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Adenosine Deaminase Deficient Severe Combined Immunodeficiency Presenting as Atypical Haemolytic Uraemic Syndrome

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An Erratum to this article was published on 07 March 2016

Abstract

Purpose

Adenosine deaminase (ADA) deficiency is a systemic disorder of purine metabolism. Deficiency of the purine salvage enzyme ADA leads to the build-up of the toxic metabolites, deoxyadenosine triphosphate and deoxyadenosine. ADA is ubiquitously expressed in all tissues of the body but most profoundly affects lymphocyte development and function leading to severe combined immunodeficiency (SCID). Unlike most other forms of SCID, ADA deficiency also results in non-immunologic manifestations. Associations between ADA deficiency and sensorineural hearing loss, behavioural abnormalities, non-infectious pulmonary disease and skeletal dysplasia are all recognised, and affect the long term outcome for these patients. Identification of new non-immunological manifestations and clinical presentations of ADA deficiency is essential to allow early optimisation of supportive care.

Methods and Results

Here we report four patients with ADA deficiency whose presenting feature was haemolytic uremic syndrome (HUS). 3 of 4 patients were diagnosed with ADA deficiency only after developing HUS, and one diagnosis was made post mortem, after a sibling was diagnosed with SCID. Shiga-toxigenic organisms were not isolated from any of the patients. 2 patients made a good recovery from their HUS with supportive treatment and initiation of PEG-ADA. Both remain well on enzyme replacement with mild or no residual renal impairment.

Conclusions

Clinicians should be aware of this previously unreported non-immunologic manifestation of ADA deficiency.

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References

  1. Sauer AV, Brigida I, Carriglio N, Aiuti A. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol. 2012;3:265.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972;2(7786):1067–9.

    Article  CAS  PubMed  Google Scholar 

  3. Hirschhorn R, Ratech H. Isozymes of adenosine deaminase. Isozymes Curr Top Biol Med Res. 1980;4:131–57.

    CAS  PubMed  Google Scholar 

  4. Hirschhorn R, Nicknam MN, Eng F, Yang DR, Borkowsky W. Novel deletion and a new missense mutation (Glu 217 Lys) at the catalytic site in two adenosine deaminase alleles of a patient with neonatal onset adenosine deaminase- severe combined immunodeficiency. J Immunol. 1992;149(9):3107–12.

    CAS  PubMed  Google Scholar 

  5. Apasov SG, Blackburn MR, Kellems RE, Smith PT, Sitkovsky MV. Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest. 2001;108(1):131–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Van De Wiele CJ, Vaughn JG, Blackburn MR, Ledent CA, Jacobson M, Jiang H, et al. Adenosine kinase inhibition promotes survival of fetal adenosine deaminase-deficient thymocytes by blocking dATP accumulation. J Clin Invest. 2002;110(3):395–402.

    Article  Google Scholar 

  7. Van De Wiele CJ, Joachims ML, Fesler AM, Vaughn JG, Blackburn MR, McGee ST, et al. Further differentiation of murine double-positive thymocytes is inhibited in adenosine deaminase-deficient murine fetal thymic organ culture. J Immunol. 2006;176(10):5925–33.

    Article  Google Scholar 

  8. Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood. 2009;114(17):3524–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ozsahin H, Arredondo-Vega FX, Santisteban I, Fuhrer H, Tuchschmid P, Jochum W, et al. Adenosine deaminase deficiency in adults. Blood. 1997;89(8):2849–55.

    CAS  PubMed  Google Scholar 

  10. Bollinger ME, Arredondo-Vega FX, Santisteban I, Schwarz K, Hershfield MS, Lederman HM. Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency. N Engl J Med. 1996;334(21):1367–71.

    Article  PubMed  Google Scholar 

  11. Ratech H, Hirschhorn R, Greco MA. Pathologic findings in adenosine deaminase deficient-severe combined immunodeficiency. II. Thymus, spleen, lymph node, and gastrointestinal tract lymphoid tissue alterations. Am J Pathol. 1989;135(6):1145–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Sauer AV, Mrak E, Hernandez RJ, Zacchi E, Cavani F, Casiraghi M, et al. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood. 2009;114(15):3216–26.

    Article  CAS  PubMed  Google Scholar 

  13. Booth C, Algar VE, Xu-Bayford J, Fairbanks L, Owens C, Gaspar HB. Non-infectious lung disease in patients with adenosine deaminase deficient severe combined immunodeficiency. J Clin Immunol. 2012;32(3):449–53.

