Chen X, Zhao X, Pan B
… +6 more, Wang L, Xie W, Jiang W, Yang J, Wu W, Li Y
J Clin Immunol
· 2025 Jul · PMID 40650809
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Congenital neutropenia (CN) is a rare hereditary blood disorder characterized by a significant reduction in neutrophils, making patients prone to recurrent and severe infections and even a risk of developing myelodysplas...Congenital neutropenia (CN) is a rare hereditary blood disorder characterized by a significant reduction in neutrophils, making patients prone to recurrent and severe infections and even a risk of developing myelodysplastic syndrome or acute leukemia, often caused by the ELANE variants, and the complex relationship between ELANE variants and clinical phenotypes, as well as the natural course of the disease, remains unclear. We describe a case of CN in a Chinese infant caused by the De Novo missense variant c.170 C > A in the ELANE gene, presented with persistent neutropenia since the neonatal period, accompanied by recurrent infections. He did not receive G-CSF treatment due to the declination of his parents, but antibiotics were administered during infections or with high hsCRP levels. During the early neonatal stage, the patient consistently exhibited severe neutropenia (ANC < 0.5 × 10^9/L). Periodic fluctuations in neutrophil counts observed twice a week during particular months suggest a cyclical pattern. Until now, he still experiences varying degrees of neutropenia persistently, with ANC occasionally exceeding 1.0 × 10^9/L during infections. Multiple prediction scoring tools and models support the pathogenicity of this missense variant. This case highlights a rare pathogenic variant of ELANE, which, to our knowledge, is the first case of the variant c.170 C > A (p.Ala57Asp) of the intermediate phenotype of CN in mainland China and a rare variant globally, indicating phenotypic variability in ELANE-related neutropenia due to an Ala57 mutation. The clinical management of CN caused by ELANE variants poses a challenge for clinicians and deserves attention. Timely diagnosis, treatment, and extended follow-up are of paramount value.
Perrard N, Collet A, Stabler S
… +9 more, Poizot S, Labalette M, Durand G, Batteux F, Mirgot F, Lopez B, Dubucquoi S, Chevrier L, Lefèvre G
J Clin Immunol
· 2025 Jul · PMID 40637813
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Streptococcus pneumoniae can be responsible for severe infections, especially in patients with primary antibody deficiencies like selective anti-polysaccharide antibodies deficiency (SPAD). The reference method recommane...Streptococcus pneumoniae can be responsible for severe infections, especially in patients with primary antibody deficiencies like selective anti-polysaccharide antibodies deficiency (SPAD). The reference method recommaned by the World Health Organization for assessment of anti-pneumococcal capsular polysaccharides (PCPs) IgG antibodies is a standardized serotype-specific ELISA (WHO-SSA), but this manual method is time-consuming and limit the number of evaluated PCPs. We aim to evaluate the performance values of a multiplex assay based on electrochemiluminescence (ECL-plex). A panel of 164 sera from 82 patients sampled before and 4-8 weeks after immunization by the 23-valent pneumococcal polysaccharide vaccine (PPV23) were assessed by the reference WHO-SSA (7 to 13 serotypes) and by an 18-plex ECL assay (18 serotypes). All patients had normal serum Ig/subclasses levels and were classified as good (n = 43) or poor responders (n = 39, i.e. SPAD patients) according to the American Academy of Asthma, Allergy and Immunology's (AAAAI) current guidelines. We observed excellent correlations between the two methods for anti-PCPs titers against 7 serotypes (r = 0.88 [95% CI: 0.87-0.90], n = 124 sera) and 13 serotypes (r = 0.87 [0.87-0.89], n = 40 sera). Using the AAAAI's guidelines for interpretation, the test performance of the 18-plex ECL assay for SPAD diagnosis showed a sensitivity of 95% and specificity of 84%, positive and negative predictive values of 84% and 95%, respectively. The percentage of agreement was 89% between the SSA and the 18-plex ECL assay. The 18-plex ECL assay is a reliable, rapid, and simple method for evaluating anti-PCPs response and screening for SPAD diagnosis.
