Zhao L, Ma J, Sun Y
… +5 more, Yu X, Lu Y, Qian H, Yan R, Zhang Y
J Clin Immunol
· 2025 May · PMID 40360799
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Anti-interferon-gamma autoantibody (AIGA)-associated adult-onset immunodeficiency (AOID) is an emerging disease that can lead to serious opportunistic infections, which has a history of 20 years since it was first report...Anti-interferon-gamma autoantibody (AIGA)-associated adult-onset immunodeficiency (AOID) is an emerging disease that can lead to serious opportunistic infections, which has a history of 20 years since it was first reported in 2004. It's a hard-detected AOID caused by AIGA. In recent years, there has been an increasing number of reports on the disease, but there is still a lack of consensus on the diagnosis and treatment. We here report a case of a 70-year-old Chinese male who had had AIGA in serum and suffered from recurrent pyothorax. Although his condition improved with antimicrobial therapy each time, his pyothorax frequently relapsed, requiring repeated hospitalizations. A literature review of AIGA-associated AOID was conducted. We searched PubMed, Web of Science, Embase, and the Chinese literature database for manuscripts concerning AIGA. Cases detected with AIGA and met our criteria were included. A total of 502 patients were retrospectively analyzed, with 256 (51.0%) males and 246 (49.0%) females. The majority of patients are from Southeast Asia (98.2%). Lymph node (83.7%) is the most commonly involved organ, followed by the lung (60.6%). Nontuberculous mycobacteria (NTM) was identified as the predominant pathogen reported in 77.49% of the patients. The clinical manifestations are diverse and non-specific for the disease often presenting with multi-organ involvement and multiple infections. Timely identification of patients with AIGA, appropriate diagnosis, and individualized treatment are critical; thus, we propose a reasonable diagnostic criterion and a structured diagnostic and treatment process based on our findings to provide clinicians with comprehensive information for clinical practice.
Zárate-Pinzón L, Mejía-Salgado G, Cifuentes-González C
… +7 more, Correa-Jiménez O, Amaris S, Alfaro-Murillo A, Téllez-Zambrano J, Verbel A, Monje-Tobar P, de-la-Torre A
J Clin Immunol
· 2025 May · PMID 40358744
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BACKGROUND: Although some reports indicate ocular involvement in Inborn Errors of Immunity (IEI) patients, the characteristics of this association remain unclear. Increased awareness can facilitate early diagnosis and pr...BACKGROUND: Although some reports indicate ocular involvement in Inborn Errors of Immunity (IEI) patients, the characteristics of this association remain unclear. Increased awareness can facilitate early diagnosis and prevention of visual complications. OBJECTIVE: To determine the prevalence and characterize ophthalmological manifestations in patients with IEI. METHODS: A systematic literature search was performed across Embase, PubMed, and Lilacs. Observational studies with at least 10 IEI patients exhibiting ophthalmological manifestations were reviewed. A meta-analysis using a random effects model, weighted proportion, and 95% confidence intervals were reported as appropriate. RESULTS: Sixty-two articles out of the 6,884 studies were included. The pooled prevalence of ocular manifestations in IEI patients was 54% (95%CI = 39-69), with a mean age of 11.1 ± 7.8 years and male predominance. Regarding the type of IEI with ocular involvement, the most frequently affected group was the Combined immunodeficiencies with associated or syndromic features (82%, 95%CI = 66-91), followed by the diseases of immune dysregulation (73%, 95%CI = 27-95), auto-inflammatory disorders (48%, 95%CI = 10-88), and congenital defects of phagocytes (39%, 95%CI = 11-76). Europe had the highest prevalence of patients with ocular manifestations (68%, 95%CI = 32-90). The most common ocular manifestations observed in IEI patients were those affecting ocular mobility, followed by those that involved the anterior segment, posterior segment, eyelids, and adnexal structures. CONCLUSIONS: These results highlight a significant burden of ocular involvement in IEI patients, mainly during childhood and associated with amblyogenic factors. Therefore, ophthalmologists, pediatricians, and immunologists must be involved in early detection to prevent ocular complications and overall well-being.
