Skip to main content

Advertisement

Springer Nature Link
Log in

Hematologic Manifestations of Deficiency of Adenosine Deaminase 2 (DADA2) and Response to Tumor Necrosis Factor Inhibition in DADA2-Associated Bone Marrow Failure

  • Letter to Editor
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. 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(10):911–20. https://doi.org/10.1056/NEJMoa1307361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370(10):921–31. https://doi.org/10.1056/NEJMoa1307362.

    Article  PubMed  Google Scholar 

  3. Bras J, Guerreiro R, Santo GC. Mutant ADA2 in vasculopathies. N Engl J Med. 2014;371(5):478–80. https://doi.org/10.1056/NEJMc1405506#SA3.

    Article  PubMed  Google Scholar 

  4. Van Eyck L, Liston A, Mutant WC. ADA2 in vasculopathies. N Engl J Med. 2014;371(5):480.

    PubMed  Google Scholar 

  5. van Montfrans J, Zavialov A, Zhou Q. Mutant ADA2 in vasculopathies. N Engl J Med. 2014;371(5):478. https://doi.org/10.1056/NEJMc1405506#SA1.

    Article  PubMed  Google Scholar 

  6. Ben-Ami T, Revel-Vilk S, Brooks R, Shaag A, Hershfield MS, Kelly SJ, et al. Extending the clinical phenotype of adenosine deaminase 2 deficiency. J Pediatr. 2016;177:316–20. https://doi.org/10.1016/j.jpeds.2016.06.058.

    Article  CAS  PubMed  Google Scholar 

  7. Van Montfrans JM, EAR H, KPJ B, EAM H, Hak EA, Nederkoorn PJ, et al. Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford). 2016;55(5):902–10. https://doi.org/10.1093/rheumatology/kev439.

    Article  Google Scholar 

  8. Nanthapisal S, Murphy C, Omoyinmi E, Hong Y, Standing A, Berg S, et al. Deficiency of adenosine deaminase Type 2: a description of phenotype and genotype in fifteen cases. Arthritis Rheumatol (Hoboken, NJ). 2016;68(9):2314–22.

    Article  CAS  Google Scholar 

  9. Caorsi R, Penco F, Schena F, Gattorno M. Monogenic polyarteritis: the lesson of ADA2 deficiency. Pediatr Rheumatol Online J. 2016;14(1):51. https://doi.org/10.1186/s12969-016-0111-7.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Batu ED, Karadag O, Taskiran EZ, Kalyoncu U, Aksentijevich I, Alikasifoglu M, et al. A case series of adenosine deaminase 2-deficient patients emphasizing treatment and genotype-phenotype correlations. J Rheumatol. 2015;42(8):1532–4. https://doi.org/10.3899/jrheum.150024.

    Article  CAS  PubMed  Google Scholar 

  11. Uettwiller F, Sarrabay G, Rodero MP, Rice GI, Lagrue E, Marot Y, et al. ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters. RMD Open. 2016;2(1):e000236. https://doi.org/10.1136/rmdopen-2015-000236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hashem H, Egler R, Dalal J. Refractory pure red cell aplasia manifesting as deficiency of adenosine deaminase J Pediatr Hematol Oncol 2017.

  13. Maciejewski J, Selleri C, Anderson S, Young NS. Fas antigen expression on CD34+ human marrow cells is induced by interferon gamma and tumor necrosis factor alpha and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood. 1995;85(11):3183–90.

    CAS  PubMed  Google Scholar 

  14. Hara T, Ando K, Tsurumi H, Moriwaki H. Excessive production of tumor necrosis factor-alpha by bone marrow T lymphocytes is essential in causing bone marrow failure in patients with aplastic anemia. Eur J Haematol. 2004;73(1):10–6. https://doi.org/10.1111/j.1600-0609.2004.00259.x.

    Article  CAS  PubMed  Google Scholar 

  15. Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005;90(8):1128–32.

    PubMed  Google Scholar 

  16. Schepp J, Bulashevska A, Mannhardt-Laakmann W, Cao H, Yang F, Seidl M, et al. Deficiency of adenosine deaminase 2 causes antibody deficiency. J Clin Immunol. 2016;36(3):179–86. https://doi.org/10.1007/s10875-016-0245-x.