Diab F, Louvrier C, Fabre M
… +11 more, Lin C, Rabbaa M, Assrawi E, Daskalopoulou A, Mani R, Dastot Le Moal F, Piterboth W, Legendre M, Amselem S, Karabina SA, Giurgea I
J Clin Immunol
· 2025 Jul · PMID 40627075
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Autoinflammatory diseases (AIDs) are a group of disorders caused by a dysregulation of the innate immune system, among which inflammasomopathies are characterized by recurrent episodes of fever associated with systemic i...Autoinflammatory diseases (AIDs) are a group of disorders caused by a dysregulation of the innate immune system, among which inflammasomopathies are characterized by recurrent episodes of fever associated with systemic inflammation and organ involvement. Gain-of-function variants in the inflammasome-related gene NLRC4 underlie severe phenotypes such as infantile enterocolitis and macrophage activation syndrome (MAS). While most NLRC4 variants are germline, somatic mosaic variants remain rare, with only three documented cases. In this study, following a targeted deep next-generation sequencing approach, we identified a NLRC4 variant —c.398C>T p.(Thr133Ile)— in a somatic mosaic state (variant allele fraction of 5%) in a 28-year-old patient with recurrent episodes of systemic inflammation without MAS. Functional analyses revealed that this variant, as well as two previously reported NLRC4 mosaic variants, resulted in a gain-of-function effect on NLRC4 inflammasome and NF-κB pathway activation. While relying on data from all reported patients with NLRC4 mosaic variants, we also showed that all mosaic variants cluster near the NLRC4 adenosine-diphosphate binding site and that patients with high levels of mosaicism had earlier and more severe symptoms than those with lower mosaicism levels. Overall, our findings, which unveil a correlation between the percentage of mosaicism and the age of onset and severity of the disease, underline the need to recognize the full spectrum of NLRC4-AIDs, which can often be underdiagnosed, particularly in patients with low mosaicism levels. Such a diagnosis is, however, essential, as targeted treatments —such as anti-IL-1 therapies, which proved highly effective for our patient— can significantly improve patient outcomes.
Mora-Buch R, Tomás-Marín M, Pasamar H
… +3 more, Enrich E, Peña-Gómez C, Rudilla F
J Clin Immunol
· 2025 Jun · PMID 40537681
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PURPOSE: The increasing application of virus-specific T cell therapy for treating BK virus infections in immunocompromised patients highlights the necessity for rapid identification of compatible cell donors with optimal...PURPOSE: The increasing application of virus-specific T cell therapy for treating BK virus infections in immunocompromised patients highlights the necessity for rapid identification of compatible cell donors with optimal BK-specific T cell response. This study aims to characterize the BK virus-specific T cell response in relation to demographic factors, blood group, serological status, and HLA genotypes using samples from a cell donor registry. METHODS: Peripheral blood mononuclear cells from cell donors were stimulated with peptide pools derived from VP1 and LTA proteins, and the IFN-γ production was analyzed using ELISpot and validated by flow cytometry. RESULTS: Our findings provide an overview of the T cell response to BK virus proteins in healthy donors, revealing associations with demographic characteristics, RhD status, CMV or EBV serological status, and HLA alleles. Remarkably, RhD-negative, CMV-seronegative, and EBV-seronegative donors showed a major T cell response against BK virus proteins. Notably, certain HLA alleles were associated with either enhanced or diminished T cell response. Furthermore, our results suggest that HLA-B leader dimorphism, specifically the presence of threonine at position 2, influences the VP1-specific immune response, resulting in enhanced T cell activation. CONCLUSION: This study, beyond advancing our understanding of the relationship between donor characteristics and BK virus-specific T cell response, has significant implications for improving the selection of optimal cell donors for patient-specific adoptive therapy.
