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Expanding spectrum of DADA2: a review of phenotypes, genetics, pathogenesis and treatment

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Abstract

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in ADA2 gene (previously CECR1). The aim of this review was to describe the clinical phenotypes, genetics, pathogenesis and treatment of DADA2. ADA2 is highly expressed on myeloid cells and deficiency leads to polarisation of macrophages to an M1 inflammatory type and activation of neutrophils. The pathogenesis of immunological and haematological manifestations is less clear. The spectrum of clinical presentations varies widely from asymptomatic individual to severe vasculitis, several autoinflammatory, immunological and haematological manifestations. Initially considered a childhood disease, the first presentation is now being reported well into adulthood. Vasculitis closely resembles polyarteritis nodosa. Livedoid reticularis/racemosa like skin rash and central nervous system involvement in the form of ischemic or haemorrhagic stroke are dominant manifestations. Immunological manifestations include hypogammaglobulinemia and recurrent infections. Lymphopenia is the most common haematological manifestation; pure red cell aplasia and bone marrow failure has been reported in severe cases. The disease is extremely heterogeneous with variable severity noted in patients with the same mutation and even within family members. Tumour necrosis factor inhibitors are currently the treatment of choice for vasculitic and inflammatory manifestations and also prevent strokes. Haematopoietic stem cell transplantation is a curative option for severe haematological manifestations like pure red cell aplasia, bone marrow failure and immunodeficiency. Further research is required to understand pathogenesis and all clinical aspects of this disease to enable early diagnosis and prompt treatment.

Key Points

• Deficiency of adenosine deaminase 2 (DADA2) is a monogenic disease caused by biallelic mutations in ADA2 gene.

• The clinical features include vasculitis resembling polyarteritis nodosa, autoinflammation, haematological manifestations and immunodeficiency.

• The severity varies widely from mild to fatal even in patients within a family and with the same mutation.

• The treatment of choice for inflammatory and vasculitic disease is tumour necrosis factor α blockers. Bone marrow transplant may be considered for severe haematological disease.

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References

  1. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee CCR, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I (2014) Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 370:911–920. https://doi.org/10.1056/NEJMoa1307361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Elkan PN, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, Zlotogorski A, Berkun Y, Press JJ, Mukamel M, Voth I, Hashkes PJ, Harel L, Hoffer V, Ling E, Yalcinkaya F, Kasapcopur O, Lee MK, Klevit RE, Renbaum P, Weinberg-Shukron A, Sener EF, Schormair B, Zeligson S, Marek-Yagel D, Strom TM, Shohat M, Singer A, Rubinow A, Pras E, Winkelmann J, Tekin M, Anikster Y, King MC, Levy-Lahad E (2014) Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 370:921–931. https://doi.org/10.1056/NEJMoa1307362

    Article  CAS  Google Scholar 

  3. Meyts I, Aksentijevich I (2018) Deficiency of adenosine deaminase 2 (DADA2): Updates on the phenotype, genetics, pathogenesis, and treatment. J Clin Immunol 38:569–578. https://doi.org/10.1007/s10875-018-0525-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V, Bhatia P, Sharma V, Bhattad S, Chengappa, Gupta V, Misra DP, Chavan PP, Malaviya S, Dudam R, Sharma B, Kumar S, Bhojwani R, Gupta P, Agarwal V, Sharma K, Singhal M, Rathi M, Nada R, Minz RW, Chaturvedi V, Aggarwal A, Handa R, Grossi A, Gattorno M, Huang Z, Wang J, Jois R, Negi V, Khubchandani R, Jain S, Arostegui JI, Chambers EP, Hershfield MS, Aksentijevich I, Zhou Q, Lee PY (2020) Deficiency of adenosine deaminase 2 (DADA2) in adults and children: experience from India. Arthritis Rheumatol 73:276–285. https://doi.org/10.1002/art.41500

    Article  CAS  PubMed  Google Scholar 

  5. Van Montfrans JM, Hartman EAR, Braun KPJ, Hennekam EAM, Hak EA, Nederkoorn PJ, Westendorp WF, Bredius RGM, Kollen WJW, Schölvinck EH, Elizabeth Legger G, Meyts I, Liston A, Lichtenbelt KD, Giltay JC, Van Haaften G, De Vries Simons GM, Leavis H, Sanders CJG, Bierings MB, Nierkens S, Van Gijn ME (2016) Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford) 55:902–910. https://doi.org/10.1093/rheumatology/kev439

    Article  CAS  Google Scholar 

  6. Lee PY (2018) Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2. Front Pediatr 6:1–8. https://doi.org/10.3389/fped.2018.00282

    Article  CAS  Google Scholar 

  7. Lee PY, Kellner ES, Huang Y, Furutani E, Huang Z, Bainter W, Alosaimi MF, Stafstrom K, Platt CD, Stauber T, Raz S, Tirosh I, Weiss A, Jordan MB, Krupski C, Eleftheriou D, Brogan P, Sobh A, Baz Z, Lefranc G, Irani C, Kilic SS, El-Owaidy R, Lokeshwar MR, Pimpale P, Khubchandani R, Chambers EP, Chou J, Geha RS, Nigrovic PA, Zhou Q (2020) Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2). J Allergy Clin Immunol 145:1664–1672.e10. https://doi.org/10.1016/j.jaci.2019.12.908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Human A, Pagnoux C (2019) Diagnosis and management of ADA2 deficient polyarteritis nodosa. Int J Rheum Dis 22:69–77. https://doi.org/10.1111/1756-185X.13283

