Purine nucleoside phosphorylase (PNP) deficiency causes inadequate purine metabolite detoxification, which leads to combined immunodeficiency and variable neurologic symptoms. Hematopoietic stem cell transplantation (HSCT) cures the immunodeficiency, but large studies on the long-term outcomes are lacking. In a retrospective study of the European Society for Blood and Marrow Transplantation, we investigated 46 patients with PNP deficiency from 21 centers. We analyzed the presenting clinical signs and outcomes after HSCT. Cognition (0-3), hearing (0-3), interaction (0-4), movement (0-4), and occupation (0-3) (CHIMO) were scored at the last follow-up (FU) visit (no impairment, 17; mild, 15-16; moderate, 12-14; and severe impairment, <12). The median age at initial presentation was 7.5 (1-48) months. The patients presented with infections (41%), neurological dysfunction (39%), both (15%), or autoimmune disease (5%). At the time of HSCT (median age, 26 [2-192] months), neurological abnormalities were observed in 88% of patients. After a median FU of 7.9 (1.0-22.3) years, 40 patients were alive with a 3-year overall survival (OS)/event-free survival (EFS) probabilities of 86% (confidence interval [CI], 77%-97%)/75% (CI, 64%-89%), respectively. High-level (>50%-100%)/low-level donor chimerism (11%-50%) was observed in 85%/15% of patients, respectively, leading to resolution of T lymphopenia. The median overall CHIMO score was 14 (6-17), while the median scores for each component were 3 (0-3), 3 (1-3), 4 (1-4), 3 (1-4), and 2 (0-3), respectively. Patients who underwent HSCT before 24 months after the initial presentation demonstrated superior OS (P = .049). Neurological symptoms that occurred before 11 months of age were associated with reduced OS (P = .027). While the overall results were satisfactory, earlier diagnosis could further improve outcomes.

BackgroundMajor histocompatibility complex (MHC) class II deficiency is a rare, life-threatening primary immunodeficiency that presents in early infancy with a SCID phenotype. However, emerging data indicate substantial clinical and immunological heterogeneity, including atypical presentations and neurological involvement.MethodsWe retrospectively evaluated the clinical, immunological, genetic, and treatment-related characteristics and outcomes of 22 patients from 19 unrelated families diagnosed with MHC class II deficiency at a single referral center (2000–2019). Ten patients underwent HSCT at our center; transplant-related outcomes were evaluated, and long-term follow-up data were available for the six surviving patients through 2025.ResultsThe median age at symptom onset and diagnosis was 9 and 12 months, respectively. Pneumonia, chronic diarrhea, and failure to thrive were the most common presenting features; neurological manifestations and developmental delay were observed in a subset of patients. Two patients showed residual HLA-DR expression and survived with a milder clinical course. CD4+ T cell lymphopenia and humoral dysfunction were consistent, while total lymphocyte counts were variable. RTE levels were mildly to moderately reduced in all tested patients, suggesting impaired thymic output. Severe viral infections were frequent and could be rapidly fatal. Fourteen patients required PICU admission, associated with high mortality. Genetic analysis (n:15) identified homozygous pathogenic variants in RFXANK (n=5), RFXAP (n=4), RFX5 (n=3), and CIITA (n=3). Ten patients underwent HSCT, with superior survival compared to non-transplanted patients (60% vs. 18%). Among transplanted patients, survival appeared higher following RTC than MAC (75% vs. 50%). Post-transplant mortality was observed in association with severe pre-transplant disease, delayed diagnosis, graft failure, and infectious complications. At ≥10 years post-HSCT, all survivors were IVIG-independent; CD4+ T cell recovery was higher after MAC than RTC, while T-cell chimerism remained mixed in both groups.ConclusionMHC class II deficiency is a SCID-like pediatric immunological emergency that is fatal without HSCT in most patients. Early diagnosis is critical, as initial infections may be rapidly progressive. HSCT provides durable engraftment and sustained clinical stability in long-term survivors. Incorporating HLA-DR expression analysis into first-line immunological screening, even in the absence of profound lymphopenia, may facilitate earlier diagnosis, prompt HSCT referral, and improve survival.

