Case Reports Open access

Atypical adult polyarteritis nodosa unmasking deficiency of adenosine deaminase 2: a case report about the importance of genetic testing in adults

Authors

Published
10 November 2026
Issue
Early Access
Section
Case Reports
DOI
10.4081/reumatismo.2026.2408

Abstract

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder caused by biallelic mutations in the ADA2 gene. It presents as a monogenic vasculitis with heterogeneous manifestations that often resemble small- and medium-vessel vasculitis, particularly polyarteritis nodosa (PAN)-like disease, leading to frequent misdiagnosis, especially in adults. Early recognition of DADA2 is crucial, as prompt treatment can control inflammation, preserve vascular integrity, and prevent irreversible organ damage. 

Rising awareness of the wide clinical spectrum of DADA2 is fundamental to improve recognition and facilitate timely diagnosis, ultimately enhancing prognosis. We herein describe the case of a middle-aged woman with skin lesions, central nervous system, peripheral nervous system, and gastrointestinal tract ischemic manifestations who was initially diagnosed with PAN. The patient was treated with glucocorticoids as well as several steroid-sparing immunosuppressive agents (methotrexate, azathioprine, rituximab, tocilizumab, and cyclophosphamide), which all proved to be ineffective. Meanwhile, the patient developed cytopenias and hypogammaglobulinemia. Subsequent genetic testing identified a homozygous missense mutation in the ADA2 gene (c.1358A>G, p.Tyr453Cys), supporting the diagnosis of DADA2 and enabling the initiation of effective therapy with the tumor necrosis factor-α inhibitor etanercept. This case underscores the importance of considering DADA2 in adult patients presenting with recurrent vasculitic manifestations refractory to conventional immunosuppressive therapy, as timely genetic testing can be pivotal in redirecting treatment toward targeted and effective therapy.

Keywords

References

  1. Yu H, Lin S, Li L, Li J, Chen Q, Wu Y, et al. Case report: novel ADA2 variants cause atypical adenosine deaminase 2 deficiency. Front Genet 2024; 15: 1478581. DOI: https://doi.org/10.3389/fgene.2024.1478581
  2. Hassanzadeh S, Bahadoram M, Mowla K. Deficiency of adenosine deaminase 2: a challenging differential diagnosis of polyarteritis nodosa. Reumatologia 2023; 61: 45-54. DOI: https://doi.org/10.5114/reum.2023.124878
  3. Chen KR. Cutaneous vasculitis in autoinflammatory diseases. J Dermatol 2024; 51: 150-9. DOI: https://doi.org/10.1111/1346-8138.17030
  4. Ates MB, Karup S, Ugurlu S. Infliximab as successful treatment option in a case of adenosine deaminase 2 deficiency. Reumatismo 2023; 75: 1543. DOI: https://doi.org/10.4081/reumatismo.2023.1543
  5. Öztürk A, Yagci L, Ugurlu S. Mimics and challenging presentations of DADA2. Clin Exp Immunol 2025; 219: uxaf017. DOI: https://doi.org/10.1093/cei/uxaf017
  6. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014; 370: 911-20. DOI: https://doi.org/10.1056/NEJMoa1307361
  7. Meyts I, Aksentijevich I. Deficiency of adenosine deaminase 2 (DADA2): Updates on the phenotype, genetics, pathogenesis, and treatment. J Clin Immunol 2018; 38: 569-78. DOI: https://doi.org/10.1007/s10875-018-0525-8
  8. Li GM, Han X, Wu Y, Wang W, Tang H, Lu M, et al. A cohort study on deficiency of ADA2 from China. J Clin Immunol 2023; 43: 835-45. DOI: https://doi.org/10.1007/s10875-023-01432-8
  9. 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: 405-24. DOI: https://doi.org/10.1038/gim.2015.30
  10. Lee PY, Davidson BA, Abraham RS, Alter B, Arostegui JI, Bell K, et al. Evaluation and management of deficiency of adenosine deaminase 2: an international consensus statement. JAMA Netw Open 2023; 6: e2315894. DOI: https://doi.org/10.1001/jamanetworkopen.2023.15828
  11. Wolff L, Horisberger A, Moi L, Karampetsou MP, Comte D. Polyarteritis nodosa: old disease, new etiologies. Int J Mol Sci 2023; 24: 16668. DOI: https://doi.org/10.3390/ijms242316668
  12. Maccora I, Maniscalco V, Campani S, Carrera S, Abbati G, Marrani E, et al. A wide spectrum of phenotype of deficiency of deaminase 2 (DADA2): a systematic literature review. Orphanet J Rare Dis 2023; 18: 117. DOI: https://doi.org/10.1186/s13023-023-02721-6
  13. Özen S, Batu ED, Taşkıran EZ, Özkara HA, Ünal S, Güleray N, et al. A monogenic disease with a variety of phenotypes: deficiency of adenosine deaminase 2. J Rheumatol 2020; 47: 117-25. DOI: https://doi.org/10.3899/jrheum.181384
  14. Schnappauf O, Zhou Q, Moura NS, Ombrello AK, Michael DG, Deuitch N, et al. Deficiency of adenosine deaminase 2 (DADA2): hidden variants, reduced penetrance, and unusual inheritance. J Clin Immunol 2020; 40: 917-26. DOI: https://doi.org/10.1007/s10875-020-00817-3
  15. Webster H. DADA2 as an autosomal dominant disease. Nat Rev Rheumatol 2025; 21: 650. DOI: https://doi.org/10.1038/s41584-025-01312-y
  16. Barron KS, Aksentijevich I, Deuitch NT, Stone DL, Hoffman P, Videgar-Laird R, et al. The spectrum of the deficiency of adenosine deaminase 2: an observational analysis of a 60 patient cohort. Front Immunol 2021; 12: 811473. DOI: https://doi.org/10.3389/fimmu.2021.811473
  17. Karadag O, Bolek EC, Ayan G, Mohammad AJ, Grayson PC, Pagnoux C, et al. Clinical characteristics and outcomes of polyarteritis nodosa: an international study. Arthritis Rheumatol 2024; 76: 1120-9. DOI: https://doi.org/10.1002/art.42817
  18. Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med 2020; 383: 2628-38. DOI: https://doi.org/10.1056/NEJMoa2026834

Metrics

Citations and online attention from Dimensions, Altmetric and PlumX.

PlumX Metrics

License

Copyright (c) 2026 the Author(s)

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.