Research

Front Pediatr. 2025 Dec 12;13:1693297. doi: 10.3389/fped.2025.1693297. eCollection 2025.

ABSTRACT

BACKGROUND: Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by severe eczema, recurrent skin and respiratory infections, and markedly elevated serum IgE levels. Early diagnosis and management are crucial for prognosis, but clinical misdiagnosis is common due to its rarity. We report a case of a 6-year-old girl with HIES, where a rarely reported STAT3 mutation was discovered through genetic testing, aiming to enhance disease awareness and diagnostic accuracy.

METHODS: The patient underwent comprehensive history taking, physical examination, serum IgE measurement, and ancillary tests. Whole-exome sequencing via next-generation sequencing (NGS) was used to analyze the STAT3 gene, with mutation validation by Sanger sequencing. Novelty was assessed against the Genome Aggregation Database (gnomAD). Management included anti-infective therapy, skin care, nutritional support, and a long-term home care plan.

RESULTS: The child presented with a 5-year history of eczema and skin pustules, growth delay, and malnutrition, along with significantly elevated serum IgE. Genetic testing revealed a heterozygous c.1915C > T missense mutation in STAT3, which was unreported in gnomAD and consistent with HIES pathogenicity based on literature. Supportive care, including anti-infectives and skin management, led to substantial improvement, and long-term home care was implemented post-discharge.

CONCLUSION: The STAT3 c.1915C > T mutation is likely causative of HIES, expanding its genetic mutation spectrum. This case highlights the critical role of genetic testing in rare disease diagnosis and the importance of integrating acute treatment with long-term home care, providing insights for improved early detection and management of HIES.

PMID:41458089 | PMC:PMC12741137 | DOI:10.3389/fped.2025.1693297

Front Immunol. 2025 Dec 11;16:1709657. doi: 10.3389/fimmu.2025.1709657. eCollection 2025.

ABSTRACT

INTRODUCTION: Severe combined immunodeficiency (SCID) and other profound T- and B-cell lymphopenias are life-threatening conditions that benefit from early diagnosis and treatment. In October 2022, Ukraine launched a nationwide newborn screening (NBS) program for SCID using the T-cell receptor excision circle/kappa-deleting recombination excision circle/spinal muscular atrophy (TREC/KREC/SMA) assay, despite ongoing war-related challenges. The aim of this study was to analyze the results of the SCID NBS program in Ukraine, evaluate its effectiveness, and outline the current challenges and future directions for its development.

METHODS: We analyzed data of screened newborns for SCID and related lymphopenias using the TREC/KREC/SMA assay from October 2022 to April 2025. The results of lymphocyte flow cytometry values, genetic testing, and clinical management of patients with positive TREC/KREC results were evaluated.

RESULTS: Among 398,415 screened newborns, 57 were identified with positive results (32 TREC ± KREC and 25 only KREC). The program demonstrated a high diagnostic yield, with an overall referral rate of 0.01%. In total, 18 newborns with inborn errors of immunity were diagnosed due to NBS (7 SCID/leaky SCID and 11 non-SCID). One case of ZAP70 deficiency was missed due to normal levels of T cells. The incidence of SCID/leaky SCID detected by NBS was 1 in 57,000 live births, and 1 in 49,800 live births when all diagnosed cases, including one initially missed case, were taken into account, which is comparable to data from other countries. All patients with SCID/leaky SCID identified by NBS received hematopoietic stem cell transplantation, with a survival rate of 85.7%. Nijmegen breakage syndrome was the most common syndromic cause of non-SCID T-cell lymphopenias (three cases). The use of the KREC assay enabled the first-time identification in Ukraine of B-cell lymphopenias associated with variants in IGLL1 gene.

CONCLUSIONS: The nationwide NBS program in Ukraine demonstrated high sensitivity and specificity in detecting SCID, with a low referral rate and high survival rates among diagnosed patients.

PMID:41459527 | PMC:PMC12738327 | DOI:10.3389/fimmu.2025.1709657

Front Immunol. 2025 Dec 11;16:1615039. doi: 10.3389/fimmu.2025.1615039. eCollection 2025.

ABSTRACT

INTRODUCTION: The Bacille Calmette-Guerin (BCG) vaccine is widely administered in countries with high tuberculosis (TB) prevalence to protect against severe forms of childhood TB. Despite its efficacy, the vaccine can lead to adverse effects like BCGosis, a severe but rare condition marked by systemic granulomatous inflammation. This is because the vaccine is comprised of attenuated BCG bacteria which has the potential to cause uncontrolled dissemination beyond the injection site. Immunocompromised children are particularly vulnerable to this side effect. Through a systematic review of the current literature, this analysis seeks to determine the global incidence of BCGosis and identify critical risk factors associated with its onset.