FLNA encodes filamin A, a ubiquitously expressed actin-binding cytoskeletal protein that cross-links actin filaments and links them to membrane-associated signaling complexes. Although FLNA has been implicated in T-cell signaling and regulatory T-cell development in murine models, its role in human immune-cell function remains incompletely understood. Here, we investigated the immunological phenotype associated with a novel hemizygous FLNA variant identified in a pediatric patient presenting with recurrent infections and inflammatory manifestations. Whole-exome sequencing revealed a hemizygous c.7405C>T (p.Pro2469Ser) variant in FLNA, which was confirmed by Sanger sequencing. Its potential impact on immune-cell function and cytoskeletal organization was evaluated using confocal microscopy, flow cytometry, and molecular assays. Patient-derived T cells showed impaired activation and proliferation following CD3/CD28 and IL-2 stimulation, accompanied by reduced CD25 and CD69 upregulation. CD4+ T cells also exhibited reduced IFN-γ, TNF-α, and IL-2 production after stimulation. Despite elevated basal phospho-STAT5 levels, IL-2-induced STAT5 phosphorylation and TCR-associated signaling responses, including pZAP70, pLCK, and p38 MAPK activation, were attenuated. Confocal imaging together with image-based quantification demonstrated altered cortical cytoskeletal organization in patient T cells despite preserved FLNA expression. In parallel, NK cells showed impaired activation responses and reduced cytotoxic activity under the assay conditions used. Increased apoptosis was observed in CD4⁺, CD8⁺, and NK-cell populations. Inflammatory cytokines were elevated in plasma and colonic tissue, whereas colonic ZO-1 and FLNA expression were reduced. Collectively, these findings indicate that the FLNA p.Pro2469Ser variant is associated with altered immune-cell signaling, disturbed cortical cytoskeletal organization, and immune dysregulation. This study expands the phenotypic spectrum linked to FLNA variants and supports a role for filamin A in human immune-cell regulation.

BACKGROUND:Delayed-type cutaneous adverse drug reactions (CADRs) are T-cell-mediated hypersensitivity reactions that may present with variable clinical severity in children. They range from mild maculopapular exanthema (MPE) to severe, life-threatening mucocutaneous syndromes such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Data on pediatric delayed-type CADRs remain limited. They represent an important cause of morbidity in pediatric patients and require careful diagnostic evaluation. OBJECTIVE:This study aimed to describe the clinical characteristics, etiologic agents, management strategies, and outcomes of pediatric patients with delayed-type CADR followed at a tertiary pediatric center. METHODS:This retrospective case series included 33 pediatric patients diagnosed with delayed-type CADR between January 2013 and December 2024. Demographic features, suspected culprit drugs, clinical manifestations, laboratory and histopathologic findings, treatment approaches, and outcomes were reviewed. RegiSCAR, EuroSCAR, and SCORTEN criteria were applied for diagnostic classification and severity assessment of DRESS, AGEP, and SJS/TEN, respectively. RESULTS:The median age was 9 years (range: 9 days-16 years); 17 patients were female. The most frequent diagnosis was MPE (n=18, 54.5%), followed by DRESS (n=5, 15.1%), SJS/TEN (n=3, 9.1%), AGEP/ALEP (n=3, 9.1%), erythema multiforme (n=2, 6.0%), and SDRIFE (n=2, 6.0%). Antibiotics and antiepileptic drugs were the most commonly implicated drug classes. Systemic corticosteroids were administered in moderate-to-severe cases, and intravenous immunoglobulin was used in selected patients with DRESS and SJS/TEN. Four patients died due to underlying primary diseases; no CADR-related mortality was observed. CONCLUSION:This retrospective case series describes the heterogeneous clinical spectrum of delayed-type CADRs in children in a tertiary referral setting. In our cohort, maculopapular exanthema was the most frequent phenotype, while antibiotics and antiepileptic drugs were the most commonly implicated agents. A high burden of comorbidities, including immunosuppression and polypharmacy, was notable and may have influenced the observed clinical spectrum. Severe reactions required multidisciplinary management.

INTRODUCTION:The severity and incidence of invasive pneumococcal infections increase in inborn errors of immunities. However, there are limited number of studies in the literature evaluating pneumococcal antibody levels in patients with a prediagnosis of transient hypogammaglobulinemia (THI) and unclassified hypogammaglobulinemia (UH). The aim of our study was to serologically evaluate pneumococcal antibody levels in children aged 24-72 months with THI or UH who had completed the primary PCV schedule, and to compare these levels with those of age-matched healthy control. METHODS:Patients aged between 24 and 72 months who were admitted to the Pediatric Immunology Allergy Department Outpatient Clinic between January 2024 and July 2024 and who were considered to have transient or unclassifiable hypogammaglobulinemia. Healthy children of similar age group, without signs of infection or chronic disease and with complete vaccination according to their age were included in the study as a healthy control group. Serum samples obtained were separated and stored at -20 C0 until the day anti-PNP IgG levels were studied by ELISA method. RESULTS:No statistically significant difference was found when anti-PCP IgG levels were compared according to the diagnosis of THI and UH in the patient group (p = 0.410). It was determined that both patient groups produced similar antibody levels. There were no statistically significant differences in anti-PCP IgG levels between patients and control group (p = 0.427). When the correlation between the time elapsed since the last dose of PCV13 and anti-PCP IgG levels was evaluated in the patient group (both in all patients and age groups) and in the control group, no statistically significant correlation was found. In the patient group, anti-PNP IgG levels were found to be lower in the group in which both IgG and IgM values were low compared to the other groups. No statistically significant difference was found between the clinical characteristics of the patients and anti-PCP IgG levels. CONCLUSION:This study is one of the few to evaluate pneumococcal antibody levels in children with THI and UH who have completed the primary PCV13 vaccination series. Further prospective studies involving serotype-specific tests and different pneumococcal vaccine formulations are needed.