Sharma S, Basu S, Goyal T
… +17 more, Sharma M, Barman P, Kaur G, Shandilya JK, Vignesh P, Pilania RK, Jindal AK, Dhaliwal M, Bhatia P, Sreedharanunni S, Rastogi P, Mallik N, Sharma P, Kaur A, Suri D, Rawat A, Singh S
J Clin Immunol
· 2025 Jun · PMID 40536602
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Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is the commonest cause of familial hemophagocytic lymphohistiocytosis (FHLH). In this retrospective study, we analyzed 8 patients with a genetic diagnosis of FHL2...Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is the commonest cause of familial hemophagocytic lymphohistiocytosis (FHLH). In this retrospective study, we analyzed 8 patients with a genetic diagnosis of FHL2 and then examined their clinicopathological and perforin flow cytometry results (< 10% expression). The atypical clinical features in our cohort included tuberculosis, lymphoreticular malignancy, and necrotizing enterocolitis in 3 patients. A disease-causing variant was identified in the PRF1 gene in all eight patients, comprising missense (n = 6), null (n = 1), and in-frame deletion (n = 1). Five patients had homozygous exon 3 disease-causing variants, two had homozygous exon 2 disease-causing variants, and one had compound heterozygous disease-causing variants in exon 2 and exon 3. After an extensive literature search, the mutations present in our North Indian cohort, including c.1284G > A, c.895C > T, c.853_855del, c.203G > A, and c.757G > A, are reported for the first time from India. Clinical and immunological phenotypes of c.1284G > A and c.203G > A variants have not been published in the literature. Hemophagocytosis was evident in bone marrow in 6 cases. Hyperferritinemia was absent in 3 cases, including c.148G > A, c. 895C > T, and c.1349C > T homozygous variants. Neurological involvement, lymphoreticular malignancy, and necrotizing enterocolitis were seen in 2, 1, and 1 cases, respectively. Infections were present in 4 cases. Five children succumbed to HLH, and three are alive and planned for a hematopoietic stem cell transplant. FHL2 should be suspected in children with HLH irrespective of the age of onset, atypical clinical phenotype, family history, ferritin and fibrinogen levels, and infections. Flow cytometry-based perforin assay helps in rapid diagnosis of FHL2.
Signa S, Bartolucci M, Bonacini M
… +24 more, Bertoni A, Del Zotto G, Corcione A, Petretto A, Della Bella S, Bertelli R, Di Silvestre D, Lomagno A, Mauri P, Caorsi R, Bruschi M, Balin S, Bocca P, Volpi S, Catanoso MG, Cafaro A, Tripodi G, Pellottieri L, Mavilio D, Insalaco A, Croci S, Salvarani C, Gattorno M, Schena F
J Clin Immunol
· 2025 Jun · PMID 40518491
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PURPOSE: Adenosine deaminase 2 Deficiency (DADA2) is an autoinflammatory disease characterized by systemic vasculopathy, strokes and mild immunodeficiency. Recently NETosis has been implicated in the pathogenesis of Defi...PURPOSE: Adenosine deaminase 2 Deficiency (DADA2) is an autoinflammatory disease characterized by systemic vasculopathy, strokes and mild immunodeficiency. Recently NETosis has been implicated in the pathogenesis of Deficiency of Adenosine Deaminase 2. To deep investigate the possible effects of NETs on the immune system we characterized proteomic profile of NETs from DADA2 as compared to HD and Polyarteritis Nodosa (PAN) patients. To determine if NETs contain possibly immunogenic antigens we study functional aspects on Dendritic Cells after in vitro stimulation with NETs. METHODS: Twenty-three DADA2 patients were enrolled. We analyzed NETosis by Imaging Flow Citometry. We evaluated NETs remnants and DNAse in the plasma samples by ELISA assay whereas DNAse activity by DNA digestion. We used quantitative proteomics approach and network analysis to identify NET proteins and pathways in 6 DADA2, 7 PAN and 7 HD. We analyzed circulating and monocyte-derived dendritic cells by flow cytometry. RESULTS: Neutrophils from DADA2 patients show a significant increased suicidal NETosis. DNAse enzymes were not normal in the level or activity. By proteomic analysis we identified 1356 proteins among which a hundred of proteins were significantly up or down-modulated in DADA2 NETs as compared to normal and disease control NETs in resting condition and after stimulation with PMA, Adenosine and TNFα. DADA2 NETs are significantly more efficient than normal NETs in stimulating patients' monocyte-derived dendritic cells. CONCLUSION: We identified different pathways significantly modulated in DADA2 NETs versus PAN/HD NETs. This peculiar protein profile could contribute in activating inflammatory pathways in Dendritic cells in DADA2.
