Case Report
  

Diverse Phenotypic Expressions of ADA2 Deficiency: Two Case Studies

Abstract

Adenosine deaminase 2 (ADA2) deficiency is an autosomal recessive disease with varying degrees of clinical phenotypes and disease severity. The phenotypic spectrum of the disorder has expanded from vasculitis with stroke to include pure red cell aplasia, bone marrow failure, autoimmune cytopenia, lymphoproliferation, and variable degrees of immunodeficiency.
Here, we describe two cases of ADA2 deficiency: one presented with an early-onset stroke that resembled an early-onset polyarteritis nodosa (PAN), and the other as an adult-onset vasculitis that progressed to severe neutropenia with recurrent infection and lymphoproliferation. Patient 1, a 10-year-old male, had a reported pathogenic ADA2 homozygote variant; c.139G˃C (p.Gly47Arg), and patient 2, a 34-year-old male, had a reported likely pathogenic homozygous ADA2 variant; c.578C>T (p.Pro193Lys).
Our second patient was the first DADA2 patient who showed that DADA2 is not a static disease and can progress from vasculitis to bone marrow failure in the course of the disease. Therefore, the previous recommendation introducing anti–TNF-α as a preferred treatment for vasculitis manifestations and hematopoietic stem cell transplantation as the preferred treatment for bone marrow failure can no longer apply. We should consider HSCT for DADA2 patients from the very beginning.
The Physician has to be aware of this monogenic disorder's varied presentation and multi-organ involvement. Early recognition and proper treatment are crucial for this potentially fatal disease.

1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24.
2. Ehlers L, Meyts I. What a difference ADA2 makes: Insights into the pathophysiology of ADA2 deficiency from single‐cell RNA sequencing of monocytes. Wiley Online Library; 2021. p. 405-7.
3. 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. 2018;38:129-36.
4. 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(6):1664-72. e10.
5. 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(5):523-6.
6. Signa S, Bertoni A, Penco F, Caorsi R, Cafaro A, Cangemi G, et al. Adenosine deaminase 2 deficiency (DADA2): a crosstalk between innate and adaptive immunity. Front Immunol. 2022;13.
7. Pilania RK, Banday AZ, Sharma S, Kumrah R, Joshi V, Loganathan S, et al. Deficiency of Human Adenosine Deaminase Type 2–A Diagnostic Conundrum for the Hematologist. Front Immunol. 2022;13.
8. Moens L, Hershfield M, Arts K, Aksentijevich I, Meyts I. Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity. Immunological Rev. 2019;287(1):62-72.
9. 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, The Journal of the American Society of Hematology. 2017;130(24):2682-8.
10. 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. Ped Rheumatol. 2017;15:1-5.
11. Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. J Clin Immunol. 2018;38(5):569-78.
12. Pinto B, Deo P, Sharma S, Syal A, Sharma A. Expanding spectrum of DADA2: a review of phenotypes, genetics, pathogenesis and treatment. Clin Rheumatol. 2021;40:3883-96.
13. Lee PY. Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2. Front Pediatr. 2018;6:282.
14. Fayand A, Chasset F, Boutboul D, Queyrel V, Tieulié N, Guichard I, et al. editors. DADA2 diagnosed in adulthood versus childhood: a comparative study on 306 patients including a systematic literature review and 12 French cases. Seminars in Arthritis and Rheumatism; 2021: Elsevier.
15. 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.
16. 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(1):117-25.
17. Akgun-Dogan O, Simsek-Kiper PO, Taskiran E, Lissewski C, Brinkmann J, Schanze D, et al. 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. 2019;179(12):2474-80.
18. Belot A, Wassmer E, Twilt M, Lega JC, Zeef LA, Oojageer A, et al. Mutations in CECR1 associated with a neutrophil signature in peripheral blood. Pediatr Rheumatol Online J. 2014;12:44.
19. Li GM, Han X, Wu Y, Wang W, Tang HX, Lu MP, et al. A Cohort Study on Deficiency of ADA2 from China. J Clin Immunol. 2023;43(4):835-45.
20. Lee PY, Davidson BA, Abraham RS, Alter B, Arostegui JI, Bell K, et al. Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement. JAMA Netw Open. 2023;6(5):e2315894.
21. Surace AEA, Hedrich CM. The role of epigenetics in autoimmune/inflammatory disease. Front Immunol. 2019;10:1525.
22. 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. 2016;55(5):902-10.
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Keywords
Adenosine deaminase 2 Autoinflammation Bone marrow aplasia Deficiency of adenosine deaminase 2 Hematopoietic stem cell transplant
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How to Cite
1.
Razaghian A, Alizadeh Z, Meyts I, Kalantari A, Rostami Hir S, Wouters M, Fazlollahi MR. Diverse Phenotypic Expressions of ADA2 Deficiency: Two Case Studies. Iran J Allergy Asthma Immunol. 2025;:1-7.