    Article  CAS  PubMed  Google Scholar 

  14. Ratech H, Greco MA, Gallo G, Rimoin DL, Kamino H, Hirschhorn R. Pathologic findings in adenosine deaminase-deficient severe combined immunodeficiency. I. Kidney, adrenal, and chondro-osseous tissue alterations. Am J Pathol. 1985;120(1):157–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Cederbaum SD, Kaitila I, Rimoin DL, Stiehm ER. The chondro-osseous dysplasia of adenosine deaminase deficiency with severe combined immunodeficiency. J Pediatr. 1976;89(5):737–42.

    Article  CAS  PubMed  Google Scholar 

  16. Albuquerque W, Gaspar HB. Bilateral sensorineural deafness in adenosine deaminase-deficient severe combined immunodeficiency. J Pediatr. 2004;144(2):278–80.

    Article  PubMed  Google Scholar 

  17. Hirschhorn R, Paageorgiou PS, Kesarwala HH, Taft LT. Amerioration of neurologic abnormalities after “enzyme replacement” in adenosine deaminase deficiency. N Engl J Med. 1980;303(7):377–80.

    Article  CAS  PubMed  Google Scholar 

  18. Honig M, Albert MH, Schulz A, Sparber-Sauer M, Schutz C, Belohradsky B, et al. Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications. Blood. 2007;109(8):3595–602.

    Article  PubMed  Google Scholar 

  19. Titman P, Pink E, Skucek E, O’Hanlon K, Cole TJ, Gaspar J, et al. Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies. Blood. 2008;112(9):3907–13.

    Article  CAS  PubMed  Google Scholar 

  20. Grunebaum E, Cutz E, Roifman CM. Pulmonary alveolar proteinosis in patients with adenosine deaminase deficiency. J Allergy Clin Immunol. 2012;129(6):1588–93.

    Article  CAS  PubMed  Google Scholar 

  21. Manson D, Diamond L, Oudjhane K, Hussain FB, Roifman C, Grunebaum E. Characteristic scapular and rib changes on chest radiographs of children with ADA-deficiency SCIDS in the first year of life. Pediatr Radiol. 2013;43(5):589–92.

    Article  PubMed  Google Scholar 

  22. Wakamiya M, Blackburn MR, Jurecic R, McArthur MJ, Geske RS, Cartwright Jr J, et al. Disruption of the adenosine deaminase gene causes hepatocellular impairment and perinatal lethality in mice. Proc Natl Acad Sci U S A. 1995;92(9):3673–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gaspar HB. Bone marrow transplantation and alternatives for adenosine deaminase deficiency. Immunol Allergy Clin N Am. 2010;30(2):221–36.

    Article  Google Scholar 

  24. Taylor CM, Machin S, Wigmore SJ, Goodship TH. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol. 2010;148(1):37–47.

    Article  CAS  PubMed  Google Scholar 

  25. Constantinescu AR, Bitzan M, Weiss LS, Christen E, Kaplan BS, Cnaan A, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004;43(6):976–82.

    Article  PubMed  Google Scholar 

  26. Besbas N, Karpman D, Landau D, Loirat C, Proesmans W, Remuzzi G, et al. A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int. 2006;70(3):423–31.

    Article  CAS  PubMed  Google Scholar 

  27. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361(17):1676–87.

    Article  CAS  PubMed  Google Scholar 

  28. Jokiranta TS, Zipfel PF, Fremeaux-Bacchi V, Taylor CM, Goodship TJ, Noris M. Where next with atypical hemolytic uremic syndrome? Mol Immunol. 2007;44(16):3889–900.

    Article  CAS  PubMed  Google Scholar 

  29. Hirt-Minkowski P, Dickenmann M, Schifferli JA. Atypical hemolytic uremic syndrome: update on the complement system and what is new. Nephron Clin Pract. 2010;114(4):c219–35.

    Article  PubMed  Google Scholar 

  30. Bu F, Maga T, Meyer NC, Wang K, Thomas CP, Nester CM, et al. Comprehensive genetic analysis of complement and coagulation genes in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2014;25(1):55–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bu F, Borsa N, Gianluigi A, Smith RJ. Familial atypical hemolytic uremic syndrome: a review of its genetic and clinical aspects. Clin Dev Immunol. 2012;2012:370426.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Rees L. Atypical HUS: time to take stock of current guidelines and outcome measures? Pediatr Nephrol. 2013;28(5):675–7.