Kawai T, Kanegane H, Ishimura M
… +5 more, Okada S, Okamatsu N, Nakagawa K, Go M, Noto S
J Clin Immunol
· 2025 May · PMID 40332698
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Patients with primary immunodeficiency disease (PID) have an increased susceptibility to infection and may experience negative impacts on health-related quality of life (HR-QOL) and activities of daily living. This prosp...Patients with primary immunodeficiency disease (PID) have an increased susceptibility to infection and may experience negative impacts on health-related quality of life (HR-QOL) and activities of daily living. This prospective observational study of patients aged ≥ 12 years with PID assessed HR-QOL, work impairment, and disease-related daily burden over a full year, with a focus on seasonal variation. The study period was from October 2021 to November 2023. Data were collected using an online system. HR-QOL was assessed using EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), work impairment with the Work Productivity and Activity Impairment (WPAI) questionnaire, and disease-related burden with a questionnaire designed for this study. In patients with PID (N = 56) and healthy volunteers (N = 43), no significant seasonal variation was observed in EQ-5D-5L, SF-36, or WPAI scores. With few exceptions, patients with PID had significantly lower EQ-5D-5L, SF-36, and WPAI scores than healthy volunteers in all seasons. In patients with PID, disease-related symptoms and limitations of daily living persisted throughout the year, regardless of season. In conclusion, patients with PID had lower quality of life and were more socially, physically, and mentally stressed in all seasons compared with healthy individuals.
Lu HY, Vaseghi-Shanjani M, Lam AJ
… +26 more, Sharma M, Mohajeri A, Silva LBR, Gillies J, Yang GX, Lin S, Fu MP, Salman A, Rahmanian R, Armstrong L, Halparin J, Yang CL, Chilvers M, Henkelman E, Rehmus W, Morrison D, Setiadi A, Mostafavi S, Kobor MS, Kozak FK, Biggs CM, van Karnebeek C, Hildebrand KJ, Anna Lehman on behalf of the Care4Rare Canada Consortium, Levings MK, Turvey SE
J Clin Immunol
· 2025 Apr · PMID 40295428
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Monogenic defects that impair the control of inflammation and tolerance lead to profound immune dysregulation, including autoimmunity and atopy. Studying these disorders reveals important molecular and cellular factors t...Monogenic defects that impair the control of inflammation and tolerance lead to profound immune dysregulation, including autoimmunity and atopy. Studying these disorders reveals important molecular and cellular factors that regulate human immune homeostasis and identifies potential precision medicine targets. Here, we provide a detailed immunological assessment of a pediatric patient with a recently discovered syndrome causing Immunodysregulation, Craniofacial anomalies, Hearing impairment, Athelia, and Developmental delay (or ICHAD syndrome). The immunodysregulation resulted in autoimmune hemolytic anemia (AIHA) and atopic dermatitis. The patient carried a de novo germline heterozygous c.406+540_574+13477dup;p.Gly136_Ser191dup variant in IKAROS family zinc finger 2 (IKZF2), which encodes HELIOS. This variant led to reduced HELIOS protein expression and dominant interference of wild-type HELIOS-mediated repression of the IL2 promoter. Multi-parameter flow cytometry analyses of patient peripheral blood mononuclear cells revealed strongly impaired natural killer cell differentiation and function, and increased CD8 T cell activation and cytokine secretion. Strikingly, patient CD4 T cells were hyperactive, produced elevated levels of nearly all T helper (T) cytokines, and readily proliferated in response to stimulation. Patient regulatory T cells (Tregs) developed normally but aberrantly produced high levels of many T cytokines. Single-cell RNA sequencing revealed largely normal Tregs (albeit mostly memory), but naïve CD4 T cells that were more enriched in genes related to activation, proliferation, metabolism, and T differentiation. This work describes the immunological phenotype of one of the first reported cases of germline dominant negative HELIOS deficiency, expands our understanding of the pathogenesis of AIHA on a single cell level, and provides valuable insights into HELIOS function in a variety of lymphocyte subsets.