The Nuclear Factor Kappa B (NF-kB) signalling pathway is essential for regulating inflammation, cell survival, and adaptive immune responses through its canonical (NF-κB1-associated) and noncanonical (NF-κB2-associated) branches. The canonical pathway mediates rapid and broad reactions to immune stimuli, whereas the noncanonical pathway is activated by specific signals and contributes to lymphoid organ development, B-cell maturation including germinal centre activity, T-cell differentiation, thymic selection and antiviral defence. NF-κB transcription factors consist of five subunits: NF-kB1 (p105/p50), NF-kB2 (p100/p52), RelA, RelB and c-Rel-and heterozygous variants in NFKB1 or NFKB2 genes result in a wide range of immune dysregulation. NFKB1 mutations have been associated with common variable immunodeficiency, autoinflammatory or rheumatologic manifestations, Epstein-Barr virus-related lymphoproliferation, gastrointestinal involvement and susceptibility to recurrent or opportunistic infections. Clinical features of NFKB2 deficiency show considerable variability depending on mutation location, but recurrent infections and hypogammaglobulinemia remain the most frequently reported findings. Despite growing recognition of NF-κB-related inborn errors of immunity, the phenotypic spectrum continues to expand and genotype-phenotype correlations remain challenging. In this study, we describe seven individuals from five families with NFKB1 or NFKB2 variants and demonstrate considerable clinical and immunological heterogeneity, including marked intrafamilial variability.

BackgroundInborn errors of immunity (IEI) predispose patients to malignancy, particularly lymphoma, but data on diagnostic sequence and outcomes are limited.MethodsWe retrospectively analyzed IEI-associated malignancies diagnosed at a single center between January 2004 and December 2025.ResultsAmong 1,668 patients with IEI, 67 (4.0%) developed malignancy. Median ages at IEI and malignancy diagnosis were 8 and 10 years, respectively. Malignancy-first presentation occurred in 45 patients (67%), especially adolescents, and was associated with advanced-stage disease (p = 0.007). Lymphoid malignancies accounted for 90% of cases; non-Hodgkin lymphoma and Hodgkin lymphoma comprised 54% and 36%, respectively, and 84.7% presented with stage III-IV disease. Median event-free and overall survival were 66 and 155 months, respectively. In a clinically selected multivariable Cox model, NHL, solid/plasma cell tumors, older age at malignancy diagnosis, and DNA repair defect status were associated with worse OS. Twelve patients underwent allogeneic HSCT; one died early, and no post-transplant relapses occurred. ConclusionEarly immunologic evaluation and timely, individualized consideration of HSCT may support optimized management in children and adolescents, in whom cancer may be the first manifestation of IEI.

Background:Major histocompatibility complex (MHC) Class I deficiency is a rare form of primary immunodeficiency that typically presents with recurrent sinopulmonary infections, bronchiectasis, and granulomatous skin lesions during late childhood or adolescence. Methods:This retrospective study describes the clinical, immunological, and long-term follow-up data of 11 patients diagnosed MHC Class I deficiency. Results:The cohort included 11 patients (6 males, 5 females) with a median age of 26 years (range 19-44). The median age at diagnosis was 19 years, with a diagnostic delay of 14 years. Bronchiectasis was seen in 10 patients, granulomatous skin lesions in 6, uveitis in 5, and nasal septum perforation in 3. All but one patient survived during a median follow-up of 11 years. HLA-ABC expression ranged from 0% to 73%, with persistently low mean fluorescence intensity (0.4-3.8). IgM levels were reduced in 7 patients. Ten patients were persistently positive for anti-rubella IgM, including all six with granulomatous skin lesions. Immunophenotyping revealed reduced CD3+ (n=2), CD4+ (n=3), CD8+ (n=3), CD19+ (n=5), CD3-CD16+CD56+ (n=3), CD19+ IgM-27+ IgD- (switched memory B cells) (n=7), and CD19+ IgM-27+ IgD+ (marginal zone B cells) (n=8). All patients had elevated γδ+ T cells, and NK cells were reduced in three. Seven patients had TAP1 and four had TAP2 mutations, with no significant genotype-phenotype differences. Conclusion:MHC Class I deficiency presents a broad clinical spectrum from asymptomatic to life-threatening disease. Granulomatous tissue damage and uveitis contributed to morbidity. Persistent rubella-specific IgM in most patients, including those without granulomas, is a novel serologic finding that may reflect altered antiviral immunity. Its clinical significance remains uncertain and, further studies with tissue-based viral detection are needed to clarify this observation.