    Article  PubMed  Google Scholar 

  33. Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zimmerhackl LB, Besbas N, Jungraithmayr T, Van de Kar N, Karch H, Karpman D, et al. Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost. 2006;32(2):113–20.

    Article  PubMed  Google Scholar 

  35. Migchielsen AA, Breuer ML, van Roon MA, te Riele H, Zurcher C, Ossendorp F, et al. Adenosine-deaminase-deficient mice die perinatally and exhibit liver-cell degeneration, atelectasis and small intestinal cell death. Nat Genet. 1995;10(3):279–87.

    Article  CAS  PubMed  Google Scholar 

  36. Churchill PC, Bidani AK. Hypothesis: adenosine mediates hemodynamic changes in renal failure. Med Hypotheses. 1982;8(3):275–85.

    Article  CAS  PubMed  Google Scholar 

  37. Fredholm BB. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. 2007;14(7):1315–23.

    Article  CAS  PubMed  Google Scholar 

  38. Loirat C, Noris M, Fremeaux-Bacchi V. Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2008;23(11):1957–72.

    Article  PubMed  Google Scholar 

  39. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5(10):1844–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Printza N, Sapountzi E, Dotis J, Papachristou F. Hemolytic uremic syndrome related to cryptosporidium infection in an immunocompetent child. Pediatr Int. 2013;55(6):788–90.

    Article  PubMed  Google Scholar 

  41. Nester CM, Thomas CP. Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated? Hematol Am Soc Hematol Educ Program. 2012;2012:617–25.

    Google Scholar 

  42. Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010;31(6):E1445–60.

    Article  CAS  PubMed  Google Scholar 

  43. Guigonis V, Fremeaux-Bacchi V, Giraudier S, Favier R, Borderie D, Massy Z, et al. Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. Am J Kidney Dis. 2005;45(3):588–95.

    Article  CAS  PubMed  Google Scholar 

  44. Salmon JE, Heuser C, Triebwasser M, Liszewski MK, Kavanagh D, Roumenina L, et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 2011;8(3):e1001013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dragon-Durey MA, Loirat C, Cloarec S, Macher MA, Blouin J, Nivet H, et al. Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16(2):555–63.

    Article  CAS  PubMed  Google Scholar 

  46. Skerka C, Jozsi M, Zipfel PF, Dragon-Durey MA, Fremeaux-Bacchi V. Autoantibodies in haemolytic uraemic syndrome (HUS). Thromb Haemost. 2009;101(2):227–32.

    CAS  PubMed  Google Scholar 

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Acknowledgments

HBG acknowledges the support of the Great Ormond Street Hospital Children’s charity.

Conflict of Interest Disclosure

HBG has been an occasional consultant for Enzon Inc., former manufacturers of PEG-ADA. The remaining authors have no competing interests.

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    Authors and Affiliations

    1. Department of Clinical Immunology and Bone Marrow Transplantation, Great Ormond Street Hospital National Health Service Trust, London, UK

      Olga Nikolajeva, Austen Worth, Stuart Adams, E. Graham Davies & H. Bobby Gaspar

    2. Department of Paediatric Immunology and Infectious Diseases, Royal Hospital for Sick Children (Yorkhill), Glasgow, UK

      Rosie Hague

    3. Department of Paediatric Infectious Diseases and Immunology, Guy’s and St Thomas’s NHS Trust, London, UK

      Nuria Martinez-Alier

    4. Department of Allergy and Immunology, Royal Children’s Hospital, Melbourne, Australia

      Joanne Smart

    5. Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK

      H. Bobby Gaspar

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    1. Olga Nikolajeva
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    Correspondence to H. Bobby Gaspar.

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    Olga Nikolajeva and Austen Worth contributed equally to this work.

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    Nikolajeva, O., Worth, A., Hague, R. et al. Adenosine Deaminase Deficient Severe Combined Immunodeficiency Presenting as Atypical Haemolytic Uraemic Syndrome. J Clin Immunol 35, 366–372 (2015). https://doi.org/10.1007/s10875-015-0158-0

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    • DOI: https://doi.org/10.1007/s10875-015-0158-0

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