Abstract
Deficiency of Adenosine Deaminase 2 (DADA2) is a systemic disorder that is inherited in an autosomal recessive manner. Initially identified as a monogenic form of systemic vasculitis that mirrors polyarteritis nodosa (PAN), DADA2 is attributed to biallelic pathogenic variants in the adenosine deaminase 2 gene (ADA2; formerly known as CECR1) on chromosome 22q11. DADA2 presents with variable symptoms that can manifest as vasculitis, immune dysfunction, or hematological abnormalities. The primary disease phenotypes consist of polyarteritis nodosa (PAN)-like vasculitis, Diamond-Blackfan anemia (DBA)-like hematologic findings, and immunodeficiency. The vasculitic condition often manifests through severe ischemic or hemorrhagic strokes that can be life-threatening. To confirm the diagnosis of DADA2, it is imperative to analyze the ADA2 gene and measure low or unnoticeable ADA2 activity in plasma or serum. The use of anti-tumor necrosis factor agents has proven to be efficacious in treating patients with an inflammatory phenotype. Hematopoietic stem cell transplantation (HSCT) stands out as a promising treatment alternative for patients presenting with predominant hematologic or immunologic manifestations.
Keywords: ADA2, vasculitis, immunodeficiency
References
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.
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;370:921-31.
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;42:1532-4.
Van Montfrans JM, Hartman EA, Braun KP, Hennekam EA, Hak EA, Nederkoorn PJ, et al. Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford). 2016;55:902-10.
Jee H, Huang Z, Baxter S, Huang Y, Taylor ML, Henderson LA, et al. Comprehensive analysis of ADA2 genetic variants and estimation of carrier frequency driven by a function-based approach. J Allergy Clin Immunol. 2022;149:379-87.
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;76:1648-56.
Schnappauf O, Sampaio Moura N, Aksentijevich I, Stoffels M, Ombrello AK, Hoffmann P, et al. Sequence-Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2. Arthritis Rheumatol. 2021;73:512-9.
Ulirsch JC, Verboon JM, Kazerounian S, Guo MH, Yuan D, Ludwig LS, et al. The Genetic Landscape of Diamond-Blackfan Anemia. Am J Hum Genet. 2018;103:930-47.
Huang Z, Li T, Nigrovic PA, Lee PY. Polyarteritis nodosa and deficiency of adenosine deaminase 2 - Shared genealogy, generations apart. Clin Immunol. 2020;215:108411.
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. 2016;68:2314-22.
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.
Lee PY, Kellner ES, Huang Y, Furutani E, Huang Z, Bainter W, et al. Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2). J Allergy Clin Immunol. 2020;145:1664-72.
Schnappauf O, Ombrello AK, Kastner DL. Deficiency of adenosine deaminase 2: Is it an elephant after all? J Allergy Clin Immunol. 2020;145:1560-1.
Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V, et al. Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India. Arthritis Rheumatol. 2021;73:276-85.
Özen S, Batu ED, Taşkıran EZ, Özkara HA, Ünal Ş, Güleray N, et al. A Monogenic Disease with a Variety of Phenotypes: Deficiency of Adenosine Deaminase 2. J Rheumatol. 2020;47:117-25.
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;130:2682-8.
Hashem H, Kelly SJ, Ganson NJ, Hershfield MS. Deficiency of Adenosine Deaminase 2 (DADA2), an Inherited Cause of Polyarteritis Nodosa and a Mimic of Other Systemic Rheumatologic Disorders. Curr Rheumatol Rep. 2017;19:70.
Lee PY, Huang Z, Hershfield MS, Nigrovic PA. Response to: ‘Total adenosine deaminase highly correlated with adenosine deaminase 2 activity in serum’ by Gao et al. Ann Rheum Dis. 2022;81:e31.
Zavialov AV, Engström A. Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity. Biochem J. 2005;391:51-7.
Zavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G. Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J Leukoc Biol. 2010;88:279-90.
Carmona-Rivera C, Khaznadar SS, Shwin KW, Irizarry-Caro JA, O’Neil LJ, Liu Y, et al. Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood. 2019;134:395-406.