Objective: Common variable immunodeficiency (CVID) is a type of inborn errors of immunity (IEI) characterized by antibody deficiency, recurrent infections, autoimmunity, autoinflammation, lymphoproliferation, and malignancy, representing a broad phenotypic spectrum. Unlike other subgroups, only about 10% of CVID cases have a detectable genetic etiology, suggesting a complex inheritance pattern for this group. However, in cases with early onset, a positive family history and consanguinity with monogenic inheritance is considered likely. This study aimed to investigate the genetic etiology in patients diagnosed with CVID. Materials and Methods: This study included 27 patients classified as CVID based on ESID diagnostic criteria, who were followed for antibody deficiency in our clinic between 2000 and 2017. Whole exome sequencing (WES) or gene panel sequencing was performed for each patient. For cases where standard analysis yielded no results, copy number variation (CNV) analysis was applied. Results: The median age of diagnosis for patients included in the study was 11 years, with a consanguinity rate of 46%. Genetic factors were identified in 13 patients (48.1%). Whole exome sequencing was performed in 73% of the patients, while 37% underwent gene panel sequencing. In 8 cases with detected mutations, standard analysis was sufficient, but CNV analysis provided the result in 2 cases. In 2 patients, BTK mutations associated with X-linked agammaglobulinemia (XLA) were detected, and ICOS mutations were identified in another 2 patients. Heterozygous mutations in NFKB1 and NFKB2 were found in 2 patients without consanguinity or a family history. Mutations in IGLL1 and IGHM, two known causes of autosomal recessive agammaglobulinemia, were found in 2 patients with early onset and positive family history. In one patient with EBV-associated lymphoma, an ADA2 mutation was identified. Conclusion: Although the efficacy of next-generation sequencing in CVID diagnosis is reported to be limited, we observed a higher prevalence of monogenic forms of CVID in our country, where consanguineous marriages are common, compared to the literature.

Objective: Inborn errors of immunity (IEIs) are caused by deficiencies or functional abnormalities in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and/or malignancies. Primary hemophagocytic lymphohistiocytosis (HLH) arises from genetic mutations affecting the function of cytotoxic T lymphocytes and natural killer cells, while secondary HLH is triggered by infections, malignancies, rheumatologic disorders, or immune deficiencies. Treatment consists of remission induction, control of triggers, maintenance of remission, rescue treatment, and hematopoietic stem cell transplantation (HSCT) as curative steps. The aim of this study is to evaluate the clinical and laboratory features, as well as the outcomes, of primary HLH patients who were diagnosed and treated in a multidisciplinary manner over the past 25 years. Materials and Methods: The study included 30 patients with primary HLH/IEI who were diagnosed and treated in the departments of pediatric hematology, immunology, and oncology of the Ankara University Faculty of Medicine Children's Hospital and Bone Marrow Transplantation Unit from 2000 to 2025. Results: Of the 30 patients, 18 were boys and 12 were girls. The median age at the onset of the first symptom was 10 months (range: 0.5-204 months), while the median age at the time of admission to our center was 12.5 months (range: 1-204 months). Pedigree analysis showed that 21 patients were born to consanguineous parents. All patients had a fever lasting longer than 5 days, with a mean duration of 13.30+-14.05 days (range: 5-60 days). Splenomegaly was detected in 29 patients (96.6%) and hepatomegaly in 25 (83%). Anemia was observed in 27 patients (90%), neutropenia in 23 (76.6%), and thrombocytopenia in 30 (100%). Genetic evaluation was performed for all patients and a causative gene was identified in 19 of 30 cases (63%). The most common genetic diagnosis was perforin deficiency (FHLH2), detected in 8 patients (26.6%), followed by UNC13D defect (FHLH3) in 4 patients (13,3%). HSCT was performed for 17 patients (56.6%), with 6 receiving transplants from matched related donors, 4 from matched sibling donors, 5 from matched unrelated donors, and 2 from mismatched related donors. Thirteen patients remain alive, with mean survival of 119.89 months. Seventeen patients (56.6%) died, primarily due to multiorgan dysfunction syndrome, acute respiratory distress syndrome, HLH reactivation, septic shock, or heart failure. HSCT patients had a significantly longer survival (mean: 165.6 months) compared to patients who did not undergo HSCT (45.36 months; p<0.01). Admission to the pediatric intensive care unit, organ failure, and neurological involvement were identified as adverse prognostic factors, all significantly associated with higher mortality (p<0.05). Conclusion: Given the increasing recognition of HLH as a possible manifestation of IEIs, comprehensive immunological and genetic evaluations should be pursued without delay in suspected cases. Our findings, in line with the results of national and international cohorts, confirm that HSCT remains the only curative option for familial HLH and should be performed as early as possible after achieving disease remission. Improving access to early diagnostics and HSCT could significantly enhance outcomes, particularly in genetically predisposed populations.

