AB0021 EXPANDING SPECTRUM OF ADA2 DEFICIENCY IN SOUTH ASIA: A CASE SERIES FROM NORTH INDIA
Authors: S. Balakrishnan, A. Aggarwal, R. Chatterjee, A. Balakrishnan, R. Kharbanda, F. Hasan, A. Lawrence, K. Mandal, U. Poddar
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Deficiency of Adenosine deaminase enzyme 2 (DADA-2) is a rare autoinflammatory disease. It results from autosomal recessive mutations in the ADA2 gene on chromosome 22q11.1. It was initially described in patients of medium vessel vasculitis with recurrent strokes. With widely available genetic testing the spectrum has expanded considerably in recent years. <h3>Objectives:</h3> To describe the clinical profile, genetic etiology and outcomes of DADA-2. <h3>Methods:</h3> We retrospectively reviewed 9 genetically proven DADA-2 patients from our institute from 2015 to 2023. Patient demographics, clinical manifestations and genetic test reports were collated from case records and electronic databases. <h3>Results:</h3> Among the 9 patients 4 patients were males. Median age of onset of disease, age of diagnosis and delay in diagnosis were 18 years (13-19.5), 23 years (17-46), and 5 years (2-25) respectively. Our patients can be divided into two distinct phenotypes, one group with predominantly vasculitis (n=7, 77 %) and another with predominantly hematological (n=6, 66%) manifestations. Most common vasculitic manifestation were fever (n=4, 44%) followed by cutaneous ulcers (n=3, 33%), mononeuritis multiplex (N=3, 33%) followed by central retinal artery occlusion (n=2, 22%) while only a single patient had the classically described recurrent strokes. Most common hematological manifestation were pancytopenia (n=3, 33%),) followed by neutropenia (n=2, 22 %) and thrombocytopenia (n=1, 11%) and. One patient who presented with severe anemia was found to have pure red cell aplasia associated with low immunoglobulin M levels and a <i>Giardia lamblia</i> infection. A family history of their sibling death due to medium vessel vasculitis was present in 2 (28%) patients. In a single family both parents and youngest child were carriers. Among the two elder siblings, one had very early onset inflammatory bowel disease (VEOIBD) with neutropenia and other had young onset hypertension. On genetic analysis 4 patients were homozygous and 5 were compound heterozygous for the pathogenic mutation in ADA-2 gene. All patient had a mutation in exon 2 resulting in a protein change due to amino acid substitution from Glycine to Arginine or Tryptophan at position 47. Four out of the 9 patients had mutation in exon 4 resulting in protein change due to amino acid substitution from Leucine to Valine at position 188.(Table 1) We had 29.45 admission per 100-person year follow up. One patient with recurrent fever and neutropenia who was awaiting allogenic stem cell transplant succumbed due to sepsis. Seven out of the 9 patients received multiple immunosuppression including Cyclophosphamide, Azathioprine, Mycophenolate mofetil, Cyclosporine. Patient with VEOIBD was managed with Azathioprine and Mesalamine. Anaemia and cytopenia responded to immunosuppression in all. Even though only one patient received anti TNF therapy, there were no incident strokes in the cohort till date. <h3>Conclusion:</h3> In our cohort, patient phenotypes are delineated similar to the existing literature as predominantly vasculitis or hematological. Exon 2 of the ADA2 gene is a mutational hotspot in India. <h3>REFERENCES:</h3> [1] Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014 Mar 6;370(10):911-20. doi: 10.1056/NEJMoa1307361. [2] Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2). J Allergy Clin Immunol. 2020 Jun;145(6):1664-1672.e10. doi: 10.1016/j.jaci.2019.12.908. [3] Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients. J Clin Immu nol. 2021 Oct;41(7):1633-1647. doi: 10.1007/s10875-021-01098-0. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>