Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India

Abstract

Objective Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India. Methods A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects. Results In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one‐half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported. Conclusion This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients

“…Treatment of DADA2 is challenging and case mortality is estimated to be around 8%, mostly in childhood and related to vasculopathy-associated complications and infections [13][14][15]. None of the classical immunosuppressive drugs are an option for the long-term treatment of DADA2, because their efficacy is temporary, especially for the DADA2 related cytopenia, or because of the toxicity associated with longterm use.…”

‘More Than Just Skin in the Game’. DADA2 Autoinflammatory Syndrome and Stroke in the Young

“…The clinical features of DADA2 in childhood-onset and adult-onset cases are quite similar; however, children have an increased prevalence of constitutional symptoms and adults have an increased prevalence of anaemia or other hematologic manifestations. [ 6 ]…”

Genetic epidemiology of autoinflammatory disease variants in Indian population from 1029 whole genomes

“…The functional analysis showed a marked reduction of ADA2 activity in comparison with the wild type in the homozygous state [ 57 , 58 ]. Recently, a case series of 33 DADA2-affected patients from India has been reported and found this variant p.G47R to be prevalent in the Jain/Aggarwal community [ 59 ]. Another ADA2 variant at the same amino acid position of the ADA2 protein (p.G47V) rs200930463 was in a trans compound heterozygous state with p.W246S in the patient affected with DADA2 [ 57 ].…”

“…In IndiGen, out of the five individuals harboring these variants, three of them had European admixture, one East Asian, and one South Asian ancestry. A recent study performed in Indian DADA2 patients identified p.G47R as a founder variant in the Aggarwal/Jain community [ 59 ]. The Aggarwal community mainly resides in North India and is a descendant of the Indo-European migrants that had high frequency of the ADA2 causal variant [ 59 , 79 ].…”

“…A recent study performed in Indian DADA2 patients identified p.G47R as a founder variant in the Aggarwal/Jain community [ 59 ]. The Aggarwal community mainly resides in North India and is a descendant of the Indo-European migrants that had high frequency of the ADA2 causal variant [ 59 , 79 ]. The RNASEH2C variant p.R69W (rs78635798) implicated in AGS found in a single individual of IndiGen had South Asian haplotype ancestry.…”