Aytekin ES, Tagiyev A, Silleli O
… +5 more, Samur İ, Demirel F, Esenboğa S, Sağlam EA, Çağdaş D
J Clin Immunol
· 2025 Apr · PMID 40266382
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PURPOSE: Chronic inflammation in inborn errors of immunity(IEI) caused by the infections or immune dysregulation is associated with the amyloid A (AA) amyloidosis development. This study aims to analyze the clinical char...PURPOSE: Chronic inflammation in inborn errors of immunity(IEI) caused by the infections or immune dysregulation is associated with the amyloid A (AA) amyloidosis development. This study aims to analyze the clinical characteristics, management strategies, and outcomes of patients with IEI complicated by AA amyloidosis, focusing on demographics, disease manifestations, treatment modalities, and survival rates. METHODS: Thirteen patients diagnosed with IEI and AA amyloidosis, along with an additional 10 patients previously reported from Türkiye, were reviewed retrospectively. RESULTS: The median ages at diagnosis of IEI and amyloidosis were 20 years (2-61) and 25 years (7-70), respectively. Renal (74%) and gastrointestinal involvement (44%) were the most common, followed by skin(9%), pulmonary (9%), and cardiac involvement (9%). Primary antibody deficiencies(48%), combined immunodeficiencies(31%), hyperimmunoglobulin E syndrome(9%), congenital neutropenia (4%), autoinflammatory disorders (4%), and chronic mucocutaneous candidiasis (4%) were the IEI types associated with amyloidosis. Bronchiectasis (74%) and malignancy (17%) were observed in given ratio of patients. Treatment modalities for amyloidosis include colchicine (n = 12, 52%), steroids (n = 5, 22%) and tocilizumab (n = 2, 9%) without significant benefit. Thirteen patients (57%) died with a median age of 24 years (8-45), predominantly due to sepsis (52%). Familial Mediterranean fever (FMF) gene analysis was negative in all patients except for one, who had a heterozygous MEFV gene defect (M694V). CONCLUSION: AA amyloidosis in IEI is associated with severe morbidity and mortality. Early diagnosis and management of IEI are crucial to prevent amyloidosis development. However, colchicine appears ineffective once amyloidosis has occurred, highlighting the need for further research into early diagnostic biomarkers and novel treatment options.
Maimaris J, Payne J, Roa-Bautista A
… +27 more, Breuer J, Storey N, Morfopoulou S, Bamford A, D'Arco F, Gilmour K, Aquilina K, Hassell J, Hacohen Y, Silva AHD, Merve A, Jacques TS, Rao K, Chiesa R, Amrolia P, Silva J, Braggins H, Xu-Bayford J, Goldblatt D, Worth A, Booth C, Ip W, Qasim W, Kusters M, Kaliakatsos M, Brown JR, Elfeky R
J Clin Immunol
· 2025 Apr · PMID 40237937
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Unexplained neurological symptoms can pose a diagnostic challenge in patients with inborn errors of immunity (IEI) where the aetiology can be varied, and diverse pathologies may require contrasting treatments. Brain biop...Unexplained neurological symptoms can pose a diagnostic challenge in patients with inborn errors of immunity (IEI) where the aetiology can be varied, and diverse pathologies may require contrasting treatments. Brain biopsy, the process of sampling brain tissue directly, has historically provided histological and microbiological information and can now be exploited for deep metagenomic next generation analysis (mNGS). We conducted a retrospective analysis of clinical and diagnostic data on paediatric patients with IEI who had a brain biopsy between 2010 and 2022 at a UK tertiary centre where 14 patients fulfilled our search criteria. We report on clinical characteristics, adverse events and the additional impact of mNGS of brain biopsies, where these were conducted. We found that brain biopsy enabled diagnostics with manageable complications in most cases, either by tissue or metagenomics analysis (n = 11/14, 79%). We found that mNGS analysis improved the diagnostic yield of brain biopsy in 29% of IEI cases (n = 4/14). Brain biopsy enabled a change in management in 71% of cases (n = 10/14). This series provides compelling evidence for the safe and purposeful use of brain biopsy in children with IEI.