Baggio C, Oliviero F, Galozzi P
… +5 more, Guidea I, Doria A, Ramonda R, Bindoli S, Sfriso P
J Clin Immunol
· 2025 Jun · PMID 40493122
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Familial Mediterranean Fever (FMF) is caused by mutations in the MEFV gene, which encodes for pyrin. Although genetic testing is commonly employed for FMF diagnosis, the interpretation of genetic results is often challen...Familial Mediterranean Fever (FMF) is caused by mutations in the MEFV gene, which encodes for pyrin. Although genetic testing is commonly employed for FMF diagnosis, the interpretation of genetic results is often challenging. Therefore, we aimed to functionally characterise the p.R202Q MEFV alteration. Furthermore, we hypothesized that inflammation may affect genomic stability and neutrophilic (N) subsets. A cohort comprising patients with FMF (n = 4), p.R202Q variant (n = 18) and FMF-like (n = 8) were selected from the Outpatient Clinic for Autoinflammatory diseases of Padova University Hospital. Primary monocytes were incubated for 3 h in the presence of LPS or LPS + PKN1/2 inhibitor (UCN-01). Colchicine pretreatment was applied to assess its anti-inflammatory effect. Pro-inflammatory cytokines were measured by ELISA and leukocytes were examined using May-Grünwald-Giemsa staining on blood smears. We did not find significant differences in IL-1 and IL-18 levels in monocytes treated with LPS + UCN-01 between p.R202Q patients and healthy donors (HDs). The levels of IL-1β released from LPS-stimulated patients were higher in p.R202Q patients than in HDs. We found that immature and hypersegmented neutrophils were higher in p.R202Q patients than in HD. Nuclear abnormalities were higher in FMF and p.R202Q patients than in HD. Finally, we found a higher cell rate in leukocytes from p.R202Q patients than in HDs. The p.R202Q variant did not appear to affect pyrin function, albeit these patients presented cytological alterations similar to those observed in FMF patients. These changes may contribute to FMF pathophysiology by influencing inflammation progression.
Süleyman M, Cagdas D, Kiper PÖŞ
… +3 more, Ütine GE, Çavdar MK, Tezcan Fİ
J Clin Immunol
· 2025 Jun · PMID 40461840
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BACKGROUND: DiGeorge Syndrome (DGS), a microdeletion syndrome, shows a broad spectrum from mild T-cell lymphopenia to severe combined immunodeficiency. AIM: To define the clinical/immunophenotypical biomarkers for DGS. P...BACKGROUND: DiGeorge Syndrome (DGS), a microdeletion syndrome, shows a broad spectrum from mild T-cell lymphopenia to severe combined immunodeficiency. AIM: To define the clinical/immunophenotypical biomarkers for DGS. PATIENTS AND METHODS: A total of 72 patients with 22q11.2 deletion(n = 66) and those fulfilling the DGS criteria without deletion (n = 6) were enrolled. RESULTS: The male/female ratio was 41/31. Median age at clinical diagnosis was 1.7 years (0 days-22 years) with follow-up for 21.7 months (0 days-17.3 years). Common evaluation reasons were cardiac features (30.6%), failure to thrive (15.3%), and neurological features (15.3%). Craniofacial dysmorphism (64/66, 97%), central nervous system findings (62/72, 86.1%), and congenital cardiovascular defect (43/70, 61.4%) were common. We noted lymphopenia (30/72, 41.7%) and low IgM (25/69, 36.2%). T helper cell counts were low in 49.3% (33/67). T cytotoxic and NK cell counts were normal/high in 80.6% (54/67) and 97% (65/67) of patients, respectively. 42.3% (11/26) had low CD4 + TEMRA, and 34.6% (9/26) had low CD8 + TEM percentages. None had low CD8 + TEMRA. B cells were normal/high (52/67, 77.6%). 30.8%(8/26) had low switched-memory and 38.5% (10/26) had low active B cell percentages. Low IgA levels were associated with decreased lymphocyte activation and recent thymic emigrant (RTE) cell percentages. Six(8.3%) patients with lymphopenia, three of whom had congenital athymia, died. CONCLUSION: CD4 lymphopenia was more common than CD8 lymphopenia. Normal/high CD8 + and NK cell counts were remarkable. Increased CD8+ TEMRA cells seem to indicate peripheral homeostatic proliferation following viral infections. Low serum IgA correlated with low RTE% and impaired T-cell function. DGS severity markers include hypocalcemia, congenital cardiac anomaly, and T-cell lymphopenia.