Acute generalized exanthematous pustulosis (AGEP) is a rare, acute, and severe cutaneous adverse reaction, primarily associated with drug exposure. AGEP is characterized by the rapid onset of edema and erythema, followed by the appearance of numerous non-follicular, sterile pustules, which subsequently evolve into desquamation. The reaction typically develops within 1 to 11 days after drug exposure and resolves spontaneously within approximately 15 days. Acute localized exanthematous pustulosis (ALEP) is a localized variant of AGEP, in which pustular lesions are confined to one or more specific areas of the skin. In this article, we present three pediatric cases with rare manifestations of AGEP and ALEP, diagnosed based on the EuroSCAR criteria. The cases include a male neonate with localized pustular involvement of the scalp and forehead triggered by phenobarbital, a 7-year-old male diagnosed with AGEP following anti-thymocyte globulin (ATG) administration with back and arm involvement, and a 15-yearold female with a diagnosis of ALEP after postoperative use of amoxicillin-clavulanic acid. These cases highlight the diverse clinical spectrum of AGEP and ALEP in pediatric patients and underscore the importance of early diagnosis and appropriate management. In conclusion, while AGEP and ALEP are rare in pediatric patients, they should be considered in children of all ages presenting with characteristic pustular eruptions following suspected drug exposure. Early recognition and differentiation from other pustular dermatoses are essential for timely and appropriate management.

BackgroundThe majority of monogenic inborn errors of immunity presenting as actinopathies were reported originally from the Middle East and North Africa (MENA) countries indicating a high prevalence of these entities in the region. However, their prognosis is unclear due to rarity and lack of comprehensive treatment outcomes.MethodsWe evaluated clinical, immunological, and genetic abnormalities associated with 15 genetic entities of actinopathies. Based on the function of mutant genes in actin-regulatory pathways, patients were classified into CDC42- and RAC2-related subcategories.ResultsA total of 503 individuals (29.5% females) from 17 countries were considered with a median age of 120 months. Although most patients presented initially with allergic phenotypes (37.7%), the most prevalent manifestations throughout the lifespan were infection in respiratory tracts (72.2%). Primary clinical diagnosis was mainly combined immunodeficiencies (48.3%) and the majority of cases were molecularly assigned to the CDC42 pathway (64.8%). The most common genetic defects were reported within the DOCK8 (n = 209) followed by the WAS (n = 94) and the CARMIL2 (n = 15) genes. Hematopoietic stem cell transplantation (HSCT) was conducted on 24.0% of patients, which significantly improved survival in patients with defects in WAS, DOCK8 and DOCK2. Overall mortality was 23.0%, mainly due to sepsis and malignancy.ConclusionPatients with defects in RAC2-associated regulators of actin usually present with late-onset symptoms due to normal immune profiles, but a higher rate of EBV and HPV infections, autoimmune cytopenia, asthma, and lymphoproliferation compared to defects in the CDC42 pathway. The severity of mutations in patients of the CDC42 group helps to estimate the prognosis of the disease and prioritization of HSCT.