    Article  CAS  PubMed  Google Scholar 

  9. Zavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G (2010) Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J Leukoc Biol 88:279–290. https://doi.org/10.1189/jlb.1109764

    Article  CAS  PubMed  Google Scholar 

  10. Kaljas Y, Liu C, Skaldin M, Wu C, Zhou Q, Lu Y, Aksentijevich I, Zavialov AV (2017) Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells. Cell Mol Life Sci 74:555–570. https://doi.org/10.1007/s00018-016-2357-0

    Article  CAS  PubMed  Google Scholar 

  11. Karmouty-Quintana H, Xia Y, Blackburn MR (2013) Adenosine signaling during acute and chronic disease states. J Mol Med (Berl) 91:173–181. https://doi.org/10.1007/s00109-013-0997-1

    Article  CAS  Google Scholar 

  12. Haskó G, Cronstein B (2013) Regulation of inflammation by adenosine. Front Immunol 4. https://doi.org/10.3389/fimmu.2013.00085

  13. Belot A, Wassmer E, Twilt M, Lega JC, Zeef LAH, Oojageer A, Kasher PR, Mathieu AL, Malcus C, Demaret J, Fabien N, Collardeau-Frachon S, Mechtouff L, Derex L, Walzer T, Rice GI, Durieu I, Crow YJ (2014) Mutations in CECR1 associated with a neutrophil signature in peripheral blood. Pediatr Rheumatol 12:1–7. https://doi.org/10.1186/1546-0096-12-44

    Article  Google Scholar 

  14. Carmona-Rivera C, Khaznadar SS, Shwin KW, Irizarry-Caro JA, O’Neil LJ, Liu Y, Jacobson KA, Ombrello AK, Stone DL, Tsai WL, Kastner DL, Aksentijevich I, Kaplan MJ, Grayson PC (2019) Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood 134:395–406. https://doi.org/10.1182/blood.2018892752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Insalaco A, Moneta GM, Pardeo M, Caiello I, Messia V, Bracaglia C, Passarelli C, De Benedetti F (2019) Variable clinical phenotypes and relation of interferon signature with disease activity in ADA2 deficiency. J Rheumatol 46:523–526. https://doi.org/10.3899/jrheum.180045

    Article  CAS  PubMed  Google Scholar 

  16. Uettwiller F, Sarrabay G, Rodero MP, Rice GI, Lagrue E, Marot Y, Deiva K, Touitou I, Crow YJ, Quartier P (2016) ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters. RMD Open 2:1–5. https://doi.org/10.1136/rmdopen-2015-000236

    Article  Google Scholar 

  17. Skrabl-Baumgartner A, Plecko B, Schmidt WM, König N, Hershfield M, Gruber-Sedlmayr U, Lee-Kirsch MA (2017) Autoimmune phenotype with type i interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation. Pediatr Rheumatol 15:1–5. https://doi.org/10.1186/s12969-017-0193-x

    Article  Google Scholar 

  18. Zavialov AV, Yu X, Spillmann D, Lauvau G, Zavialov AV (2010) Structural basis for the growth factor activity of human adenosine deaminase ADA2. J Biol Chem 285:12367–12377. https://doi.org/10.1074/jbc.M109.083527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schepp J, Proietti M, Frede N, Buchta M, Hübscher K, Rojas Restrepo J, Goldacker S, Warnatz K, Pachlopnik Schmid J, Duppenthaler A, Lougaris V, Uriarte I, Kelly S, Hershfield M, Grimbacher B (2017) Screening of 181 patients with antibody deficiency for deficiency of adenosine deaminase 2 sheds new light on the disease in adulthood. Arthritis Rheumatol 69:1689–1700. https://doi.org/10.1002/art.40147

    Article  CAS  PubMed  Google Scholar 

  20. Schena F, Volpi S, Faliti CE, Penco F, Santi S, Proietti M, Schenk U, Damonte G, Salis A, Bellotti M, Fais F, Tenca C, Gattorno M, Eibel H, Rizzi M, Warnatz K, Idzko M, Ayata CK, Rakhmanov M, Galli T, Martini A, Canossa M, Grassi F, Traggiai E (2013) Dependence of immunoglobulin class switch recombination in B cells on vesicular release of ATP and CD73 ectonucleotidase activity. Cell Rep 3:1824–1831. https://doi.org/10.1016/j.celrep.2013.05.022

    Article  CAS  PubMed  Google Scholar 

  21. Schena F, Penco F, Volpi S, Pastorino C, Caorsi R, Kalli F, Fenoglio D, Salis A, Bertoni A, Prigione I, Bocca P, Insalaco A, De Benedetti F, Antonini F, Grossi A, Signa S, Damonte G, Ceccherini I, Filaci G, Traggiai E, Gattorno M (2020) Dysregulation in B cell responses and T follicular helper cell function in ADA2 deficiency patients. Eur J Immunol 51:4–5. https://doi.org/10.1002/eji.202048549

