Deficiency of adenosine deaminase 2 (DADA2) is a recently described monogenic vasculopathy that occurs due to variants in the ADA2 gene (previously known as CECR1, cat eye syndrome chromosome region, candidate 1 gene). It presents with varied clinical manifestations like fever, livedoid rash, early-onset lacunar stroke, and polyarteritis nodosa like vasculitis. 1 Over the years, the spectrum of DADA2 has widened to include hematological manifestations Pure Red Cell Aplasia (PRCA), Diamond-Blackfan anemia (DBA), and neutropenia; lymphoproliferation; immunodeficiency; hepatic and gastrointestinal manifestations. 1 Of late, patients with lymphoreticular neoplasms have also been reported in association with DADA2. 1-4 Herein, we report 3 children of a family with ADA2 gene mutation who had varied hematological manifestations, including fatal Hodgkin lymphoma. A 10-year-old boy (P1), born to a non-consanguineously married couple, presented with daily fever (up to 104°F) and generalized lymphadenopathy for 4 months. He had progressive pallor associated with easy fatiguability and night sweats. There was no history of bone pain or bleeding manifestations. Prior to this presentation, parents did not report any significant past illness; he had normal growth and development and was immunized as per the national schedule without any complications. On examination, he was noted to have pallor, generalized lymphadenopathy, and massive hepatosplenomegaly. The remaining physical examination was unremarkable. His younger brother (P2, aged 5 years) was clinically asymptomatic but was noted to have firm splenomegaly on examination. Their youngest sibling (P3, an 18-month-old boy) had received a working hypothesis of thalassemia at the local primary healthcare facility where he was noted to have repeated falls in hemoglobin level without other cell lineages being affected since 2 months of age. Hemoglobin high-performance liquid chromatography was not suggestive of hemoglobinopathies. Bone marrow examination was not done but was advised to receive regular packed red cell transfusions. No dysmorphism, lymphadenopathy, or organomegaly was noted in P3. Laboratory investigations of P1 revealed anemia, leukopenia, and thrombocytopenia (Table 1). Fine needle aspiration cytology of the right cervical lymph node showed reactive changes. However, subsequent lymph node excision biopsy revealed Reed Sternberg cells with immunopositivity for CD30, CD15, occasional CD20, and PAX5 (dim nuclear) suggestive of Hodgkin lymphoma (nodular sclerosis, syncytial variant) (Figure 1, Panel A–D). Tissue staining for EBV could not be performed. Bone marrow biopsy showed large cells with prominent nucleoli that were CD20 and CD45 positive, suggesting infiltration. Immunological investigations showed pan-hypogammaglobulinemia and low CD19 B cells (Table 1). Flow cytometric estimation of Bruton tyrosine kinase (Btk) protein and Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) were normal. Percentage of double-negative T cells were also normal (Table 1). Epstein–Barr virus (EBV) viral load was 1. 7 million copies/ml. On day 4 of hospitalization, the patient had persistent temperature and features of multiorgan dysfunction. Laboratory markers suggested hemophagocytic lymphohistiocytosis (HLH) (Table 1). He was administered 1 g/kg of intravenous immunoglobulin and pulse methylprednisolone (30 mg/kg/dose for 5 days) ; however, poor response and rapid progression resulted in his demise. Targeted next-generation sequencing panel for primary immunodeficiency genes revealed a compound heterozygous state with two novel variants in exon 5 of the ADA2 gene a nonsense mutation: c. 806dup, (p. Tyr269Ter), and a frameshift mutation with premature truncation: c. 777₇80dup, (p. Asp261ProfsTer2). Plasma ADA2 levels could not be estimated. CD19+ B cells (N: 13%–27%) CD3+ T cells (N: 51%–77%) CD56+ NK cells (N: 03%–14%) 1. 2% 91. 47% 3. 89% Detailed evaluation of siblings was later carried out at follow-up. Bone marrow examination in P3 revealed erythroblastopenia with preservation of other cell lines along with peripheral blood reticulocytopenia, consistent with PRCA (Figure S1). Serology for antibodies against parvovirus and EBV (IgM) was negative. Laboratory investigations of the siblings (P2 and P3) have also been summarized in Table 1. Plasma ADA2 levels were measured using extracts of dried plasma spots in P3 and the parents. P3 was found to be deficient (4. 4 mU/g protein, N: 76–183) while it was 51. 5 and 31. 9 mU/g protein (normal range: 76–183 mU/g protein; reported range in carriers: 33. 3–77. 