IntroductionBiallelic mutations in MAP3K14, encoding NF-κB-inducing kinase (NIK), disrupt non-canonical NF-κB signaling and lead to a rare inborn error of immunity marked by impaired lymphoid organ development, defective lymphocyte maturation, and susceptibility to recurrent infections. Hematopoietic stem cell transplantation (HSCT) has been considered a curative approach, yet its long-term efficacy remains unclear.MethodWe report long-term outcomes of two patients with genetically confirmed NIK deficiency who underwent HSCT.ResultsBoth patients achieved full donor chimerism and early T-cell reconstitution with normalized CD3+, CD4+, and CD8+ counts and naïve T-cell subsets. However, memory T-cell differentiation remained impaired, with persistently reduced central memory T cells and circulating T follicular helper cells. Immune dysregulation emerged years after HSCT, with one patient developing seropositive arthritis and the other exhibiting autoimmune hepatitis. Thymic dysfunction was suspected as an underlying contributor to impaired central tolerance in this pathology. Similarly, B-cell reconstitution was incomplete, characterized by persistent hypogammaglobulinemia and a marked deficiency in class-switched memory B cells, despite donor-derived chimerism. Lymphoscintigraphy confirmed absence of lymph nodes. Both patients suffered from recurrent, severe infections and ultimately died of infection-related complications. Our findings indicate that HSCT alone is insufficient to fully correct the immune disorder in MAP3K14 deficiency, likely due to non-hematopoietic defects in lymph node stromal structures and thymic central tolerance.DiscussionThese results highlight the importance of long-term immunologic monitoring, including assessments for immune dysregulation and anti-cytokine autoantibodies. Future therapies should consider adjunct strategies such as thymic regeneration or targeted immune modulation to address the underlying architectural defects in this disorder.

Background: Severe combined immunodeficiency (SCID) is the most severe form of inborn errors of immunity (IEIs) and typically leads to death within the first year of life. Combined immunodeficiencies (CID) are immune disorders that are less severe than SCID and are characterized by qualitative or quantitative defects in T and B cells. Objectives: To explore the clinical, laboratory, and genetic diagnostic approaches for patients diagnosed with SCID and CID. Methods: In this retrospective single-center study, we evaluated 54 patients diagnosed with SCID and CID between 2006 and 2019. Results: The male to female ratio was 30:24 and the rate of consanguinity was 77.8%. Among the patients, 23 were diagnosed with SCID and 31 diagnosed with CID. The most common phenotype in the SCID group was T-B-NK+ while in the CID group it was MHC class II deficiency. The median age at symptom onset for SCID and CID were 1 month and 5 months, respectively, while the median age at diagnosis was 4 months for SCID and 11 months for CID. The age at diagnosis of SCID and the age at diagnosis of symptoms were earlier than CID (P<0.05). Lymphopenia was present in 90.9% of patients with SCID and 51.6% of patients with CID (P<0.05). HSCT was performed in 10 out of 23 (43.4%) SCID patients and 10 out of 31 (32.2%) CID patients (total of 20 out of 54, 37%). The survival rates of SCID and CID patients who underwent HSCT were 80% and 70%, respectively. Conclusions: Consanguineous marriage, sibling death and family members with similar characteristics should be investigated for early diagnosis. Further investigations should be performed in the presence of lymphopenia. With the increasing number of genetic diagnosis facilities and HSCT centers, the survival rate of patients is expected to rise.

BACKGROUND:Dedicator of cytokinesis protein 8 (DOCK8) is a guanine nucleotide exchange factor highly expressed in, and critical for, the function of various innate and adaptive immune cells. DOCK8 deficiency leads to combined immunodeficiency characterized by susceptibility to infections, autoimmunity, and a severe Th2-type immune response. While dysfunction in various T cell subsets has been implicated in these phenotypes, a comprehensive analysis of the T-cell receptor (TCR) repertoire in these patients has not yet been documented. This study investigates the αβ TCR repertoire in DOCK8-deficient patients to identify features related to disease pathogenesis and explore the potential role of TCR repertoire alterations in disease development. METHODS:We compared immune repertoire profiles determined by high-throughput TCR sequencing of circulating CD4+ and CD8+ T cells from patients with DOCK8 deficiency (n = 10) to healthy controls (n = 7) and patients with ataxia-telangiectasia (AT) (n = 5). RESULTS:Different diversity analyses revealed a restricted TRA and TRB repertoire in both CD4+ and CD8+ T cells from DOCK8-deficient patients, with the restriction being more pronounced in CD8+ T cells. Skewed usage of individual variable (V) and joining (J) genes and potentially self-reactive CD8+ T cell clones, as determined by hydrophobicity and cysteine indices, were identified in DOCK8-deficient patients. CONCLUSION:Our study represents the most comprehensive immune repertoire analysis in DOCK8 deficiency. The identification of a significantly restricted αβ TCR repertoire, along with the detection of potentially autoreactive clones, highlights the crucial role of immune repertoire profiling in elucidating the pathogenesis of DOCK8 deficiency.