    Article  CAS  Google Scholar 

  22. Infevers: an online database for autoinflammatory mutations. Copyright. Available at https://infevers.umai-montpellier.fr/. Accessed: 17th February 2021

  23. de Menthière CS, Terrière S, Pugnère D, Ruiz M, Demaille J, Touitou I (2003) INFEVERS: the registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res 31:282–285

    Article  Google Scholar 

  24. Gibson KM, Morishita KA, Dancey P, Moorehead P, Drögemöller B, Han X, Graham J, Hancock REW, Foell D, Benseler S, Luqmani R, Yeung RSM, Shenoi S, Bohm M, Rosenberg AM, Ross CJ, Cabral DA, Brown KL (2019) Identification of novel adenosine deaminase 2 gene variants and varied clinical phenotype in pediatric vasculitis. Arthritis Rheumatol 71:1747–1755. https://doi.org/10.1002/art.40913

    Article  CAS  PubMed  Google Scholar 

  25. Garg N, Kasapcopur O, Foster J, Barut K, Tekin A, Kızılkılıç O, Tekin M (2014) Novel adenosine deaminase 2 mutations in a child with a fatal vasculopathy. Eur J Pediatr 173:827–830. https://doi.org/10.1007/s00431-014-2320-8

    Article  PubMed  Google Scholar 

  26. Lamprecht P, Humrich JY, Diebold I, Riemekasten G (2018) Diagnosis of deficiency of adenosine deaminase 2 with early onset polyarteritis nodosa in an adult patient with a novel compound heterozygous CECR1 mutation. Clin Exp Rheumatol 36:S177

    Google Scholar 

  27. Chong-Neto HJ, Segundo GRS, Bandeira M, Chong-Silva DC, Rosário CS, Riedi CA, Hershfield MS, Ochs H, Torgerson T, Rosário NA (2019) Homozygous splice ADA2 gene mutation causing ADA-2 deficiency. J Clin Immunol 39:842–845. https://doi.org/10.1007/s10875-019-00697-2

    Article  CAS  PubMed  Google Scholar 

  28. Schnappauf O, Zhou Q, Moura NS, Ombrello AK, Michael DG, Deuitch N, Barron K, Stone DL, Hoffmann P, Hershfield M, Applegate C, Bjornsson HT, Beck DB, Witmer PD, Sobreira N, Wohler E, Chiorini JA, Center TAG, Dalgard CL, Center NIS, Kastner DL, Aksentijevich I (2020) Deficiency of adenosine deaminase 2 (DADA2): hidden variants, reduced penetrance, and unusual inheritance. J Clin Immunol 40:917–926. https://doi.org/10.1007/s10875-020-00817-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ganhão S, Loureiro GB, Oliveira DR, dos-Reis-Maia R, Aguiar F, Quental R, Moura C, Barreira JL, Rodrigues M, Brito I (2020) Two cases of ADA2 deficiency presenting as childhood polyarteritis nodosa: novel ADA2 variant, atypical CNS manifestations, and literature review. Clin Rheumatol 39:3853–3860. https://doi.org/10.1007/s10067-020-05210-4

    Article  PubMed  Google Scholar 

  30. Özen S, Batu ED, Taşkiran EZ, Özkara HA, Ünal Ş, Güleray N, Erden A, Karadaǧ Ö, Gümrük F, Çetin M, Sönmez HE, Bilginer Y, Ayvaz DÇ, Tezcan I (2020) A monogenic disease with a variety of phenotypes: deficiency of adenosine deaminase 2. J Rheumatol 47:117–125. https://doi.org/10.3899/jrheum.181384

    Article  CAS  PubMed  Google Scholar 

  31. Nanthapisal S, Murphy C, Omoyinmi E, Hong Y, Standing A, Berg S, Ekelund M, Jolles S, Harper L, Youngstein T, Gilmour K, Klein NJ, Eleftheriou D, Brogan PA (2016) Deficiency of adenosine deaminase type 2: a description of phenotype and genotype in fifteen cases. Arthritis Rheumatol 68:2314–2322. https://doi.org/10.1002/art.39699

    Article  CAS  PubMed  Google Scholar 

  32. Surace AEA, Hedrich CM (2019) The role of epigenetics in autoimmune/inflammatory disease. Front Immunol 10:1–16. https://doi.org/10.3389/fimmu.2019.01525

    Article  CAS  Google Scholar 

  33. Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, Conti G, Marchetti F, Picco P, Tommasini A, Martino S, Malattia C, Gallizi R, Podda RA, Salis A, Falcini F, Schena F, Garbarino F, Morreale A, Pardeo M, Ventrici C, Passarelli C, Zhou Q, Severino M, Gandolfo C, Damonte G, Martini A, Ravelli A, Aksentijevich I, Ceccherini I, Gattorno M (2017) ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis 76:1648–1656. https://doi.org/10.1136/annrheumdis-2016-210802

    Article  CAS  PubMed  Google Scholar 

  34. Van Nieuwenhove E, Humblet-Baron S, Van Eyck L, De Somer L, Dooley J, Tousseyn T, Hershfield M, Liston A, Wouters C (2018) ADA2 deficiency mimicking idiopathic multicentric castleman disease. Pediatrics 142:e20172266. https://doi.org/10.1542/peds.2017-2266

