Abstract
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease caused by ADA2 gene mutation that is characterized by three phenotype domains: vasculopathy and inflammation, hematological abnormality, and immunodeficiency. Most patients are pediatric patients; adult-onset patients are only occasionally reported. To describe a Chinese case of adult-onset DADA2 in a Chinese patient and explore the genotype and phenotype characteristics of adult-onset DADA2. We examined the clinical, serological, and genetic features of a Chinese adult-onset DADA2 patient. English literature on DADA2 was reviewed. The clinical and genetic characteristics of different age and mutation subgroups were compared. A Chinese Han male presented with recurrent fever, rash, immunodeficiency, and significant vascular events since the age of 25 years. Serum ADA2 activity was diminished, and genotyping revealed a unique compound heterozygous mutation of exon2-10del/exon7del in the ADA2 gene leading to complete exon 7 deletion. Treatment with a TNFα inhibitor achieved disease control. A total of 269 cases carrying 102 mutations were analyzed through a literature review. Adult-onset patients had few symptoms in all three clinical domains; vasculopathy and inflammation were the major symptoms. Patients with null mutations had early disease onset and more frequent hematological abnormalities and immunodeficiency. Patients in all subgroups responded well to TNFα inhibitors. We reported the first Chinese adult-onset DADA2 patient, with a unique mutation. Screening for and differentiation of DADA2 are recommended for patients of all ages, as they might become symptomatic later in life and treatment strategies differ from those of traditional vasculitis.
Key Points • We report a novel compound heterozygous deletion mutations of exons 2–10 and exon 7, leading to complete loss of exon 7 in the ADA2 gene. • Adult-onset DADA2 patients had high similarity to systemic vasculitis. • Null mutations contribute to earlier disease onset and more aggressive disease. • We suggest screening for DADA2 in patients with significant central vasculitis, hematological abnormality and immunodeficiency. |
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The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.
References
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 CC, 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, Virginia Pascual M, 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
Navon Elkan P, 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
Kendall JL, Springer JM (2020) The many faces of a monogenic autoinflammatory disease: adenosine deaminase 2 deficiency. Curr Rheumatol Rep 22(10):64
Caso F, Costa L, Nucera V, Barilaro G, Masala IF, Talotta R, Caso P, Scarpa R, Sarzi-Puttini P, Atzeni F (2018) From autoinflammation to autoimmunity: old and recent findings. Clin Rheumatol 37:2305–2321
Lee PY (2018) Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2. Front Pediatr 6:282
Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone JH, Takahashi K, Watts RA (2013) 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 65:1–11
de Boysson H, Guillevin L (2019) Polyarteritis nodosa neurologic manifestations. Neurol Clin 37(2):345–357
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
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 1456:1664–1672
Cipe FE, Aydogmus C, Serwas NK, Keskindemirci G, Boztug K (2018) Novel mutation in CECR1 leads to deficiency of ADA2 with associated neutropenia. J Clin Immunol 38:273–277
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
Bras J, Guerreiro R, Santo GC (2014) Mutant ADA2 in vasculopathies. N Engl J Med 371:478–480
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
Schepp J, Proietti M, Frede N, Buchta M, Hubscher K, Rojas Restrepo J, Goldacker S, Warnatz K, Pachlopnik Schmid J, Duppenthaler A, Lougaris V, Uriarte I, Kelly S, Hershfield M, Gimbacher 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
Trotta L, Martelius T, Siitonen T, Hautala T, Hamalainen S, Juntti H, Taskinen M, Ilander M, Andersson EI, Zavialov A, Kaustio M, Keski-Filppula R, Hershfield M, Mustjoki S, Tapiainen T, Seppanen M, Saarela J (2018) ADA2 deficiency: clonal lymphoproliferation in a subset of patients. J Allergy Clin Immunol 141:1534–1537 e1538
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
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, Kone-Paut I, Hentgen V, Boursier G, Touitou I, Sarrabey 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
Sharma A, Naidu G, 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
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
Özen S, Batu ED, Taşkıran EZ, Özkara HA, Ünal Ş, Güleray N, Erden A, Karadağ 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
