ruth R. Montgomery
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  13. Jason Catanzaro
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Contributions

S.J.O. and M.K. performed experiments, analyzed data, and wrote the manuscript. S.K.O. performed CyTOF and analyzed data. M.L.B., D.B.U.K., P.M.T., and F.A. cloned ELF4 variants, performed the luciferase reporter assay, and analyzed data. K.M.J. processed samples. H.S., S.K.O., L.K., and K.F. coordinated clinical samples and data. R.R.M. oversaw experiments by S.K.O. S.A.L., N.W., C.I.vdM., and A.H. oversaw genetic analyses. J.C., H.D., E.P.A.H.H., D.V.D., H.R., C.J.M., P.O., O.N., A.R.M, J.M.L.S., A.M.C.vR., V.A.S.H.D., and A.M.M. provided clinical care and insights with genetic analyses. C.L.L. supervised overall research and data analysis, performed experiments, and wrote/edited the manuscript. All authors discussed and reviewed the manuscript.

Corresponding author

Correspondence to Carrie L. Lucas.

Ethics declarations

Ethics Approval

All human subjects in this study provided informed consent to use their samples for research and to publish de-identified data, in accordance with Helsinki principles for enrollment in research protocols that were approved by the Institutional Review Boards of Yale University, The Hospital for Sick Children, Erasmus University Medical Center, Radboud University Medical Center (regional Arnhem and Nijmegen Medical Ethics Committee), Hospital Universitario Virgen del Rocío, Children’s Hospital of Chongqing Medical University, the Children’s Hospital of Fudan University, Xiangya Hospital Central South University, West China Second University Hospital, and Shenzhen Children’s Hospital. Blood from healthy donors was also obtained under approved protocols. All relevant ethical regulations for work with human participants were followed.

Consent to Participate

All human subjects in this study provided informed consent to participate.

Consent for Publication

All human subjects in this study provided informed consent to publish de-identified data.

Competing Interests

C.L.L. reports an advisory/consulting role for Pharming Healthcare Inc. and unrelated funding support from Ono Pharma. S.A.L. is part owner of Qiyas Higher Health, a startup company unrelated to this work. All other authors declare no competing interests.

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Sam J. Olyha and Shannon K. O’Connor are co-first authors.

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Olyha, S.J., O’Connor, S.K., Kribis, M. et al. “Deficiency in ELF4, X-Linked”: a Monogenic Disease Entity Resembling Behçet’s Syndrome and Inflammatory Bowel Disease. J Clin Immunol 44, 44 (2024). https://doi.org/10.1007/s10875-023-01610-8

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