    Article  PubMed  Google Scholar 

  35. Rama M, Duflos C, Melki I, Bessis D, Bonhomme A, Martin H, Doummar D, Valence S, Rodriguez D, Carme E, Genevieve D, Heimdal K, Insalaco A, Franck N, Queyrel-Moranne V, Tieulie N, London J, Uettwiller F, Georgin-Lavialle S, Belot A, Koné-Paut I, Hentgen V, Boursier G, Touitou I, Sarrabay G (2018) A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience. Eur J Hum Genet 26:960–971. https://doi.org/10.1038/s41431-018-0130-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bulut E, Erden A, Karadag O, Oguz KK, Ozen S (2019) Deficiency of adenosine deaminase 2; special focus on central nervous system imaging. J Neuroradiol 46:193–198. https://doi.org/10.1016/j.neurad.2018.05.002

    Article  PubMed  Google Scholar 

  37. Trotta L, Martelius T, Siitonen T, Hautala T, Hämäläinen S, Juntti H, Taskinen M, Ilander M, Andersson EI, Zavialov A, Kaustio M, Keski-Filppula R, Hershfield M, Mustjoki S, Tapiainen T, Seppänen M, Saarela J (2018) ADA2 deficiency: clonal lymphoproliferation in a subset of patients. J Allergy Clin Immunol 141:1534–1537.e8. https://doi.org/10.1016/j.jaci.2018.01.012

    Article  PubMed  Google Scholar 

  38. Hashem H, Kumar AR, Müller I, Babor F, Bredius R, Dalal J, Hsu AP, Holland SM, Hickstein DD, Jolles S, Krance R, Sasa G, Taskinen M, Koskenvuo M, Saarela J, Van Montfrans J, Wilson K, Bosch B, Moens L, Hershfield M, Meyts I (2017) Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2. Blood 130:2682–2688. https://doi.org/10.1182/blood-2017-07-798660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sahin S, Adrovic A, Barut K, Ugurlu S, Turanli ET, Ozdogan H, Kasapcopur O (2018) Clinical, imaging and genotypical features of three deceased and five surviving cases with ADA2 deficiency. Rheumatol Int 38:129–136. https://doi.org/10.1007/s00296-017-3740-3

    Article  CAS  PubMed  Google Scholar 

  40. Chasset F, Fayand A, Moguelet P, Kouby F, Bonhomme A, Franck N, Goldman-lévy G, Fraitag S, Barbaud A, Queyrel V, Touitou I, Boursier G, Sarrabay G, Ducharme-Benard S, Dupin N, Francès C, Bessis D, Georgin-Lavialle S (2020) Clinical and pathological dermatological features of deficiency of adenosine deaminase 2: multicenter retrospective observational study. J Am Acad Dermatol 83:1794–1798. https://doi.org/10.1016/j.jaad.2020.03.110

    Article  CAS  PubMed  Google Scholar 

  41. van Well GTJ, Kant B, van Nistelrooij A, Sirma Ekmekci S, Henriet SV, Hoppenreijs E, van Deuren M, van Montfrans J, Nierkens S, Gül A, van Gijn ME (2019) Phenotypic variability including Behçet’s disease-like manifestations in DADA2 patients due to a homozygous c.973-2A > G splice site mutation. Clin Exp Rheumatol 37:142–146

    PubMed  Google Scholar 

  42. Santo GC, Baldeiras I, Guerreiro R, Ribeiro JA, Cunha R, Youngstein T, Nanthapisal S, Leitão J, Fernandes C, Caramelo F, Almeida MDR, Brás J, Santana I (2019) Adenosine deaminase two and immunoglobulin M accurately differentiate adult Sneddon’s syndrome of unknown cause. Cerebrovasc Dis 46:257–264. https://doi.org/10.1159/000495794

    Article  CAS  Google Scholar 

  43. Sozeri B, Ercan G, Dogan OA, Yıldız J, Demir F, Doğanay L (2019) The same mutation in a family with adenosine deaminase 2 deficiency. Rheumatol Int 41:227–233. https://doi.org/10.1007/s00296-019-04444-z

    Article  CAS  PubMed  Google Scholar 

  44. Ben-Ami T, Revel-Vilk S, Brooks R, Shaag A, Hershfield MS, Kelly SJ, Ganson NJ, Kfir-Erenfeld S, Weintraub M, Elpeleg O, Berkun Y, Stepensky P (2016) Extending the clinical phenotype of adenosine deaminase 2 deficiency. J Pediatr 177:316–320. https://doi.org/10.1016/j.jpeds.2016.06.058

    Article  CAS  PubMed  Google Scholar 

  45. Tanatar A, Karadağ ŞG, Sözeri B, Sönmez HE, Çakan M, Kendir Demirkol Y, Aktay Ayaz N (2020) ADA2 deficiency: case series of five patients with varying phenotypes. J Clin Immunol 40:253–258. https://doi.org/10.1007/s10875-019-00734-0

    Article  CAS  PubMed  Google Scholar 

  46. Batu ED, Karadag O, Taskiran EZ, Kalyoncu U, Aksentijevich I, Alikasifoglu M, Özen S, Series AC, Patients D (2015) A case series of adenosine deaminase 2-deficient patients emphasizing treatment and genotype-phenotype correlations The Journal of Rheumatology is a monthly international serial edited by Earl D . Silverman featuring research a. J Rheumatol 42:8–11