Biglari S, Youssefian L, Tabatabaiefar MA
… +23 more, Saeidian AH, Abtahi-Naeini B, Khorram E, Sherkat R, Moghaddam AS, Mohaghegh F, Rahimi M, Rahimi H, Babaei S, Shahrooei M, Mozafari N, Zaresharifi S, Vahidnezhad F, Homayouni V, Tsoi LC, Gudjonsson JE, Hakonarson H, Casanova JL, Jouanguy E, Béziat V, Zhang Q, Cobat A, Vahidnezhad H
J Clin Immunol
· 2025 Mar · PMID 40153067
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The life-threatening coronavirus disease 2019 (COVID-19) affects about 1 in 1,000 healthy people under 50 without underlying conditions. Among patients with critical COVID-19 pneumonia, rare germline variants at genes co...The life-threatening coronavirus disease 2019 (COVID-19) affects about 1 in 1,000 healthy people under 50 without underlying conditions. Among patients with critical COVID-19 pneumonia, rare germline variants at genes controlling type I IFN immunity have been reported in up to 5% of patients. Causal etiologies in 80-85% of cases are still unknown. We analyzed two families with hypoxemic COVID-19 pneumonia for known single-gene inborn errors of immunity. In Family 1, two siblings with critical COVID-19 were homozygous for a DOCK2 variant, c.3624+5G>A. DOCK2 deficiency is a known T-cell disorder underlying severe viral diseases. The variant resulted in skipping exon 35, which was predicted to produce a frameshift truncated protein (p.L1157Ifs*12). The proband showed markedly decreased blood CD4 T-helper cell counts, impaired T lymphocyte transformation test, and increased serum IgG, IgA, and IgE levels, as documented in other DOCK2-deficient patients. In Family 2, the proband had lethal COVID-19 and HPV-2-associated multiple recalcitrant warts. She was heterozygous for a deletion in GATA2:c.1075_1102del28, p.W360Sfs*18. GATA2 haploinsufficiency is a known cause of severe viral diseases due to a lack of plasmacytoid dendritic cell (pDC) development. The proband had monocytopenia and a lack of circulating pDCs, as reported in other patients with GATA2 haploinsufficiency. Overall, both DOCK2 deficiency and GATA2 haploinsufficiency are associated with critical and often fatal COVID-19 pneumonia.
Dorsey MJ, Butte MJ, Lieberman JA
… +17 more, Lehman H, Fausnight T, Keller MD, Fradette C, Hershfield MS, Pozos TC, Rozova A, Wall LA, Bednarski JJ, Tarrant TK, Chong HJ, Geng B, Temin NT, Laubach SS, Lin L, Mousallem T, Walter JE
J Clin Immunol
· 2025 Mar · PMID 40140214
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PURPOSE: The safety and tolerability of elapegademase (elapegademase-lvlr; Revcovi) a PEGylated recombinant adenosine deaminase (ADA), were demonstrated in two Phase 3 clinical trials in the U.S. and Japan in patients wi...PURPOSE: The safety and tolerability of elapegademase (elapegademase-lvlr; Revcovi) a PEGylated recombinant adenosine deaminase (ADA), were demonstrated in two Phase 3 clinical trials in the U.S. and Japan in patients with ADA-deficient severe combined immunodeficiency (ADA-SCID). Elapegademase replaced Adagen (pegademase, a PEGylated bovine ADA) in 2018. This registry study (NCT03878069) was conducted as a post-marketing requirement to bolster the limited safety and effectiveness data on elapegademase in patients with ADA-SCID and to study patients starting on enzyme replacement therapy (ERT) de novo. METHODS: Patients were managed by routine clinical care and treating physicians' judgement from September 2019 to January 2023. Primary endpoints included trough plasma ADA activity and total trough erythrocyte deoxyadenosine nucleotides (dAXP). Secondary outcomes included lymphocyte counts, hospitalizations, infections, and safety outcomes. RESULTS: Thirty-two patients were grouped as ERT-naïve (n = 7; infants and children with no prior ERT [EN]); pegademase-transitioning (n = 21; from pegademase to elapegademase [PT]); and patients who had participated in the Phase 3 clinical trial (n = 4; STP-2279-002; [STP]). The EN group maintained optimal plasma ADA activity, increased lymphocyte counts, had manageable infections, and had no mortality for up to 30 months while on elapegademase. The STP group and 66.7% of the PT group continued to maintain satisfactory levels of both ADA and dAXP with stable rates of infections and hospitalizations and stable lymphocyte counts for up to 48.6 months. Variability on all measures was seen, but overall, patients did not deteriorate while on elapegademase. CONCLUSION: Effectiveness of elapegademase was maintained up to 4 years of use and with no new safety concerns.