    Article  CAS  PubMed  Google Scholar 

  17. Garg N, Kasapcopur O, Foster J, Barut K, Tekin A, Kızılkılıç O, et al. Novel adenosine deaminase 2 mutations in a child with a fatal vasculopathy. Eur J Pediatr. 2014;173(6):827–30. https://doi.org/10.1007/s00431-014-2320-8.

    Article  PubMed  Google Scholar 

  18. Van Eyck L, Hershfield MS, Pombal D, Kelly SJ, Ganson NJ, Moens L, et al. Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency. J Allergy Clin Immunol. 2015;135(1):283–287.e5. https://doi.org/10.1016/j.jaci.2014.10.010.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Belot A, Wassmer E, Twilt M, Lega J-C, Zeef LA, Oojageer A, et al. Mutations in CECR1 associated with a neutrophil signature in peripheral blood. Pediatr Rheumatol Online J. 2014;12(1):44. https://doi.org/10.1186/1546-0096-12-44.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Gonzalez Santiago TM, Zavialov A, Saarela J, Seppanen M, Reed AM, Abraham RS, et al. Dermatologic features of ADA2 deficiency in cutaneous polyarteritis nodosa. JAMA Dermatol. 2015;151(11):1230–4. https://doi.org/10.1001/jamadermatol.2015.1635.

    Article  PubMed  Google Scholar 

  21. Westendorp WF, Nederkoorn PJ, Aksentijevich I, Hak AE, Lichtenbelt KD, Braun KPJ. Unexplained early-onset lacunar stroke and inflammatory skin lesions: consider ADA2 deficiency. Neurology. 2015;84(20):2092–3. https://doi.org/10.1212/WNL.0000000000001581.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fellmann F, Angelini F, Wassenberg J, Perreau M, Arenas Ramirez N, Simon G, et al. IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation. J Allergy Clin Immunol. 2016;137(4):1189-1196-2–1196.e2. https://doi.org/10.1016/j.jaci.2015.07.053.

    Article  CAS  PubMed  Google Scholar 

  23. Elbracht M, Mull M, Wagner N, Kuhl C, Abicht A, Kurth I, et al. Stroke as initial manifestation of adenosine deaminase 2 deficiency. Neuropediatrics. 2017;48(2):111–4. https://doi.org/10.1055/s-0036-1597611.

    CAS  PubMed  Google Scholar 

  24. Keer N, Hershfield M, Caskey T, Unizony S. Novel compound heterozygous variants in CECR1 gene associated with childhood onset polyarteritis nodosa and deficiency of ADA2. Rheumatology (Oxford). 2016;55(6):1145–7. https://doi.org/10.1093/rheumatology/kew050.

    Article  Google Scholar 

  25. Hsu AP, West RR, Calvo KR, Cuellar-Rodriguez J, Parta M, Kelly SJ, et al. Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: successful hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2016;138(2):628–630.e2. https://doi.org/10.1016/j.jaci.2016.03.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Poswar F de O, da Fonseca RMT, de Albuquerque LCP, Zhou Q, Jardim LB, Monte TL, et al. Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis. J Neurol. 2016;263(4):818–20. https://doi.org/10.1007/s00415-016-8070-y.

    Article  Google Scholar 

  27. Hashem H, Kumar AR, Müller I, Babor F, Bredius R, Dalal J, et al. Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2. Blood. 2017;03

  28. Sahin S, Adrovic A, Barut K, Ugurlu S, Turanli ET, Ozdogan H, et al. Clinical, imaging and genotypical features of three deceased and five surviving cases with ADA2 deficiency. Rheumatol Int 2017;

  29. Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, et al. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis. 2017;76(10):1648–56. https://doi.org/10.1136/annrheumdis-2016-210802.

    Article  PubMed  Google Scholar 

  30. Skrabl-Baumgartner A, Plecko B, Schmidt WM, König N, Hershfield M, Gruber-Sedlmayr U, et al. Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation. Pediatr Rheumatol Online J. 2017;15(1):67. https://doi.org/10.1186/s12969-017-0193-x.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Schepp J, Proietti M, Frede N, Buchta M, Hübscher K, Rojas Restrepo J, et al. Screening of 181 patients with antibody deficiency for deficiency of adenosine deaminase 2 sheds new light on the disease in adulthood. Arthritis & Rheumatol (Hoboken, NJ). 2017.

