Case Report: Deficiency of Adenosine Deaminase 2 (DADA2) as a Cause of Brainstem Stroke in a 3-Year-Old Girl and the Importance of Early Fast-Track Genetic Diagnostics to Influence Therapy

Abstract:

Deficiency of adenosine deaminase 2 (DADA2) is a rare Mendelian, autoinflammatory multiorgan disease. We report the case of a 3.8-year-old female patient who was admitted with an acute brainstem stroke and was diagnosed with DADA2 by early initiation of exome sequencing. We recommend that DADA2 and a genetic workup should be taken into account, when evaluating strokes in children even if no other than neurological symptoms are evident.

Keywords

DADA2 - fast-track exome sequencing - inflammation - vasculitis - brainstem - early stroke

Publication History

Received: 07 March 2022

Accepted: 06 July 2022

Accepted Manuscript online:
11 July 2022

Article published online:
22 September 2022

• References

• 1 Zhou Q, Yang D, Ombrello AK. et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014; 370 (10) 911-920
• 2 Ombrello AK, Qin J, Hoffmann PM. et al. Treatment strategies for deficiency of adenosine deaminase 2. N Engl J Med 2019; 380 (16) 1582-1584
• 3 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 (10) 3883-3896
• 4 Schnappauf O, Zhou Q, Moura NS. et al. Deficiency of adenosine deaminase 2 (DADA2): hidden variants, reduced penetrance, and unusual inheritance. J Clin Immunol 2020; 40 (06) 917-926
• 5 Karczewski KJ, Francioli LC, Tiao G. et al; Genome Aggregation Database Consortium. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020;581(7809):434–443. Erratum in: Nature 2021;590(7846):E53. Erratum in: Nature. 2021 Sep;597(7874):E3–E4
• 6 Jee H, Huang Z, Baxter S. 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 (01) 379-387
• 7 Van Montfrans JM, Hartman EA, Braun KP. et al. Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford) 2016; 55 (05) 902-910
• 8 Moens L, Hershfield M, Arts K, Aksentijevich I, Meyts I. Human adenosine deaminase 2 deficiency: a multi-faceted inborn error of immunity. Immunol Rev 2019; 287 (01) 62-72
• 9 Bulut E, Erden A, Karadag O, Oguz KK, Ozen S. Deficiency of adenosine deaminase 2; special focus on central nervous system imaging. J Neuroradiol 2019; 46 (03) 193-198
• 10 Lee PY. Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2. Front Pediatr 2018; 6: 282
• 11 Caorsi R, Penco F, Grossi A. 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) 1648-1656 . Erratum in: Ann Rheum Dis. 2019;78(7):e73. PMID: 28522451
• 12 Zoccolillo M, Brigida I, Barzaghi F. et al. Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency. Blood Adv 2021; 5 (16) 3174-3187
• 13 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. 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 (05) 405-424
• 14 Ben-Ami T, Revel-Vilk S, Brooks R. et al. Extending the clinical phenotype of adenosine deaminase 2 deficiency. J Pediatr 2016; 177: 316-320
• 15 Robinson JT, Thorvaldsdóttir H, Wenger AM, Zehir A, Mesirov JP. Variant review with the Integrative Genomics Viewer. Cancer Res 2017; 77 (21) e31-e34
• 16 Meyts I, Aksentijevich I. Deficiency of adenosine deaminase 2 (DADA2): updates on the phenotype, genetics, pathogenesis, and treatment. J Clin Immunol 2018; 38 (05) 569-578
• 17 Elbracht M, Mull M, Wagner N. et al. Stroke as initial manifestation of adenosine deaminase 2 deficiency. Neuropediatrics 2017; 48 (02) 111-114