Almojali A, Alrasheed A, Alharbi B
… +4 more, Alharbi R, Alsuwairi W, Alroqi F, Alqanatish J
J Clin Immunol
· 2025 Mar · PMID 40097865
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PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease resulting from biallelic loss-of-function mutations in ADA2 gene. It has variable clinical manifestations, some of which c...PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease resulting from biallelic loss-of-function mutations in ADA2 gene. It has variable clinical manifestations, some of which can mimic Behçet's disease (BD). Herein, we present a family of three siblings diagnosed with DADA2, two of whom were initially misdiagnosed as BD based on clinical phenotype including positive human leukocyte antigen B51 (HLA-B*51). METHODS: Gene mutational analysis was performed by whole exome (WES) and Sanger sequencing. RESULTS: We reported two siblings presented with recurrent oral ulcers, fever, arthritis, and skin lesions, alongside elevated inflammatory markers and HLA-B*51 positivity, leading to an initial misdiagnosis of BD. Genetic testing later revealed a homozygous ADA2 variant (c.139G > A p.Gly47Arg) in both siblings and their asymptomatic younger sister, confirming DADA2 diagnosis. Thereafter, we reviewed the literature to identify other patients misdiagnosed with BD but later found to have DADA2. This resulted in a cohort of 10 DADA2 patients, including our two reported siblings. The median time from symptoms onset to the final diagnosis of DADA2 was 7 years. All patients exhibited BD-like phenotype, except for uveitis, and 8 were HLA-B*51 positive, which likely contributed to the diagnostic confusion. CONCLUSION: These findings highlight the broad clinical spectrum of DADA2, which can resemble BD, and suggest that HLA-B*51 positivity in DADA2 may further complicate diagnosis. Clinicians should maintain a high index of suspicion for DADA2 in early-onset BD-like cases, particularly without uveitis, or a family history of similar symptoms. Further studies are warranted to explore HLA-B*51 role in DADA2 phenotype.
Perrard N, Stabler S, Sanges S
… +15 more, Terriou L, Lamblin C, Gaillard S, Vuotto F, Chenivesse C, Mortuaire G, Batteux F, Mirgot F, Collet A, Lopez B, Dubucquoi S, Labalette M, Hachulla E, Launay D, Lefèvre G
J Clin Immunol
· 2025 Mar · PMID 40097777
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Selective anti-polysaccharide antibody deficiency (SPAD) predisposes to encapsulated bacterial infections. The diagnosis is challenging, and literature reports are scarce in adult patients, we therefore aim to describe t...Selective anti-polysaccharide antibody deficiency (SPAD) predisposes to encapsulated bacterial infections. The diagnosis is challenging, and literature reports are scarce in adult patients, we therefore aim to describe the demographics, infectious complications, therapeutic strategies, and outcome of adult patients. We conducted a multicenter observational study involving 55 adult patients with SPAD. The median [interquartile range, IQR] age was 45 [36-60] years at diagnosis of SPAD, and 75% of patients were female. Twenty-one patients (38%) had a history of allergic and/or inflammatory disease, mainly asthma (n = 12), and rheumatic diseases (n = 6). Twelve patients (22%) were diagnosed after a single severe infection and 43 (78%) in a context of recurrent benign and/or severe infections. In the latter, the median time from first infections to diagnosis was 74.5 [33-167] months. Diagnostic delay was significantly higher in patients presenting with bronchiectasis than in those without (122 months [33-219.5] vs 24 months [14.5-74.5], p = 0.0042). In 22 patients (40%) receiving immunoglobulin replacement therapy (IgRT), the mean (min-max) frequency of antibiotic courses decreased from 7.9 (2-18) to 0.7 (0-2) courses per year (p < 0.001) with a median follow-up period of 46 [27-73] months. Patients diagnosed after a single severe infection did not have any relapse during a median follow-up of 85 [80.5-104.5] months after diagnosis. Adult patients with SPAD have allergic or inflammatory disorders which could contribute to the diagnostic delay. IgRT is effective in preventing recurrent infections. Further studies are warranted to confirm if SPAD should be considered after a first unexplained severe bacterial infection.