Ombrello AK, Qin J, Hoffmann PM, Kumar P, Stone D, Jones A, et al. Treatment Strategies for Deficiency of Adenosine Deaminase 2. N Engl J Med. 2019;380:1582-4.
Insalaco A, Moneta GM, Pardeo M, Caiello I, Messia V, Bracaglia C, et al. Variable Clinical Phenotypes and Relation of Interferon Signature with Disease Activity in ADA2 Deficiency. J Rheumatol. 2019;46:523-6.
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;15:67.
Nihira H, Izawa K, Ito M, Umebayashi H, Okano T, Kajikawa S, et al. Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation. J Allergy Clin Immunol. 2021;148:550-62.
Dhanwani R, Takahashi M, Mathews IT, Lenzi C, Romanov A, Watrous JD, et al. Cellular sensing of extracellular purine nucleosides triggers an innate IFN-β response. Sci Adv. 2020;6:eaba3688.
Greinier-Tollersrud OK, Boehler V, Bartok E, Krausz M, Polyzou A, Schepp J, et al. ADA2 is a lysosomal DNase regulating the type-I interferon response. bioRxiv. 2020.
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;36:179-86.
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. 2017;69:1689-700.
Lee PY. Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2. Front Pediatr. 2018;6:282.
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.
Bourgeois G, Richard M, Danset M, Pérard L, Breton AL, Berthoux E. Deficiency of adenosine deaminase 2 diagnosed at 65 years of age. Lancet. 2021;397:913.
Trotta L, Martelius T, Siitonen T, Hautala T, Hämäläinen S, Juntti H, et al. ADA2 deficiency: Clonal lymphoproliferation in a subset of patients. J Allergy Clin Immunol. 2018;141:1534-7.
Clarke K, Campbell C, Omoyinmi E, Hong Y, Al Obaidi M, Sebire N, et al. Testicular ischemia in deficiency of adenosine deaminase 2 (DADA2). Pediatr Rheumatol Online J. 2019;17:39.
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;48:111-4.
Fayand A, Chasset F, Boutboul D, Queyrel V, Tieulié N, Guichard I, et al. DADA2 diagnosed in adulthood versus childhood: A comparative study on 306 patients including a systematic literature review and 12 French cases. Semin Arthritis Rheum. 2021;51:1170-9.
Alsultan A, Basher E, Alqanatish J, Mohammed R, Alfadhel M. Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis. Pediatr Blood Cancer. 2018;65.
Barzaghi F, Minniti F, Mauro M, Bortoli M, Balter R, Bonetti E, et al. ALPS-Like Phenotype Caused by ADA2 Deficiency Rescued by Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2019;9:2767.
Van Nieuwenhove E, Humblet-Baron S, Van Eyck L, De Somer L, Dooley J, Tousseyn T, et al. ADA2 Deficiency Mimicking Idiopathic Multicentric Castleman Disease. Pediatrics. 2018;142:e20172266.
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.
Hashem H, Egler R, Dalal J. Refractory Pure Red Cell Aplasia Manifesting as Deficiency of Adenosine Deaminase 2. J Pediatr Hematol Oncol. 2017;39:e293-6.
Sasa GS, Elghetany T, Bergstrom K, Nicholas S, Himes R, Krance RA, et al. Adenosine Deaminase 2 Deficiency as a Cause of Pure Red Cell Aplasia Mimicking Diamond Blackfan Anemia. Blood. 2015;126:3615.
Szvetnik EA, Klemann C, Hainmann I, O’Donohue MF, Farkas T, Niewisch M, et al. Diamond-Blackfan anemia phenotype caused by deficiency of adenosine deaminase 2. Blood. 2017;130:874.
Sundin M, Marits P, Nierkens S, Kolios AGA, Nilsson J. Immune Thrombocytopenia as Key Feature of a Novel ADA2 Deficiency Variant: Implication on Differential Diagnostics of ITP in Children. J Pediatr Hematol Oncol. 2019;41:155-7.
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;138:628-30.