J Clin Immunol
· 2025 Jun · PMID 40455168
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PURPOSE: Genetics of Common Variable Immunodeficiency (CVID) is complex and not fully elucidated. This study presents the clinical and genetic findings of a Danish CVID cohort and investigate whether initial genetic find...PURPOSE: Genetics of Common Variable Immunodeficiency (CVID) is complex and not fully elucidated. This study presents the clinical and genetic findings of a Danish CVID cohort and investigate whether initial genetic findings can be re-classified upon re-evaluation years later in time. METHODS: From 2016 to 2021, individuals with CVID or a CVID-like-phenotype were examined using whole exome or whole genome sequencing in combination with comprehensive gene-panels. The results were re-evaluated to ensure up-to-date American College of Medical Genetics and Genomics (ACMG) classification after a median of 3.9 years. Further, a clinical-interpretation-algorithm is proposed. RESULTS: Of 69 enrolled individuals, 57 met the current ESID-CVID-criteria of whom 29 (51%) had a genetic find. In total 67 ACMG class 3 to 5 variants were detected in 39 different genes. Class 3 variants (variants of uncertain significance (VUS)) accounted for 81% in the initial analysis. Upon re-evaluation 17 of 54 (31%) of the originally reported VUS were re-classified to a different ACMG-class or excluded. The developed clinical-interpretation-algorithm demonstrated high interobserver-agreement. A “definite/probable” disease causing (or contributing) genetic variant was found in 19% of the CVID-cohort and a “possible” in 18%. CONCLUSION: A genetic cause of CVID could be identified in a minority of CVID-individuals, whereas the majority had no or uncertain genetic findings. Re-evaluation of genetic results over time is recommended, though VUS remain a significant challenge in CVID-genetics. Therefore, continued research in both CVID-genetics and in non-genetic causes of CVID is needed.
Antolí A, Vargas-Parra G, Sierra-Fortuny A
… +12 more, Gomez-Vazquez JL, Rofes P, Munté E, Viana-Errasti J, Marín-Montes R, López-Doriga A, Feliubadaló L, Del Valle J, Pérez-González A, Poveda E, Solanich X, Lázaro C
J Clin Immunol
· 2025 May · PMID 40423910
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TLR7, which encodes a key receptor for single-stranded RNA (ssRNA) virus of the innate immune system, was recently associated with X-linked immunodeficiency and COVID-19 susceptibility. This study investigates the associ...TLR7, which encodes a key receptor for single-stranded RNA (ssRNA) virus of the innate immune system, was recently associated with X-linked immunodeficiency and COVID-19 susceptibility. This study investigates the association between TLR7 variants and susceptibility to severe COVID-19 in a multicentric Spanish cohort. The TLR7 gene was sequenced in a cohort of 365 COVID-19 patients, stratified into two groups: one comprising mild and asymptomatic patients, considered as controls (n = 87), and the other consisting of moderate to severely affected patients hospitalized due to COVID-19 pneumonia, considered as cases (n = 278). A total of 152 unique TLR7 variants were identified, of note, six rare variants were identified in 11 cases (3.96%), all of whom belonged to the case group. The functional impact of rare TLR7 variants was assessed using a luciferase reporter assay and revealed that N215S is a loss-of-function (LOF) variant, while D332G exhibits an hypomorphic behavior. Conversely, H90Y, V219I, A448V, and R902K maintained normal signaling. No skewed X-inactivation was observed in female carriers of N215S or D332G. In addition, the common variants Q11L (rs179008), c.4-151A>G (rs179009) and c.*881C>G (rs3853839) were associated with severe pneumonia, while c.4-151A>G (rs179009) was specifically linked to Intensive Care Unit (ICU) admission. These findings highlight the role of TLR7 in antiviral immune response and its association with severe COVID-19 in men. The luciferase assay proves to be a reliable tool for evaluating TLR7 signaling, effectively distinguishing between neutral, LOF, and gain-of-function (GOF) variants. Further research is needed to better understand TLR7 variants and its implications in immunodeficiency and immune dysregulation.
Zhang W, Scott AF, Mohr DW
… +8 more, Ingersoll R, Shoucair PE, Bream JH, Nilles TL, Zhang H, Chen Y, Mailliard RB, Margolick JB
J Clin Immunol
· 2025 May · PMID 40411624
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A man living with HIV was found to lack expression of CD16A on his natural killer (NK) cells and monocytes. Genetic analysis revealed compound heterozygous deletion of FCGR3A, the gene encoding CD16A. The case's NK cells...A man living with HIV was found to lack expression of CD16A on his natural killer (NK) cells and monocytes. Genetic analysis revealed compound heterozygous deletion of FCGR3A, the gene encoding CD16A. The case's NK cells showed: (a) no antibody-dependent cell-mediated cytotoxicity and very low spontaneous cytotoxicity; (b) an immature phenotype marked by high expression of CD94, CD2, NKG2A, and NKG2D, and low expression of KIR2DL2 and CD57; (c) no expression of KIR3DL1 and very low expression of FcRγ; and (d) normal cytokine production. The case's monocytes and DCs were similar phenotypically and functionally to those from the donors matched for HIV status, age, and percentage of NK cells in the peripheral blood. In contrast to previously reported people with CD16A deficiency, this man did not have a history of severe infections with herpes viruses, suggesting that other immune cells and/or immunoregulatory function of NK cells may compensate for deficiency of cytolytic NK cells.