    Article  Google Scholar 

  47. Liebowitz J, Hellmann DB, Schnappauf O (2019) Thirty years of followup in 3 patients with familial polyarteritis nodosa due to adenosine deaminase 2 deficiency. J Rheumatol 46:1059–1060. https://doi.org/10.3899/jrheum.180820

    Article  CAS  PubMed  Google Scholar 

  48. Van Eyck L, Hershfield MS, Pombal D, Kelly SJ, Ganson NJ, Moens L, Frans G, Schaballie H, De Hertogh G, Dooley J, Bossuyt X, Wouters C, Liston A, Meyts I (2015) Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency. J Allergy Clin Immunol 135:283–287.e5. https://doi.org/10.1016/j.jaci.2014.10.010

    Article  PubMed  PubMed Central  Google Scholar 

  49. Poswar F d O, da Fonseca RMT, de Albuquerque LCP, Zhou Q, Jardim LB, Monte TL, Aksentijevich I, Saute JAM (2016) Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis. J Neurol 263:818–820. https://doi.org/10.1007/s00415-016-8070-y

    Article  Google Scholar 

  50. Westendorp WF, Nederkoorn PJ, Aksentijevich I, Hak AE, Lichtenbelt KD, Braun KPJ (2015) Unexplained early-onset lacunar stroke and inflammatory skin lesions: consider ADA2 deficiency. Neurology 84:2092–2093. https://doi.org/10.1212/WNL.0000000000001581

    Article  PubMed  PubMed Central  Google Scholar 

  51. Michniacki TF, Hannibal M, Ross CW, Frame DG, DuVall AS, Khoriaty R, Vander Lugt MT, Walkovich KJ (2018) 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. https://doi.org/10.1007/s10875-018-0480-4

    Article  CAS  PubMed  Google Scholar 

  52. Krutzke S, Horneff G (2019) Treatment of two male children suffering from deficiency of adenosine deaminase type 2 (DADA2) with TNF-inhibitor etanercept. J Clin Rheumatol. Publish Ahead of Print. https://doi.org/10.1097/RHU.0000000000001145

  53. Fellmann F, Angelini F, Wassenberg J, Perreau M, Arenas Ramirez N, Simon G, Boyman O, Demaria O, Christen-Zaech S, Hohl D, Belfiore M, Von Scheven-Gete A, Gilliet M, Bochud PY, Perrin Y, Beck Popovic M, Bart PA, Beckmann JS, Martinet D, Hofer M (2016) IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation. J Allergy Clin Immunol 137:1189–1196.e2. https://doi.org/10.1016/j.jaci.2015.07.053

    Article  CAS  PubMed  Google Scholar 

  54. Springer JM, Gierer SA, Jiang H, Kleiner D, Deuitch N, Ombrello AK, Grayson PC, Aksentijevich I (2018) Deficiency of adenosine deaminase 2 in adult siblings: many years of a misdiagnosed disease with severe consequences. Front Immunol 9:1–5. https://doi.org/10.3389/fimmu.2018.01361

    Article  CAS  Google Scholar 

  55. Santiago TMG, Zavialov A, Saarela J, Seppanen M, Reed AM, Abraham RS, Gibson LE (2015) Dermatologic features of ADA2 deficiency in cutaneous polyarteritis nodosa. JAMA Dermatol 151:1230–1234. https://doi.org/10.1001/jamadermatol.2015.1635

    Article  Google Scholar 

  56. Ghurye RR, Sundaram K, Smith F, Clark B, Simpson MA, Fairbanks L, Adhya Z, Mufti GJ, Marsh JCW, Ibrahim MAA (2019) Novel ADA2 mutation presenting with neutropenia, lymphopenia and bone marrow failure in patients with deficiency in adenosine deaminase 2 (DADA2). Br J Haematol 186:e60–e64. https://doi.org/10.1111/bjh.15896

    Article  PubMed  Google Scholar 

  57. Clarke K, Campbell C, Omoyinmi E, Hong Y, Al Obaidi M, Sebire N, Brogan PA (2019) Testicular ischemia in deficiency of adenosine deaminase 2 (DADA2). Pediatr Rheumatol 17:1–7. https://doi.org/10.1186/s12969-019-0334-5

    Article  Google Scholar 

  58. Claassen D, Boals M, Bowling KM, Cooper GM, Cox J, Hershfield M, Lewis S, Wlodarski M, Weiss MJ, Estepp JH (2018) Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia. Cold Spring Harb Mol Case Stud 4:2–7. https://doi.org/10.1101/mcs.a003384

    Article  CAS  Google Scholar 

  59. Neishabury M, Mehri M, Fattahi Z, Najmabadi H, Azarkeivan A (2020) Novel variants in Iranian individuals suspected to have inherited red blood cell disorders, including bone marrow failure syndromes. Haematologica 105:E1–E4

    Article  Google Scholar 

  60. Keino D, Kondoh K, Kim Y, Sudo A, Ohyama R, Morimoto M, Nihira H, Izawa K, Iwaki-Egawa S, Mori T, Kinoshita A (2020) Successful treatment with cyclosporine and anti-tumour necrosis factor agent for deficiency of adenosine deaminase-2. Scand J Rheumatol. 28:1–3. https://doi.org/10.1080/03009742.2020.1772868