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 NIHIS, Kastner DL, Aksentijevich I (2020) Deficiency of adenosine deaminase 2 (DADA2): hidden variants, reduced penetrance, and unusual inheritance. J Clin Immunol 40:917–926
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:e000236
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 9:1361
Arts K, Bergerson JRE, Ombrello AK, Similuk M, Oler AJ, Agharahimi A, Mac EM, Hershfield M, Wouters C, Somer LD, Morren MA, Perez-de Diego R, Moens L, Freeman AF, Meyts I (2018) Warts and DADA2: a mere coincidence? J Clin Immunol 38:836–843
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
Chong-Neto HJ, Segundo GRS, Bandeira M, Chong-Silva DC, Rosario CS, Riedi CA, Hershfield MS, Ochs H, Torgerson T, Rosario NA (2019) Homozygous splice ADA2 gene mutation causing ADA-2 deficiency. J Clin Immunol 39:842–845
van Well GTJ, Kant B, van Nistelrooij A, Sirma Ekmekci S, Henriet SV, Hoppenreijs E, van Deuren M, van Montfrans J, Nierkens S, Gul A, van Gijn ME (2019) Phenotypic variability including Behcet’s disease-like manifestations in DADA2 patients due to a homozygous c.973-2A>G splice site mutation. Clin Exp Rheumatol 37(Suppl 121):142–146
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, Bohud PY, Perrin Y, Popovic MB, 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 e1182
Hashem H, Kumar AR, Muller 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, Deficiency of Adenosine Deaminase Type 2 Foundation (2017) Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2. Blood 130:2682–2688
van Montfrans J, Zavialov A, Zhou Q (2014) Mutant ADA2 in vasculopathies. N Engl J Med 371:478
Van Eyck L, Liston A, Meyts I (2014) Mutant ADA2 in vasculopathies. N Engl J Med 371:478–479
Van Montfrans JM, Hartman EA, Braun KP, Hennekam EA, Hak EA, Nederkoorn PJ, Westendorp WF, Bredius RG, Kollen WJ, Scholvinck EH, Legger GE, Meyts I, Liston A, Lichtenbelt KD, Giltay JC, Haaften GV, 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 55:902–910
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
Gibson KM, Morishita KA, Dancey P, Moorehead P, Drogemoller 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, PedVas Investigators Network (2019) Identification of novel adenosine deaminase 2 gene variants and varied clinical phenotype in pediatric vasculitis. Arthritis Rheumatol 71(10):1747–1755
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 e622
Barzaghi F, Minniti F, Mauro M, 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 (2018) ALPS-like phenotype caused by ADA2 deficiency rescued by allogeneic hematopoietic stem cell transplantation. Front Immunol 9:2767
Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V, Bhatia P, Sharma V, Bhattad S, Chengappa GV, 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 VS, 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. https://doi.org/10.1002/art.41500
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
Ombrello AK, Qin J, Hoffmann PM, Kumar P, Stone D, 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
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, Aksentjevich 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
Acknowledgments
We thank the support from the patient and all his family. We thank all the doctors and physicians who had helped and taken care of the patient.
Funding
This work was funded by the Natural Science Foundation of Beijing (Grant No. 7192170), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS) (Grant No. 2017-I2M-3-001, 2016-I2M-1-002), the National Natural Science Foundation of China (NSFC) (Grant No. 81788101), the National Key Research and Development Program of China (Grant No. 2016YFC0901500; 2016YFC0901501), Capital Medical Development Research Fund (2018-1-4012), the Clinical and Translational Medical Research Fund of Chinese Academy of Medical Sciences (No. 2019XK320013), the Fundamental Research Funds for the Central Universities (Grant No. APL20100310010301019), the CAMS Initiative for Innovative Medicine (2016-I2M-1-008), and the Capital Health Research and Development of Special (2016-2-40114).
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This study was approved by the Institutional Review Board of Peking Union Medical College Hospital and performed according to the Declaration of Helsinki. Informed consent was obtained from the patient and his family.
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Zhang, B., Sun, Y., Xu, N. et al. Adult-onset deficiency of adenosine deaminase 2—a case report and literature review. Clin Rheumatol 40, 4325–4339 (2021). https://doi.org/10.1007/s10067-021-05587-w
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DOI: https://doi.org/10.1007/s10067-021-05587-w