De Renzis C, Gambier RF, Gigante A
… +13 more, Deiana CM, Lagnese G, Gatti L, Garzi G, Costanzo G, Pagnozzi C, Nicola S, Brussino L, Spadaro G, Rattazzi M, Firinu D, Cinetto F, Milito C
J Clin Immunol
· 2025 May · PMID 40407942
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PURPOSE: There are few reports of renal involvement in Common Variable Immunodeficiencies (CVID) and, when present, is due to infections, inflammation, or treatments. The aim of this study was evaluating the prevalence o...PURPOSE: There are few reports of renal involvement in Common Variable Immunodeficiencies (CVID) and, when present, is due to infections, inflammation, or treatments. The aim of this study was evaluating the prevalence of chronic kidney disease (CKD) and to identify CVID-related clinical, laboratory and therapeutic features inducing it. METHODS: A multicenter observational retrospective study on 367 adult CVID patients from five Italian Referral Centers for Primary Immunodeficiency. RESULTS: CKD was identified in 23 (6.27%) patients that were older (p < 0.001), had arterial hypertension (p < 0.001), diabetes (p = 0.002), dyslipidemia (p = 0.002), presented different ultrasound abnormalities (p < 0.001) and received predominantly intravenous immunoglobulins (IVIG) (p = 0.016). Regarding CVID infectious and non-infectious manifestations, CKD patients presented a higher frequency of COPD (p = 0.008). In the CKD group, the median absolute count of total lymphocytes (p = 0.015), the percentage of total B (p = 0.028) and transitional B cells (p = 0.008) were lower. By binomial logistic regression analysis adjusted for age, CKD patients tend to develop autoimmune cytopenia, had lower B cells percentage, increased Neutrophil-to-lymphocyte ratio and received more frequently trimethoprim-sulfamethoxazole antibiotic prophylaxis. By multivariate analysis, only autoimmune cytopenia was independently associated with CKD. CONCLUSION: The prevalence of CKD in CVID is due to aging, age-related comorbidities, disease-related immune dysregulation and inflammation. Our results suggest evaluating renal function in all CVID patients, and mostly in those with a higher "inflammatory" burden.
Goebel GA, Cunha LAO, Minafra FG
… +1 more, Pinto JA
J Clin Immunol
· 2025 May · PMID 40374985
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Severe combined immunodeficiency (SCID) is a heterogeneous genetic disease characterized by severe T-cell lymphopenia with a profound impairment of T- and B-cells' function and, in some types, also NK cells. Hematopoieti...Severe combined immunodeficiency (SCID) is a heterogeneous genetic disease characterized by severe T-cell lymphopenia with a profound impairment of T- and B-cells' function and, in some types, also NK cells. Hematopoietic cell transplantation (HCT) is the only curative treatment currently available in Brazil. Late diagnosis and treatment are the main factors affecting the survival of these children. This study aims to describe the demographic, phenotypic, genotypic, and clinical characteristics of twenty SCID patients (including typical SCID, leaky-SCID, and Omenn Syndrome) followed at a Brazilian referral center and correlate these data with their clinical outcome. The children were analyzed into two groups: patients diagnosed early by newborn screening (NBS) or family history, n = 7, and patients with late diagnosis, by clinical presentation, n = 13. The 2-year overall survival (OS) of the late group was 29.2%, in contrast to the 2-year OS of the early diagnosis group of 71.4% (p = 0.053). However, despite early diagnosis in the first group, timely access to HCT was delayed, with a median of 11 months. This research reveals that survival depends not only on timely diagnosis but also on early definitive treatment. To improve SCID survival rates, developing countries need public policies that allow rapid access to curative treatment for these patients.