  32. Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet. 2003;362(9396):1628–30. https://doi.org/10.1016/S0140-6736(03)14797-6.

    Article  CAS  PubMed  Google Scholar 

  34. Huck K, Hanenberg H, Gudowius S, Fenk R, Kalb R, Neveling K, et al. Delayed diagnosis and complications of Fanconi anaemia at advanced age—a paradigm. Br J Haematol. 2006;133(2):188–97. https://doi.org/10.1111/j.1365-2141.2006.05998.x.

    Article  CAS  PubMed  Google Scholar 

  35. Zatterale A, Calzone R, Renda S, Catalano L, Selleri C, Notaro R, et al. Identification and treatment of late onset Fanconi’s anemia. Haematologica. 1995;80(6):535–8.

    CAS  PubMed  Google Scholar 

  36. Dokal I, Vulliamy T. Inherited aplastic anaemias/bone marrow failure syndromes. Blood Rev. 2008;22(3):141–53. https://doi.org/10.1016/j.blre.2007.11.003.

    Article  CAS  PubMed  Google Scholar 

  37. Babushok DV, Bessler M. Genetic predisposition syndromes: when should they be considered in the work-up of MDS? Best Pract Res Clin Haematol. 2015;28(1):55–68. https://doi.org/10.1016/j.beha.2014.11.004.

    Article  PubMed  Google Scholar 

  38. Chen Y, Zou Z, Wu Z, Zhao Z, Luo X, Xie C, et al. TNF-α-induced programmed cell death in the pathogenesis of acquired aplastic anemia. Expert Rev Hematol. 2015;8(4):515–26. https://doi.org/10.1586/17474086.2015.1049593.

    Article  CAS  PubMed  Google Scholar 

  39. Demeter J, Messer G, Schrezenmeier H. Clinical relevance of the TNF-alpha promoter/enhancer polymorphism in patients with aplastic anemia. Ann Hematol. 2002;81(10):566–9. https://doi.org/10.1007/s00277-002-0544-6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Michael Hershfield at the Duke University School of Medicine Department of Biochemistry for his assistance in performing plasma ADA2 analysis.

Author information

Authors and Affiliations

  1. Pediatrics and Communicable Diseases, Pediatric Hematology/Oncology, University of Michigan, 1500 E. Medical Center Drive, D4202 Medical Professional Building, Ann Arbor, MI, 48109, USA

    Thomas F. Michniacki, Mark T. Vander Lugt & Kelly J. Walkovich

  2. Pediatrics – Genetics, University of Michigan, Ann Arbor, MI, USA

    Mark Hannibal

  3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Charles W. Ross

  4. Department of Pharmacy, University of Michigan, Ann Arbor, MI, USA

    David G. Frame

  5. Pediatric Hematology/Oncology, Oregon Health Sciences University, Portland, OR, USA

    Adam S. DuVall

  6. Department of Internal Medicine, Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA

    Rami Khoriaty

Authors
  1. Thomas F. Michniacki
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Mark Hannibal
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Charles W. Ross
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. David G. Frame
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Adam S. DuVall
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Rami Khoriaty
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Mark T. Vander Lugt
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Kelly J. Walkovich
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

Dr. Michniacki drafted the manuscript with assistance from Dr. Walkovich. Drs. Hannibal, Khoriaty, Ross, Frame, DuVall, and Vander Lugt assisted in reviewing and editing the manuscript. Dr. Ross additionally provided pathology images with marrow biopsy review for patient 1 and pathology report consultation for patients 1 and 2.

Corresponding author

Correspondence to Thomas F. Michniacki.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Michniacki, T.F., Hannibal, M., Ross, C.W. et al. Hematologic Manifestations of Deficiency of Adenosine Deaminase 2 (DADA2) and Response to Tumor Necrosis Factor Inhibition in DADA2-Associated Bone Marrow Failure. J Clin Immunol 38, 166–173 (2018). https://doi.org/10.1007/s10875-018-0480-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-018-0480-4