  61. Grossi A, Cusano R, Rusmini M, Penco F, Schena F, Podda RA, Caorsi R, Gattorno M, Uva P, Ceccherini I (2019) ADA2 deficiency due to a novel structural variation in 22q11.1. Clin Genet 95:732–733. https://doi.org/10.1111/cge.13518

    Article  CAS  PubMed  Google Scholar 

  62. Maccora I, Frongia I, Azzari C, Ricci S, Cimaz R, Simonini G (2018) A misleading case of deficiency of adenosine deaminase 2 (DADA2): the magnifying glass of the scientific knowledge drives the tailored medicine in real life. Clin Exp Rheumatol 36:146

    PubMed  Google Scholar 

  63. Barzaghi F, Minniti F, Mauro M, De Bortoli M, Balter R, Bonetti E, Zaccaron A, Vitale V, Omrani M, Zoccolillo M, Brigida I, Cicalese MP, Degano M, Hershfield MS, Aiuti A, Bondarenko AV, Chinello M, Cesaro S (2019) ALPS-like phenotype caused by ADA2 deficiency rescued by allogeneic hematopoietic stem cell transplantation. Front Immunol 10. https://doi.org/10.3389/fimmu.2018.02767

  64. Ekinci RMK, Balcı S, Bisgin A, Sasmaz I, Leblebisatan G, Incecik F, Yilmaz M (2019) A homozygote novel L451W mutation in CECR1 gene causes deficiency of adenosine deaminase 2 in a pediatric patient representing with chronic lymphoproliferation and cytopenia. Pediatr Hematol Oncol 36:376–381. https://doi.org/10.1080/08880018.2019.1621973

    Article  CAS  PubMed  Google Scholar 

  65. Cipe FE, Aydogmus C, Serwas NK, Keskindemirci G, Boztuğ K (2018) Novel mutation in CECR1 leads to deficiency of ADA2 with associated neutropenia. J Clin Immunol 38:273–277. https://doi.org/10.1007/s10875-018-0487-x

    Article  CAS  PubMed  Google Scholar 

  66. Dimachkie MD, Fraga GR, Moura NS, Springer JM (2020) A rare case of adenosine deaminase 2 deficiency presenting with temporal arteritis. J Clin Rheumatol: Publish Ahead of Print. https://doi.org/10.1097/rhu.0000000000001384

  67. Çakan M, Aktay-Ayaz N, Karadağ ŞG, Tahir-Turanlı E, Stafstrom K, Bainter W, Geha RS, Chou J (2019) Atypical phenotype of an old disease or typical phenotype of a new disease: deficiency of adenosine deaminase 2. Turk J Pediatr 61:413–417. https://doi.org/10.24953/turkjped.2019.03.014

    Article  PubMed  Google Scholar 

  68. Alsultan A, Basher E, Alqanatish J, Mohammed R, Alfadhel M (2018) Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis. Pediatr Blood Cancer 65:10–13. https://doi.org/10.1002/pbc.26912

    Article  Google Scholar 

  69. Hashem H, Egler R, Dalal J (2017) Refractory pure red cell aplasia manifesting as deficiency of adenosine deaminase 2. J Pediatr Hematol Oncol 39:e293–e296. https://doi.org/10.1097/MPH.0000000000000805

    Article  PubMed  Google Scholar 

  70. Keer N, Hershfield M, Caskey T, Unizony S (2016) Novel compound heterozygous variants in CECR1 gene associated with childhood onset polyarteritis nodosa and deficiency of ADA2. Rheumatology (Oxford) 55:1145–1147. https://doi.org/10.1093/rheumatology/kew050

    Article  Google Scholar 

  71. Martin H, Bursztejn AC, Cuny JF, Sarrabay G, Schmutz JL, Touitou I, Wahl D, Bonhomme A (2018) Chronic leg ulcer revealing adenosine deaminase 2 deficiency: an atypical presentation. Eur J Dermatol 28:847–848

    PubMed  Google Scholar 

  72. Elbracht M, Mull M, Wagner N, Kuhl C, Abicht A, Kurth I, Tenbrock K, Häusler M (2017) Stroke as initial manifestation of adenosine deaminase 2 deficiency. Neuropediatrics 48:111–114. https://doi.org/10.1055/s-0036-1597611

    Article  CAS  PubMed  Google Scholar 

  73. Nihira H, Nakagawa K, Izawa K, Kawai T, Yasumi T, Nishikomori R, Nambu M, Miyagawa-Hayashino A, Nomura T, Kabashima K, Ito M, Iwaki-Egawa S, Sasahara Y, Nakayama M, Heike T (2018) Fever of unknown origin with rashes in early infancy is indicative of adenosine deaminase type 2 deficiency. Scand J Rheumatol 47:170–172. https://doi.org/10.1080/03009742.2017.1324912

