Novel pathogenic ADA2 mutations: alert to diagnosis challenge of ADA2 deficiency

Autoinflammatory and autoimmune diseases often present with complex and variable clinical manifestations, leading to challenges in making a diagnosis, particularly in cases that present with atypical clinical features. Somatic mutations contributing to rheumatologic diseases have been largely identified by sequencing approaches with advances and widespread availability of genomic DNA sequencing (1-5). Genotype-driven approaches have been used to delineate human diseases with diverse clinical features by looking for pathogenic variants in patients with or without particular clinical characteristics (6,7). This genotype-driven approach is particularly helpful in identifying rheumatologic diseases due to their heterogenous clinical presentations. Most recently, this approach has been successful in identifying VEXAS syndrome, a monogenic disease of adulthood caused by somatic mutations in UBA1 in hematopoietic stem and progenitor cells leading to both hematological and inflammatory manifestations (8).

Identification of adenosine deaminase 2 deficiency (DADA2) should be approached similarly. First reported in 2014, inflammation leading to tissue damage is a key clinical feature of this rare autosomal recessive monogenic disease due to loss-of-function mutations of ADA2 (9,10). DADA2 deficiency typically presents in childhood and is characterized by vasculopathy, stroke, inflammation, immunodeficiency, and hematologic manifestations (11-14).

In a recent study published on Translational Paediatrics, Yin and colleagues (15) reported a 3-year-old boy with DADA2 who initially presented with nonspecific clinical manifestations including recurrent fever, mildly enlarged lymph nodes, and elevated acute phase reactants, with an initial diagnosis of systemic onset juvenile idiopathic arthritis. The key events leading to a re-evaluation of the initial diagnosis were the presence of intractable hypertension and gastrointestinal complications suspicious for underlying vasculopathy, and an unsustained response to immunosuppressive treatments. This case report should alert clinicians to consider genetic testing in patients with nonspecific autoimmune or autoinflammatory disease phenotypes, especially in those who present in early childhood. Misdiagnosis is not unexpected when a patient presents with a wide spectrum of clinical manifestations and atypical features of DADA2.

Study of Yin et al., which was published on Translational Paediatrics, identified a novel compound heterozygous mutation in ADA2 gene (15), c.737 G>C (p. Arg246Thr) located in exon 3 and c.827 T>C (p.Phe276Ser) located in exon 4. Their experimental data revealed ADA2 enzyme activity was almost completely lost in this patient. These novel compound heterozygous variants are likely pathogenic due to their association with established disease phenotypes, family history, and functional studies showing reduced ADA2 enzyme activity. These novel mutations are likely associated with vasculitis rather than hematologic phenotypes as this patient did not have any hematological manifestations. This report expands our current knowledge of disease-causing variants in DADA2; future studies will help better characterize the genotype-phenotype relationship.

In conclusion, the study by Yin and colleagues presented a case of suspected juvenile idiopathic arthritis with atypical clinical features that led to the identification of novel disease-causing ADA2 variants. This case highlights the importance for clinicians to consider monogenic inherited autoinflammatory disorders when systemic vasculitis occurs in early childhood, patients who develop atypical manifestations of their suspected diagnosis, or have a suboptimal response to treatment. Whole genome sequencing is powerful in disease diagnosis and in recognizing novel pathogenic mutations and should be highly considered in these circumstances.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-2/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Briggs TA, Rice GI, Daly S, et al. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet 2011;43:127-31. [Crossref] [PubMed]
2. Manthiram K, Zhou Q, Aksentijevich I, et al. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol 2017;18:832-42. [Crossref] [PubMed]
3. Beck DB, Aksentijevich I. Biochemistry of Autoinflammatory Diseases: Catalyzing Monogenic Disease. Front Immunol 2019;10:101. [Crossref] [PubMed]
4. Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014;506:376-81. [Crossref] [PubMed]
5. Hoffman HM, Broderick L. Editorial: It Just Takes One: Somatic Mosaicism in Autoinflammatory Disease. Arthritis Rheumatol 2017;69:253-6. [Crossref] [PubMed]
6. Cooper GM, Coe BP, Girirajan S, et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011;43:838-46. [Crossref] [PubMed]
7. Large-scale discovery of novel genetic causes of developmental disorders. Nature 2015;519:223-8. [Crossref] [PubMed]
8. Beck DB, Ferrada MA, Sikora KA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2020;383:2628-38. [Crossref] [PubMed]
9. Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 2014;370:921-31. [Crossref] [PubMed]
10. Zhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014;370:911-20. [Crossref] [PubMed]
11. Moens L, Hershfield M, Arts K, et al. Human adenosine deaminase 2 deficiency: A multi-faceted inborn error of immunity. Immunol Rev 2019;287:62-72. [Crossref] [PubMed]
12. 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. [Crossref] [PubMed]
13. Watanabe N, Gao S, Wu Z, et al. Analysis of deficiency of adenosine deaminase 2 pathogenesis based on single-cell RNA sequencing of monocytes. J Leukoc Biol 2021;110:409-24. [Crossref] [PubMed]
14. Wu Z, Gao S, Watanabe N, et al. Single-cell profiling of T lymphocytes in deficiency of adenosine deaminase 2. J Leukoc Biol 2022;111:301-12. [Crossref] [PubMed]
15. Yin J, Fan X, Ma J, et al. ADA2 deficiency (DADA2) misdiagnosed as systemic onset juvenile idiopathic arthritis in a child carrying a novel compound heterozygous ADA2 mutation: a case report. Transl Pediatr 2023;12:97-103. [Crossref] [PubMed]