Background: Interleukin-10 (IL-10) is a crucial anti-inflammatory cytokine essential for maintaining immune homeostasis, particularly in the gastrointestinal system. Defects in the IL-10 signaling pathway, including mutations in interlaukin-10 receptor (IL-10R) beta, have been implicated in early-onset inflammatory bowel disease (IBD), often resistant to conventional treatments. Case Presentation: We report a 1.5-month-old male patient with IL-10R beta deficiency presenting with fever, vomiting, malnutrition, and sepsis. Despite normal initial evaluations, persistent fever and elevated inflammatory markers prompted the initiation of anakinra, an interleukin-1 receptor antagonist. Genetic testing confirmed a homozygous deletion in the IL10RB gene. Anakinra led to significant clinical improvement, including weight gain and symptom resolution. The patient was enrolled in an allogeneic hematopoietic stem cell transplantation (HSCT) program and successfully received HSCT from an HLA-matched related donor. Discussion: IL-10R beta deficiency presents with severe and early-onset symptoms, often unresponsive to standard IBD therapies. Anakinra has shown promise in bridging to HSCT by reducing inflammation and improving clinical outcomes in patients with IL-10 pathway defects. This case highlights the effectiveness of anakinra as a treatment strategy in severe, refractory IBD associated with IL-10R beta deficiency and underscores the importance of genetic testing for accurate diagnosis and treatment planning. Conclusion: Anakinra may provide significant clinical benefits in patients with IL-10R beta deficiency, serving as a bridge to definitive treatment with HSCT. Early genetic diagnosis and targeted therapy are crucial for managing this challenging condition.

To the Editors: Primary immunodeficiencies (PIDs) are rare monogenic disorders. It is also uncommon for 2 PIDs to coexist. Here, we present the first case with dedicator of cytokinesis 8 (DOCK8) and complement factor I (CFI) deficiency diagnosed after necrotizing meningoencephalitis. A 45-day-old baby boy with Streptococcus agalactiae meningitis and status epilepticus was admitted to our pediatric intensive care unit. On admission, cranial magnetic resonance imaging was performed and revealed necrotizing meningoencephalitis and brain edema. On follow-up, his clinical status deteriorated due to increased intracranial pressure. An external ventricular drain was placed, and new cerebrospinal fluid sampling revealed both S. agalactiae and cytomegalovirus positivity. He also had cytomegalovirus viremia and urinary tract infection with Candida albicans. Because of his complicated clinical course, a pediatric immunology consultation was planned. Background history revealed that he was born to consanguineous parents at term, and his neonatal period was uncomplicated. An elder brother (patient 2) was newly under intravenous immunoglobulin treatment with suspicion of chronic mucocutaneous candidiasis. An immunologic workup was performed for either. While patient 1 had low IgG, IgM and C3 levels and a reversed CD4/CD8 ratio, patient 2 had low IgM and elevated IgE levels with normal serum complement levels. Patient 2 also had low CD3+ T cell, CD3+CD4+ T cell levels, lymphocyte proliferation responses and a reversed CD4/CD8 ratio compatible with combined immunodeficiency (Table 1). Exome sequencing was performed and identified a homozygous likely pathogenic variant [c.4507C>T (p. Gln1503*)] in the DOCK8 gene and a homozygous likely pathogenic variant [c.262C>T (p. Gln88*)] in the CFI gene in the patient 1. Patient 2 had the same variant of the DOCK8 gene but was a carrier for the CFI variant. Sanger sequencing confirmed the variants in both siblings. Unfortunately, we could not assess CFI levels. Antibacterial-antifungal prophylaxis and intravenous immunoglobulin treatments were started along with donor screening for hematopoietic stem cell transplantation. TABLE 1. - Immunologic Evaluation of Patients Patient 1 Age References Patient 2 Age References IgG, mg/dL 222 294–1165 1180 640–2010 IgA, mg/dL 36 13–72 225 44–244 IgM, mg/dL <16 33–154 <18 52–297 T.IgE, IU/L <17.5 5420 16.86 C3, g/L 0.54 0.9–1.8 1.23 0.9–1.8 C4, g/L 0.28 0.1–0.4 0.26 0.1–0.4 Absolute lymphocyte count, /mm3 3400 2450–8890 2900 1130–5520 Absolute eosinophil count, /mm3 390 0–400 510 0–400 CD3+T cells, % (/mm3) 762584 51–792400–8100 35 1015 55–791900–3600 CD3+CD4+ T cells, % (/mm3) 32 1088 31–541400–5200 13 377 26–49600–2000 CD3+CD8+ T cells, % (/mm3) 461564 10–31600–3000 24696 9–35300–1300 CD4+CD45RA+ T cells, % (/mm3) 26 884 25–451200–5600 10 290 20–41500–6600 CD19+ B cells, % (/mm3) 13 442 14–44500–3600 351015 11–31300–1200 CD3-CD16+CD56+ NK cells, % (/mm3) 5 170 5–23200–1800 16464 5–28200–1200 γδ cells, % 22 5 CD45RA+CD31+, % 60 >50 42 >50 CD4/CD8 ratio 0.69 0.54 Lymphocyte activation response to PHA, % CD3+CD25+ 84 52–94 33 43–97 CD3+CD69+ 84 45–85 32 45–100 Lymphocyte activation response to anti-CD3, % CD4+CD25+ 76 15 CD4+CD69+ 74 17 CD4+ 77 15 Bold values indicate abnormal laboratory levels.NK indicates natural killer cells; PHA, phytohemagglutinin. Infections, autoimmunity, allergies, malignancies and autoinflammatory diseases are clinical signs of PIDs. Despite diverse clinical spectrum, most patients present with infections, and the infection is the most common reason for referral to a clinical immunologist1 Biallelic loss of function variants in DOCK8 results in a combined immunodeficiency. DOCK8-deficient patients present with not only severe, recurrent and life-threatening sinopulmonary and mucocutaneous viral (molluscum contagiosum virus, herpes simplex virus and human papillomavirus), bacterial (Staphylococcus aureus) and fungal (C. albicans) infections but also severe eczemas/dermatitis, allergies and malignancies.2 To date, over 200 patients have been reported globally. The only curative treatment modality is hematopoietic stem cell transplantation. CFI negatively regulates alternative and classical complement pathways. CFI deficiency is a rare autosomal recessive disease leading to secondary reduction of C3 through consumption. To date, only 60 patients are reported to have complete factor I deficiency.3,4 Complete absence of factor I results in severe and recurrent infections (encephalitis, meningitis or bacteremia with Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis), glomerulonephritis, autoimmune disease and central nervous system inflammation.5 Specific vaccination or prophylactic antibiotics should be offered. Consanguinity may result in a high likelihood of concomitant immunodeficiencies, and clinicians should consider this situation. ACKNOWLEDGMENTS The authors thank the patient and his family for their support for this publication.