Patel NC, Walter JE, Wasserman RL
… +9 more, Rubinstein A, Kankirawatana S, Shepherd MW, Greco E, Li Z, Russo-Schwarzbaum S, Saeed-Khawaja S, McCoy B, Yel L
J Clin Immunol
· 2025 Mar · PMID 40085358
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PURPOSE: To investigate the efficacy, safety, tolerability, and serum IgG trough levels of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in US pediatric patients with primary immunodeficiency diseases...PURPOSE: To investigate the efficacy, safety, tolerability, and serum IgG trough levels of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in US pediatric patients with primary immunodeficiency diseases (PIDDs). METHODS: This phase 3, open-label, prospective study (NCT03277313) was conducted at 17 US centers. Eligible patients aged 2 to < 16 years had PIDDs and had received immunoglobulin G (IgG) at a consistent dose for ≥ 3 months before screening. Participants received fSCIG 10% via dose ramp-up for up to 6 weeks (Epoch 1), then every 3-4 weeks for ≤ 3 years (Epoch 2). The primary endpoint was the rate of acute serious bacterial infections (ASBIs). RESULTS: Data were provided by 44 participants for Epoch 1 (mean ± SD age: 9.0 ± 3.6 years) and 43 (97.7%) for Epoch 2; 34 (77.3%) completed the study. Two ASBIs (both bacterial pneumonia) were reported in one participant with specific antibody deficiency. The mean rate of ASBIs was 0.04 events/participant-year (99% upper confidence interval limit: 0.20), significantly lower than the regulatory-defined threshold of 1.0 (p < 0.001). The mean rate of all infections was 3.12 events/participant-year. Stable mean serum IgG trough levels were maintained during Epoch 2 (10.4, 9.2, and 9.2 g/L at Months 0, 6, and 12, respectively). Most related treatment-emergent adverse events were mild or moderate in severity. No participant developed anti-recombinant human hyaluronidase neutralizing antibodies; 1/44 participants (2.3%) developed binding antibodies. CONCLUSION: fSCIG 10% effectively prevented ASBIs in pediatric patients with PIDDs, with a favorable safety profile consistent with previous clinical studies.
Nishinosono T, Muramatsu H, Wakamatsu M
… +13 more, Yamashita D, Fukasawa T, Shirakawa Y, Sajiki D, Maemura R, Tsumura Y, Yamamori A, Narita K, Kataoka S, Narita A, Nishio N, Miyajima Y, Takahashi Y
J Clin Immunol
· 2025 Feb · PMID 39998705
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PURPOSE: B-cell expansion with nuclear factor kappa B and T-cell anergy (BENTA) is an inborn error of immunity characterized by congenital polyclonal B-cell lymphocyte expansion. In this report, we present a case of a gi...PURPOSE: B-cell expansion with nuclear factor kappa B and T-cell anergy (BENTA) is an inborn error of immunity characterized by congenital polyclonal B-cell lymphocyte expansion. In this report, we present a case of a girl diagnosed with BENTA carrying a novel CARD11 germline mutation, aiming to clarify the clinical presentation of BENTA by conducting a literature review. METHODS: Genetic analysis, including whole-exome sequencing, was performed using genomic DNA extracted from the patient's peripheral blood, oral mucosa, and fingernails. Additionally, a comprehensive literature review of cases with BENTA was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A p.Leu251Pro germline variant in the CARD11 gene was identified in an 18-month-old girl with a genetic diagnosis of BENTA. She required adenoidectomy and tonsillectomy due to airway obstruction causing wheezing. Her symptoms improved with prednisolone and sirolimus. The literature review we conducted identified a total of 34 cases of BENTA. Among these cases, 15 were either asymptomatic or showed improvement without requiring any specific treatment. However, all six reported deaths were diagnosed before the age of 3 years, with two attributed to refractory hemophagocytic syndrome and four caused by opportunistic infections. CONCLUSION: We present a case of BENTA with life-threatening respiratory symptoms caused by a novel CARD11 germline mutation. The patient showed a positive response to immunosuppressive therapy, including sirolimus. While BENTA is typically regarded as a benign disorder, a literature review revealed that infants with BENTA are at high risk of severe outcomes and require therapeutic intervention.