    Article  CAS  PubMed  Google Scholar 

  74. Hsu AP, West RR, Calvo KR, Cuellar-Rodriguez J, Parta M, Kelly SJ, Ganson NJ, Hershfield MS, Holland SM, Hickstein DD (2016) Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: Successful hematopoietic stem cell transplantation. J Allergy Clin Immunol 138:628–630.e2. https://doi.org/10.1016/j.jaci.2016.03.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu L, Wang W, Wang Y, Hou J, Ying W, Hui X, Zhou Q, Liu D, Yao H, Sun J, Wang X (2019) A Chinese DADA2 patient: report of two novel mutations and successful HSCT. Immunogenetics 71:299–305. https://doi.org/10.1007/s00251-018-01101-w

    Article  CAS  PubMed  Google Scholar 

  76. Ekinci RMK, Balci S, Bisgin A, Hershfield M, Atmis B, Dogruel D, Yilmaz M (2018) Renal amyloidosis in deficiency of adenosine deaminase 2: Successful experience with canakinumab. Pediatrics 142:e20180948. https://doi.org/10.1542/peds.2018-0948

    Article  Google Scholar 

  77. Sahin S, Adrovic A, Barut K, Baran S, Tahir Turanli E, Canpolat N, Kizilkilic O, Ozkaya O, Kasapcopur O (2020) A 9.5-year-old boy with recurrent neurological manifestations and severe hypertension, treated initially for polyarteritis nodosa, was subsequently diagnosed with adenosine deaminase type 2 deficiency (DADA2) which responded to anti-TNF-α. Paediatr Int Child Health 40:65–68. https://doi.org/10.1080/20469047.2018.1559495

    Article  PubMed  Google Scholar 

  78. Sundin M, Marits P, Nierkens S, Kolios AGA, Nilsson J (2019) Immune thrombocytopenia as key feature of a novel ADA2 deficiency variant: implication on differential diagnostics of ITP in children. J Pediatr Hematol Oncol 41:155–157. https://doi.org/10.1097/MPH.0000000000001132

    Article  CAS  PubMed  Google Scholar 

  79. Van Eyck L, Liston A, Wouters C (2014) Mutant ADA2 in vasculopathies. N Engl J Med 371:478–481. https://doi.org/10.1056/nejmc1405506

    Article  PubMed  Google Scholar 

  80. Arts K, Bergerson JRE, Ombrello AK, Similuk M, Oler AJ, Agharahimi A, Mace EM, Hershfield M, Wouters C, De Somer L, Morren MA, de Diego RP, Moens L, Freeman AF, Meyts I (2018) Warts and DADA2: a mere coincidence? J Clin Immunol 38:836–843. https://doi.org/10.1007/s10875-018-0565-0

    Article  PubMed  Google Scholar 

  81. Göschl L, Winkler S, Dmytrus J, Heredia RJ, Lagler H, Ramharter M, Scheinecker C, Bonelli M, Schmetterer K, Pickl WF, Grabmeier-Pfistershammer K, Hershfield MS, Boztug K, Förster-Waldl E, Gualdoni GA (2020) Unreported missense mutation in the dimerization domain of ADA2 leads to ADA2 deficiency associated with severe oral ulcers and neutropenia in a female Somalian patient—addendum to the genotype-phenotype puzzle. J Clin Immunol 40:223–226. https://doi.org/10.1007/s10875-019-00700-w

    Article  PubMed  Google Scholar 

  82. Tull TJ, Martin B, Spencer J, Sangle S, Chua S, McGrath JA, D’Cruz DP, McGibbon DH (2020) Sneddon syndrome associated with two novel ADA2 gene mutations. Rheumatology (Oxford) 59:1448–1450. https://doi.org/10.1093/rheumatology/kez446

    Article  Google Scholar 

  83. Saettini F, Fazio G, Corti P, Quadri M, Bugarin C, Gaipa G, Penco F, Moratto D, Chiarini M, Baronio M, Gazzurelli L, Imberti L, Paghera S, Giliani S, Cazzaniga G, Plebani A, Badolato R, Lougaris V, Gattorno M, Biondi A (2020) Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T cell perturbations. Clin Immunol 218:108525. https://doi.org/10.1016/j.clim.2020.108525

    Article  CAS  PubMed  Google Scholar 

  84. Alabbas F, Elyamany G, Alsharif O, Hershfield M, Meyts I (2019) Childhood Hodgkin lymphoma: think DADA2. J Clin Immunol 39:26–29. https://doi.org/10.1007/s10875-019-0590-7

    Article  PubMed  Google Scholar 

  85. Le Voyer T, Boutboul D, Ledoux-Pilon A, de Fontbrune FS, Boursier G, Latour S, Le Guenno G (2020) Late-onset EBV susceptibility and refractory pure red cell aplasia revealing DADA2. J Clin Immunol 40:948–953. https://doi.org/10.1007/s10875-020-00812-8

    Article  PubMed  Google Scholar 

  86. Staples E, Simeoni I, Stephens JC, Allen HL, Wright P, Davies EG, Javid B, Gkrania-Klotsas E, Gattens M, Firth H, Shamardina O, Deevi SVV, Prapa M, Uttenthal B, Kumararatne D, Thaventhiran JED (2020) ADA2 deficiency complicated by EBV-driven lymphoproliferative disease. Clin Immunol 215:22–25. https://doi.org/10.1016/j.clim.2020.108443

