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Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite CD4+ and CD8+ lymphocytes' reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients' long-term recovery., Competing Interests: The San Raffaele Telethon Institute for Gene Therapy SR-TIGET is a joint venture between the Telethon Foundation and Ospedale San Raffaele OSR. Gene therapy for ADA-SCID was developed at SR-TIGET and licensed to GlaxoSmithKline GSK in 2010. Strimvelis Marketing Authorization in Europe occurred in 2016 under GSK holding and the product is currently licensed in Iceland, Norway, Liechtenstein, and UK. Orchard Therapeutics Netherlands B.V. is the Marketing Authorization Holder in the EU and Orchard Therapeutics Europe Limited is the Marketing Authorization Holder in the UK. AA was the PI of pilot and pivotal SR-TIGET clinical trial of gene therapy for ADA SCID. MC the PI of the Strimvelis Registry. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fratini, Migliavacca, Barzaghi, Fossati, Giannelli, Monti, Casiraghi, Ferrua, Recupero, Consiglieri, Calbi, Tucci, Gallo, Bernardo, Cenciarelli, Palmoni, Moni, Galimberti, Duse, Leonardi, Sieni, Soncini, Porta, Notarangelo, De Santis, Ladogana, Aiuti and Cicalese.)

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including vasculitis, immunodeficiency, and hematologic manifestations, potentially progressing over time. The present study describes the long-term evolution of the immuno-hematological features and therapeutic challenge of two identical adult twin sisters affected by DADA2. The absence of plasmatic adenosine deaminase 2 (ADA2) activity in both twins suggested the diagnosis of DADA2, then confirmed by genetic analysis. Exon sequencing revealed a missense (p.Leu188Pro) mutation on the paternal ADA2 allele. While, whole genome sequencing identified an unreported deletion (IVS6_IVS7del*) on the maternal allele predicted to produce a transcript missing exon 7. The patients experienced the disease onset during childhood with early strokes (Patient 1 at two years, Patient 2 at eight years of age), subsequently followed by other shared DADA2-associated features, including neutropenia, hypogammaglobulinemia, reduced switched memory B cells, inverted CD4:CD8 ratio, increased naïve T cells, reduced follicular regulatory T cells, the almost complete absence of NK cells, T-large granular cell leukemia, and osteoporosis. Disease evolution differed: clinical manifestations presented several years earlier and were more pronounced in Patient 1 than in Patient 2. Due to G-CSF refractory life-threatening neutropenia, Patient 1 successfully underwent an urgent hematopoietic stem cell transplantation (HSCT) from a 9/10 matched unrelated donor. Patient 2 experienced a similar, although delayed, disease evolution and is currently on anti-TNF therapy and anti-infectious prophylaxis. The unique cases confirmed that heterozygous patients with null ADA2 activity deserve deep investigation for possible structural variants on a single allele. Moreover, this report emphasizes the importance of timely recognizing DADA2 at the onset to allow adequate follow-up and detection of disease progression. Finally, the therapeutic management in these identical twins raises significant concerns as they share a similar phenotype, with a delayed but almost predictable disease evolution in one of them, who could benefit from a prompt definitive treatment like elective allogeneic HSCT. Additional data are required to assess whether the absence of enzymatic activity at diagnosis is associated with hematological involvement and is also predictive of bone marrow dysfunction, encouraging early HSCT to improve functional outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barzaghi, Cicalese, Zoccolillo, Brigida, Barcella, Merelli, Sartirana, Zanussi, Calbi, Bernardo, Tucci, Migliavacca, Giglio, Doglio, Canarutto, Ferrua, Consiglieri, Prunotto, Saettini, Bonanomi, Rovere-Querini, Di Colo, Jofra, Fousteri, Penco, Gattorno, Hershfield, Bongiovanni, Ponzoni, Marktel, Milani, Peccatori, Ciceri, Mortellaro and Aiuti.)

In this work we present the case of SARS-CoV-2 infection in a 1.5-year-old boy affected by severe Wiskott-Aldrich Syndrome with previous history of autoinflammatory disease, occurring 5 months after treatment with gene therapy. Before SARS-CoV-2 infection, the patient had obtained engraftment of gene corrected cells, resulting in WASP expression restoration and early immune reconstitution. The patient produced specific immunoglobulins to SARS-CoV-2 at high titer with neutralizing capacity and experienced a mild course of infection, with limited inflammatory complications, despite pre-gene therapy clinical phenotype., Competing Interests: The San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) is a joint venture between the Italian Telethon Foundation and Ospedale San Raffaele (OSR). WAS gene therapy was licensed to GlaxoSmithKline in 2014 and then transferred to Orchard Therapeutics (OTL) in April 2018. AA, FFe, MC and SC are investigators of trial # NCT03837483. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with several of the authors VG, FB, MC, FFe, and AA., (Copyright © 2020 Cenciarelli, Calbi, Barzaghi, Bernardo, Oltolini, Migliavacca, Gallo, Tucci, Fraschetta, Albertazzi, Fratini, Consiglieri, Giannelli, Dionisio, Sartirana, Racca, Camesasca, Peretto, Daverio, Esposito, De Cobelli, Silvani, Rabusin, Cara, Trabattoni, Dispinseri, Scarlatti, Piemonti, Lampasona, Cicalese, Aiuti and Ferrua.)