METHODS: The review was conducted in accordance with the PRISMA-2020 guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The review’s objectives and scope were framed using the PICOS (Population, Intervention, Comparison, Outcomes and Study Design) framework.

RESULTS: Not surprisingly, BCGosis is most prevalent in infants with underlying genetic immunodeficiencies such as severe combined immunodeficiency (SCID) and chronic granulomatous disease (CGD). We found a high correlation between the development of BCGosis and genetic mutations affecting certain immune processes, notably those involved in NADPH oxidase function and interferon-gamma signalling. The risks of developing these mutations also correlated with the prevalence of consanguinity, a common practice in certain populations. Factors like early neonatal vaccination (often within the first week of life) and variations in BCG strains may also influence BCGosis risk.

CONCLUSION: There is an urgent need for enhanced pre-vaccination screening for genetic and immunologic vulnerabilities in infants at hight risk for BCGosis, particularly in populations with high consanguinity rates. Alternatively, considerations should be made as to modifying existing vaccination schedules or postponing BCG immunization until immune competency can be confirmed in these high risk groups.

PMID:41459544 | PMC:PMC12738926 | DOI:10.3389/fimmu.2025.1615039

Virchows Arch. 2025 Dec 29. doi: 10.1007/s00428-025-04378-x. Online ahead of print.

ABSTRACT

Patients with inborn errors of immunity/primary immunodeficiency (IEI/PID) frequently present with reactive lymphadenopathy which is biopsied to rule out lymphoma or infection. We asked whether reactive lymphoid tissue from an international cohort of 35 patients with IEI/PID contains diagnostic clues to the underlying immune dysfunction as compared to 13 control pediatric patients. To this end, we investigated abnormalities of B-cell follicle architecture and Immunoglobulin G (IgG) + class-switched (CS) versus IgM/IgD + non-IgG-CS Ig production. Abnormalities of B-cell follicles including absent or naked germinal centers (GCs) and/or increased T follicular helper(TFH) cells within GCs were seen in 45.7% (16/35) of IEI/PIDs and 15.4% (2/13) of controls (X² = 3.7520, p = 0.054). There was a statistically significant association of B-cell follicle abnormalities with infectious (X² = 5.148, p = 0.023) but not autoimmune history. Abnormal IgM + , IgD + , IgG + and/or CD138 + plasmablast/plasma cell (PB/PC) density was observed in 79.4% of IEI/PIDs (27/34) as compared to 7.7% of controls (1/13, X² = 20.085, p < 0.001). Isolated deficiency of IgG CS PB/PC was present in 42% (12/33) of IEI/PID biopsies and in no control patients, 0% (0/13, X² = 6.396, p = 0.011). There was a strong and highly statistically significant positive correlation between IgG + PB/PC density and serum IgG (Kendall’s tau-b 0.567, asymptotic standard error 0.129, approximate significance < 0.001). There was also a statistically significant association of PB/PC abnormalities with infectious (X² = 12.024, p < 0.001) but not autoimmune history. Assessment of B-cell follicle architecture and Ig production may play a role in identifying patients with unexplained reactive lymphadenopathy who would benefit from immunologic evaluation.

PMID:41460331 | DOI:10.1007/s00428-025-04378-x

Br J Clin Pharmacol. 2025 Dec 28. doi: 10.1002/bcp.70420. Online ahead of print.

ABSTRACT

AIMS: Children with primary immunodeficiency (PID) and secondary antibody deficiency (SAD) often require immunoglobulin replacement therapy due to low plasma immunoglobulin G (IgG) levels and recurrent infections. Existing pharmacokinetic models for immunoglobulin in PID patients predominantly focus on adults, with limited attention to secondary antibody deficiencies and a lesser emphasis on paediatric populations. This study aims to investigate the pharmacokinetic properties of IgG in paediatric patients with PID and SAD.

METHODS: Population pharmacokinetic analysis for PID and SAD children treated with intravenous immunoglobulin at a tertiary paediatric centre was conducted using NONMEM® (7.5.1). Dosing simulations to achieve therapeutic levels of 6 and 8 gL^-1 were performed.

RESULTS: A population pharmacokinetic analysis of 64 patients (median age 4.08 years, range 0.06-16.8) was performed. A two-compartment model with first-order elimination, incorporating both additive and proportional residual error, adequately described the data. Interindividual variability was modelled on clearance, volume of distribution and baseline IgG levels, with allometric scaling to a 70-kg body weight applied a priori. The estimated clearance was 0.308 L^-1 day^-1 70 kg^-1 (95% CI 0.23, 0.67), and the volume of distribution was 10.96 L^-1 70 kg^-1 (95% CI 5.97, 15.79). Patients with SAD exhibited a lower clearance rate of 54% compared with PID patients. Dosing simulations indicated that the recommended SAD dosing regimen maintained therapeutic IgG levels in the simulated population. However, only 44.8% to 51.9% of patients with PID achieved target IgG levels with the standard regimen.