Vendemini F, Roncareggi S, L'Imperio V
… +10 more, Guerra F, Mottadelli F, Chiarini M, Maglia O, Sala S, Fazio G, Piazza R, Bonanomi S, Biondi A, Saettini F
J Clin Immunol
· 2025 Feb · PMID 39976744
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PURPOSE: GATA2 deficiency, a rare inborn error of immunity, presents with highly variable phenotypes. Bone marrow (BM) changes such as hypocellularity and myelodysplastic syndrome (MDS) are common, with hematopoietic ste...PURPOSE: GATA2 deficiency, a rare inborn error of immunity, presents with highly variable phenotypes. Bone marrow (BM) changes such as hypocellularity and myelodysplastic syndrome (MDS) are common, with hematopoietic stem cell transplantation being the only curative option due to the risk of progression to acute myeloid leukemia. Although traditional markers like cytogenetic abnormalities and somatic mutations (e.g., ASXL1) identify the risk of leukemic transformation, efforts to identify novel predictors of disease evolution are needed. CD8+ T cells are known to play a key role in MDS immune surveillance, but their specific involvement in GATA2 deficiency remains poorly defined. METHODS: In this case report, we report on a young adult with GATA2 deficiency who underwent longitudinal monitoring of both peripheral and BM lymphocyte subsets, with a focus on CD8+ T-cell evolution in relation to MDS progression. RESULTS: The patient exhibited typical GATA2-deficient immune-hematological findings, including monocytopenia, B- and NK-cell deficiency, but had no history of severe infections and remained transfusion-independent. While peripheral CD8+ T-cell levels remained stable over time, a notable reduction in BM CD8+ T cells was observed in association with MDS progression. CONCLUSION: Providing a long-term follow-up of one GATA2-deficient patient, we suggest that a decrease in BM CD8+ T cells may serve as an early marker of immune surveillance escape and disease progression. These findings underscore the need for further investigation into the role of BM CD8+ T cells in GATA2 deficiency and MDS evolution, potentially offering new insights for follow-up and therapeutic intervention.
Zhao R, Zhang Z, Mei S
… +11 more, Sun L, Zhang Q, Lv Q, Zhou F, Sun G, Zhou L, Tang X, An Y, Liu Z, Zhao X, Du H
J Clin Immunol
· 2025 Feb · PMID 39976696
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Deficiency in ELF4, X-linked (DEX) is a newly identified monogenic autoinflammatory disease. Most reported cases are male, leading to the recognition of DEX being primarily limited to male patients. Here we described 3 p...Deficiency in ELF4, X-linked (DEX) is a newly identified monogenic autoinflammatory disease. Most reported cases are male, leading to the recognition of DEX being primarily limited to male patients. Here we described 3 pediatric female patients with DEX from 3 unrelated families, who are all heterozygous for ELF4 mutations (c.320_c.321insA, c.329delA and c.685 A > G). Similar to reported male DEX patients, the main clinical features include recurring oral ulcers, abdominal pain and diarrhea with colonoscopy showing ulcers in the colon. Meanwhile, novel and effective treatment strategies, such as the use of the biologic vedolizumab and exclusive enteral nutrition (EEN), have provided additional options for the treatment of DEX. Finally, we observed skewed X chromosome inactivation patterns in all three female patients, with over-inactivation of the X chromosome carrying the wild-type allele confirmed in two of them.