    Article  CAS  Google Scholar 

  87. Al Mosawi Z, Abduljawad H, Busehail M, Al Moosawi B (2019) Adenosine deaminase 2 deficiency with a novel variant of CECR1 gene mutation: responding to tumor necrosis factor antagonist therapy. Indian J Rheumatol 14:236–240. https://doi.org/10.4103/injr.injr_36_19

    Article  Google Scholar 

  88. Akgun-Dogan O, Simsek-Kiper PO, Taskiran E, Lissewski C, Brinkmann J, Schanze D, Göçmen R, Cagdas D, Bilginer Y, Utine GE, Zenker M, Ozen S, Tezcan İ, Alikasifoglu M, Boduroğlu K (2019) ADA2 deficiency in a patient with Noonan syndrome-like disorder with loose anagen hair: The co-occurrence of two rare syndromes. Am J Med Genet A 179:2474–2480. https://doi.org/10.1002/ajmg.a.61363

    Article  CAS  PubMed  Google Scholar 

  89. Teixeira V, Oliveira-Ramos F, Teixeira V, Oliveira-Ramos F, Costa M (2020) Severe and refractory polyarteritis nodosa associated with CECR1 mutation and dramatic response to infliximab in adulthood. J Clin Rheumatol 26:E66–E69

    Article  Google Scholar 

  90. Sharma A, Naidu GSRSNK, Chattopadhyay A, Acharya N, Jha S, Jain S (2019) Novel CECR1 gene mutations causing deficiency of adenosine deaminase 2, mimicking antiphospholipid syndrome. Rheumatology (Oxford) 58:181–182. https://doi.org/10.1093/rheumatology/key258

    Article  Google Scholar 

  91. Schnappauf O, Sampaio Moura N, Aksentijevich I, Stoffels M, Ombrello AK, Hoffmann P, Barron K, Remmers EF, Hershfield M, Kelly SJ, Cuthbertson D, Carette S, Chung SA, Forbess L, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland L, Pagnoux C, Seo P, Springer JM, Sreih AG, Warrington KJ, Ytterberg SR, Kastner DL, Grayson PC, Merkel PA (2020) Sequence-based screening of patients with idiopathic polyarteritis nodosa, granulomatosis with polyangiitis, and microscopic polyangiitis for deleterious genetic variants in ADA2. Arthritis Rheumatol. 73:512–519. https://doi.org/10.1002/art.41549

    Article  CAS  Google Scholar 

  92. Schepp J, Bulashevska A, Mannhardt-Laakmann W, Cao H, Yang F, Seidl M, Kelly S, Hershfield M, Grimbacher B (2016) Deficiency of adenosine deaminase 2 causes antibody deficiency. J Clin Immunol 36:179–186. https://doi.org/10.1007/s10875-016-0245-x

    Article  CAS  PubMed  Google Scholar 

  93. Ombrello AK, Bethesda QJ, Bethesda HPM, Bethesda KP, Bethesda SD, Jones A, Romeo T, Barham B, Pinto-Patarroyo G, Toro C, Soldatos A, Zhou Q, Deuitch N, Aksentijevich I, Sheldon SL, Kelly S, Man A, Barron K, Hershfield M, Flegel WA, Kastner DL (2019) Treatment strategies for deficiency of adenosine deaminase 2. N Engl J Med 380:1582–1584. https://doi.org/10.1056/NEJMc1801927

    Article  PubMed  PubMed Central  Google Scholar 

  94. Ombrello A, Stone D, Hoffmann P, Jones A, Barham B, Barron K, Flegel W, Sheldon S, Zhou Q, Hershfield M, Aksentijevich I, Kumar P, Kastner D (2015) The deficiency of adenosine deaminase type 2-results of therapeutic intervention. Pediatr Rheumatol 13:O40. https://doi.org/10.1186/1546-0096-13-s1-o40

    Article  Google Scholar 

  95. Hashem H, Vatsayan A, Gupta A, Nagle K, Hershfield M, Dalal J (2017) Successful reduced intensity hematopoietic cell transplant in a patient with deficiency of adenosine deaminase 2. Bone Marrow Transplant 52:1575–1576. https://doi.org/10.1038/bmt.2017.173

    Article  CAS  PubMed  Google Scholar 

  96. Bucciol G, Delafontaine S, Segers H, Bossuyt X, Hershfield MS, Moens L, Meyts I (2017) Hematopoietic stem cell transplantation in ADA2 deficiency: early restoration of ADA2 enzyme activity and disease relapse upon drop of donor chimerism. J Clin Immunol 37:746–750. https://doi.org/10.1007/s10875-017-0449-8

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Immunology and Rheumatology, St. John’s National Academy of Health Sciences, Bangalore, India

    Benzeeta Pinto

  2. Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Prateek Deo & Aman Sharma

  3. Department of Obstetrics and Gynaecology, Adesh Medical College and Hospital, Mohri, Ambala, India

    Susmita Sharma

  4. Government Medical College and Hospital, Sector 32, Chandigarh, India

    Arshi Syal

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  5. Aman Sharma
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1) Made substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data: BP, PD, SS, AS, AS

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Correspondence to Aman Sharma.

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Pinto, B., Deo, P., Sharma, S. et al. Expanding spectrum of DADA2: a review of phenotypes, genetics, pathogenesis and treatment. Clin Rheumatol 40, 3883–3896 (2021). https://doi.org/10.1007/s10067-021-05711-w

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