Le Voyer T, Boutboul D, Ledoux-Pilon A, de Fontbrune FS, Boursier G, Latour S, et al. Late-Onset EBV Susceptibility and Refractory Pure Red Cell Aplasia Revealing DADA2. J Clin Immunol. 2020;40:948-53.
Staples E, Simeoni I, Stephens JC, Allen HL; NIHR-BioResource; Wright P, et al. ADA2 deficiency complicated by EBV-driven lymphoproliferative disease. Clin Immunol. 2020;215:108443.
Schena F, Penco F, Volpi S, Pastorino C, Caorsi R, Kalli F, et al. Dysregulation in B-cell responses and T follicular helper cell function in ADA2 deficiency patients. Eur J Immunol. 2021;51:206-19.
Yap JY, Moens L, Lin MW, Kane A, Kelleher A, Toong C, et al. Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency. J Clin Immunol. 2021;41:1915-35.
Claassen D, Boals M, Bowling KM, Cooper GM, Cox J, Hershfield M, et al. Complexities of genetic diagnosis illustrated by an atypical case of congenital hypoplastic anemia. Cold Spring Harb Mol Case Stud. 2018;4:a003384.
Muraoka T, Katsuramaki T, Shiraishi H, Yokoyama MM. Automated enzymatic measurement of adenosine deaminase isoenzyme activities in serum. Anal Biochem. 1990;187:268-72.
Ungerer JP, Oosthuizen HM, Bissbort SH, Vermaak WJ. Serum adenosine deaminase: isoenzymes and diagnostic application. Clin Chem. 1992;38:1322-6.
Samanta D, Cobb S, Arya K. Sneddon Syndrome: A Comprehensive Overview. J Stroke Cerebrovasc Dis. 2019;28:2098-108.
Santo GC, Baldeiras I, Guerreiro R, Ribeiro JA, Cunha R, Youngstein T, et al. Adenosine Deaminase Two and Immunoglobulin M Accurately Differentiate Adult Sneddon’s Syndrome of Unknown Cause. Cerebrovasc Dis. 2018;46:257-64.
Burillo-Sanz S, Montes-Cano MA, García-Lozano JR, Ortiz-Fernández L, Ortego-Centeno N, García-Hernández FJ, et al. Mutational profile of rare variants in inflammasome-related genes in Behçet disease: A Next Generation Sequencing approach. Sci Rep. 2017;7:8453.
Sharma A, Naidu GSRSNK, Chattopadhyay A, Acharya N, Jha S, Jain S. Novel CECR1 gene mutations causing deficiency of adenosine deaminase 2, mimicking antiphospholipid syndrome. Rheumatology (Oxford). 2019;58:181-2.
Cooray S, Omyinmi E, Hong Y, Papadopoulou C, Harper L, Al-Abadi E, et al. Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2). Rheumatology (Oxford). 2021;60:4373-8.
Lee PY, Huang Y, Zhou Q, Schnappauf O, Hershfield MS, Li Y, et al. Disrupted N-linked glycosylation as a disease mechanism in deficiency of ADA2. J Allergy Clin Immunol. 2018;142:1363-5.
Liu L, Wang W, Wang Y, Hou J, Ying W, Hui X, et al. Chinese DADA2 patient: report of two novel mutations and successful HSCT. Immunogenetics. 2019;71:299-305.
Rama M, Duflos C, Melki I, Bessis D, Bonhomme A, Martin H, et al. A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience. Eur J Hum Genet. 2018;26:960-71.
Hashem H, Vatsayan A, Gupta A, Nagle K, Hershfield M, Dalal J. Successful reduced intensity hematopoietic cell transplant in a patient with deficiency of adenosine deaminase 2. Bone Marrow Transplant. 2017;52:1575-6.
Hashem H, Bucciol G, Ozen S, Unal S, Bozkaya IO, Akarsu N, et al. Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients. J Clin Immunol. 2021;41:1633-47.
Sahin S, Adrovic A, Kasapcopur O. A monogenic autoinflammatory disease with fatal vasculitis: deficiency of adenosine deaminase 2. Curr Opin Rheumatol. 2020;32:3-14.