3 mU/g protein) in mother and father respectively, suggestive of carrier status. On genetic testing, P2 and P3 were also found to be compound heterozygous for the same variant as P1. Father was heterozygous (carrier) for the frameshift mutation in exon 5 of the ADA2 gene c. 777₇80dup, (p. Asp261ProfsTer2), whereas the mother was heterozygous (carrier) of the nonsense mutation in exon 5 of the ADA2 gene c. 806dup, (p. Tyr269Ter). After establishing the diagnosis of DADA2, P3 was initiated on oral prednisolone at 2 mg/kg/day. The transfusion requirement reduced considerably and was able to maintain stable hemoglobin between 80 and 100 g/L Need for anti TNF therapy and later hematopoietic stem cell transplantation (HSCT) was advised but due to financial constraints the family defaulted on follow-up at our centre. On recently contacting the family, it was revealed that P2 succumbed to his illness at home 2 years after the diagnosis. He received anti-TNF therapy for a few months, but the response was poor and HSCT could not be performed. P3 continues to be asymptomatic and has been initiated on anti-TNF therapy supported by the National Policy for Rare Diseases, India. We report 3 brothers with a novel compound heterozygous mutation in the ADA2 gene with varied hematological manifestations within the same family. Manifestation ranged from asymptomatic splenomegaly, red cell aplasia to fatal EBV-related Hodgkin lymphoma and HLH. ADA2 is an extracellular protein secreted predominantly by monocytes and other cells of the myeloid lineage. 1, 2 It acts as a growth factor for maintaining the integrity of endothelial cells and for promoting the differentiation of monocytes. 1, 2 ADA2-deficient monocytes differentiate preferentially into M1-type of macrophages, and this results in an increased pro-inflammatory milieu. 1 In 2018, Trotta et al. described 2 adults with T cell large granular lymphoma, while Springer et al. and Alabbas et al. reported Hodgkin lymphoma in association with ADA2 deficiency in 3 patients. 3, 4 EBV-induced lymphoproliferation in DADA2 has also been described in a patient who was successfully treated by HSCT following chemotherapy. 3 P1 had EBV-associated Hodgkin lymphoma along with fatal HLH. PRCA is a well-recognized manifestation of DADA2. PRCA may be the only initial presentation of DADA2, while other manifestations may evolve. Development of infections, cytopenias, livedoid rash, or lymphoproliferation provides clinical clues to suspect DADA2. This is evident from Table S1, a collection of reported cases of DADA2 with initial presentation with PRCA. 5, 11 It is also evident that PRCA occurs early in childhood with a median age at onset of 4 months (range: birth to 14 years). Very early age of onset of PRCA must alert to the need for early genetic testing including that for DADA2. Anti-TNF drugs are the standard of care for vasculitis and autoimmune manifestations of DADA2; however, hematological manifestations are usually less responsive to these agents. 1, 12 Thus, treatment of PRCA in the context of DADA2 remains a challenge as only ~44% of patients presenting with PRCA are steroid-responsive. 1 Other immunomodulatory agents used in treatment include intravenous immunoglobulin (IVIg), cyclosporine, sirolimus, mycophenolate mofetil, and azathioprine with variable responses. HSCT remains the only curative therapy for these patients. Correlation between genotype and phenotype in DADA2 was established recently. 1 Missense variants with subtotal functional loss of ADA2 activity were associated with vasculitic phenotype, whereas nonsense, frameshift and indel variantswith near-total functional loss of ADA2 activity were associated with severe hematologic phenotypes and increased risk of malignancy. Our patients were compound heterozygous with novel nonsense and frameshift mutations with near-total loss of functional ADA2 activity, suggesting more deleterious hematological manifestations. Albalawi et al. 13 and Gardner et al. 14 have similarly reported a 10-year-old boy with Hodgkin lymphoma and a 38-year-old patient with EBV positive DLBCL with homozygous deletion in ADA2 gene respectively. The exact pathogenesis of hematological manifestations and development of malignancy remains unclear. More research is needed to provide insights into genotypic correlation with malignancies arising from ADA2 deficiency. To conclude, patients with DADA2 are predisposed to hematological manifestations like PRCA and are predisposed to malignancy. We report a novel compound heterozygous mutation in a family with varied hematological manifestations in the same kindred. Murugan Sudhakar: Conceptualization; investigation; writing – original draft; writing – review and editing. Rajni Kumrah: Investigation; writing – review and editing. Gummadi Anjani: Investigation; conceptualization; writing – original draft; writing – review and editing. Rashmi Rikhi: Investigation; writing – review and editing. Ankur Jindal: Conceptualization; investigation; writing – review and editing. Amit Rawat: Investigation; writing – review and editing. Kirti Gupta: Investigation; writing – review and editing. Prashant Sharma: Investigation; writing – review and editing. Deepti Suri: Investigation; conceptualization; writing – original draft; writing – review and editing; methodology. Surjit Singh: Conceptualization; investigation; writing – original draft; writing – review and editing. We acknowledge Prof. Michael S. Hershfield and his laboratory at Duke University Medical Centre, Durham, USA for supporting ADA2 enzyme activity estimation. No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. The case report was approved by the Departmental Review Board (DRB 21nstitutional Review Board accepted the manuscript DRB 2-125. Original data is available with the corresponding author and shall be made available on reasonable request. Figure S1. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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Sudhakar et al. (Sun,) studied this question.