Beyls E, Duthoo E, Backers L
… +11 more, Claes K, RAPID Clinicians, De Bruyne M, Pottie L, Bordon V, Bonroy C, Tavernier SJ, Claes KBM, Vral A, Baeyens A, Haerynck F
J Clin Immunol
· 2025 Feb · PMID 39945898
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Human inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) com...Human inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially resulting in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as an influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with RS.
Cicek A, Schuster FR, Boyle JO
… +3 more, Hoenig M, Meisel R, Ghosh S
J Clin Immunol
· 2025 Feb · PMID 39932644
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Reticular dysgenesis (RD) is a rare inborn error of immune cell formation defined by severe combined immunodeficiency, agranulocytosis and sensorineural deafness. We report a case of successful haploidentical maternal he...Reticular dysgenesis (RD) is a rare inborn error of immune cell formation defined by severe combined immunodeficiency, agranulocytosis and sensorineural deafness. We report a case of successful haploidentical maternal hematopoietic stem cell transplantation (HSCT) in a boy with RD detected by TREC newborn screening. The patient was admitted to our hospital at 2 weeks of age and was kept in laminar-air flow / hepa-filtered isolation until HSCT was performed at 8 weeks of age with a busulfan, fludarabine conditioning regime. Except few episodes of acute skin graft-versus-host disease (aGVHD) the peritransplant period was uneventful. The patient was discharged 7 weeks post-HSCT. At 18 months of age cochlear implants were placed. The patient was thriving well, showed full donor chimerism and a T cell count > 1000 TCRab + CD3 + cells/µl after one year. Our case highlights that severely immune-compromised patients with RD benefit from early diagnosis by newborn screening, immediate isolation to prevent infections, and early haploidentical HSCT to overcome neonatal neutropenia and establish protective immunity.
Lima de Souza S, Asano T, Glumoff V
… +16 more, Keskitalo S, Pikkarainen K, Martelius T, Kaustio M, Saarela J, Kuismin O, Lappi-Blanco E, Jartti A, Yannopoulos F, Tiitto L, Seppänen MRJ, Boisson B, Casanova JL, Varjosalo M, Hautala T, Chen Z
J Clin Immunol
· 2025 Feb · PMID 39928202
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Signal transducer and activator of transcription 3 (STAT3) plays a key role in leukocytic and non-leukocytic cells. Germ line mutations in STAT3, which are mainly found in the SH2, DNA binding and transactivation domains...Signal transducer and activator of transcription 3 (STAT3) plays a key role in leukocytic and non-leukocytic cells. Germ line mutations in STAT3, which are mainly found in the SH2, DNA binding and transactivation domains, can be loss- or gain-of-function (LOF and GOF). STAT3 N-terminal domain (NTD) mutations are rare, and their biological effects remain incompletely understood. We explored the significance of STAT3 NTD p.Trp37* variant in a patient with chronic pulmonary aspergillosis and a low Hyper-IgE syndrome (HIES) score. In cell culture models, the expression of full-length p.Trp37* allele showed shorter STAT3 protein expression suggesting a re-initiation (Met99 or Met143). STAT3 activity using luciferase reporter assay showed a twofold-increased activity of the STAT3 p.Trp37* STAT3 protein compared with WT STAT3 at basal level and upon IL-6 stimulation. In contrast, the activity of the short pTrp37* peptide (amino acids 1 to 37) was amorphic but without dominant negative (DN) effect on transcriptional activity or STAT3 Tyr705 phosphorylation. The proteins initiated at Met99 and Met143 were surprisingly hypermorphic. In carriers' peripheral blood mononuclear cells (PBMCs), both WT and mutated STAT3 mRNA were equally present and the global amount of STAT3 protein was not significantly reduced. In stimulated heterozygous carriers' PBMCs, however, STAT3 Tyr705 phosphorylation and Th17 were reduced but not completely abolished. This suggests a DN effect of an unknown product of the p.Trp37* allele. Transcriptomics analysis of PBMCs from the index revealed selectively distinct gene expression. We conclude that heterozygosity for the NTD p.Trp37* STAT3 mutation defines a novel allelic form of STAT3 deficiency, associated with a chronic pulmonary aspergillosis and minor signs of HIES.