Objective: Data on the risk factors, outcomes, and long-term effects of SARS-CoV-2 infection (COVID-19), especially following hematopoietic stem cell transplantation (HSCT) in pediatric patients with inborn errors of immunity (IEI) are limited. The study aims to define the clinical course of infection and identify risk factors for a worse outcome and long-term effects of COVID-19 in individuals with IEIs and those who have received HSCT for IEIs. Materials and Methods: In this single-center analysis, we retrospectively analyzed 74 pediatric IEI patients with COVID-19 between March 2020 and March 2023. Sixty-four patients were evaluated about COVID-19's long-term consequences one year after the outbreak. Results: Most patients exhibited combined immunodeficiency (51%), followed by antibody deficiency (28%), and syndromic combined immunodeficiencies (12%). Two patients had liver transplants, and 27 patients had HSCT before COVID-19. Thirty-two patients (43%) were hospitalized, and 3 (4%) died. The median time from HSCT to COVID-19 infection was 59 months (min 16 days, max 192 months). The major risk factor for infection severity was chronic pulmonary illness. Severe COVID-19 was associated with musculoskeletal abnormalities (p < 0.001), chronic lung disease (p < 0.01), hypogammaglobulinemia (p < 0.001), as well as fever and dyspnea (p < 0.01). Higher severity was also linked to the use of immunoglobulin and chemoprophylaxis (both p < 0.001). Mortality was significantly higher in patients with autoinflammatory syndromes and innate immune defects (p < 0.05). There is no difference between post-HSCT patients and our IEI cohort for COVID-19 illness severity. Remdesivir and convalescent plasma were given to five reinfected-relapsing patients. In total, 28 long-term side effects were identified, with fatigue, hair loss, and red eye being the most common. Conclusion: Overall, we found that hypogammaglobulinemia, chronic lung disease, and musculoskeletal abnormalities are associated with a severe disease course. The clinical course and outcomes of post-HSCT pediatric patients with COVID-19 are generally favourable. The long-term effects of COVID-19 can be seen in both groups regardless of the clinical severity of the disease.