CONCLUSIONS: This study provides insights into immunoglobulin pharmacokinetics in paediatric PID and SAD patients, guiding optimised dosing strategies. Administering a loading dose would improve the probability of maintaining therapeutic IgG levels during the 4-week dosing interval.

PMID:41457055 | DOI:10.1002/bcp.70420

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 Oct 10;42(10):1212-1218. doi: 10.3760/cma.j.cn511374-20241207-00641.

ABSTRACT

OBJECTIVE: To explore the clinical features and genetic etiology of a child with Hoyeraal-Hreidarsson syndrome (HHS).

METHODS: A child with HHS diagnosed at the Affiliated Hospital of Jining Medical University due to “developmental delay and anaemia” on April 27, 2024 was selected as the study subject. Clinical data of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Whole-exome sequencing was carried out, and candidate variant was verified by Sanger sequencing of his family members and bioinformatics analysis using CASAVA v1.8.2. The pathogenicity of the candidate variant was rated according to the Standards and Guidelines for the Interpretation of Sequence Variants released by the American College of Medical Genetics and Genomics (ACMG). Relevant literature on HHS cases reported in China was reviewed to analyze the clinical and genetic characteristics. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2024-10-C003).

RESULTS: The child, a 7-month-old boy, had mainly manifested with growth retardation, developmental delay, microcephaly, cerebellar hypoplasia, immunodeficiency and bone marrow failure. Routine blood test indicated pancytopenia. The immunological workup showed reduction of B cells, NK cells and immunoglobulins. Cranial MRI demonstrated the volume of bilateral cerebellar hemispheres and brainstem and corpus callosum was small. Whole-exome sequencing revealed that he has harbored a hemizygous c.103_105del (p.Glu35del) variant of the DKC1 gene. Sanger sequencing showed that his mother and two sisters have carried the same variant. Based on the ACMG guidelines, the variant was predicted to be likely pathogenic (PM1+PM4+PS4_Supporting+PM2_Supporting). Four relevant literature were retrieved, which has involved 8 HHS cases. Together with the patient from this study, they have consisted of 8 males and 1 females. The most common symptoms of the 9 patients were blood system abnormalities and developmental delay. All patients had shown cerebellar dysplasia and anemia/erythrocytopenia. Among them, 3 cases have harbored TINF2 gene variants, and 6 cases had harbored DKC1 gene variants. The c.103_105del variant has not been reported in China previously.

CONCLUSION: The hemizygous c.103_105del (p.Glu35del) variant of the DKC1 gene probably underlay the disease in this child. Above finding has expanded the mutational and phenotypic spectra of the DKC1 gene, and has facilitated early diagnosis of HHS in this child.

PMID:41451493 | DOI:10.3760/cma.j.cn511374-20241207-00641

Curr Opin Allergy Clin Immunol. 2026 Feb 1;26(1):1-6. doi: 10.1097/ACI.0000000000001135. Epub 2025 Dec 3.

ABSTRACT

PURPOSE OF REVIEW: This review provides the current understanding on primary antibody deficiencies (PAD) in children with chronic rhinosinusitis (CRS).

RECENT FINDINGS: There is clear evidence that the prevalence of PAD is higher in children with CRS than in the general population. Common disorders include common variable immunoglobulin deficiency (CVID), X-linked agammaglobulinemia (XLA), specific antibody deficiency (SAD), IgG subclass deficiency (IGGSD), selective IgA deficiency (SIGAD), and hyperIgM syndrome. Despite the presence of multiple studies addressing CRS and PAD, the level of evidence supporting different treatment options continues to be lacking. Optimal management requires a multidisciplinary approach through collaboration with clinical immunology.

SUMMARY: This review outlines the current approach for diagnosis and treatment of PAD in children with CRS. While some of the disorders can be asymptomatic, children who present with more severe deficiencies will present with chronic and recurrent rhinosinusitis, as well as recurrent otitis media and pneumonia. Otolaryngologists are often at the forefront of early diagnosis of these disorders.

PMID:41451820 | DOI:10.1097/ACI.0000000000001135

Curr Opin Allergy Clin Immunol. 2026 Feb 1;26(1):67-75. doi: 10.1097/ACI.0000000000001128. Epub 2025 Dec 12.

ABSTRACT

PURPOSE OF REVIEW: Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is an autosomal dominant combined immunodeficiency (CID), often caused by increased CXCR4 pathway signaling. Against early-onset hallmark of neutropenia, diagnosis is delayed due to lack of awareness, incomplete penetrance, and requirement for specialized bone marrow evaluation to detect myelokathexis.

RECENT FINDINGS: Some infants with WHIM are identified via newborn screening for low thymic emigrant T cells. Early pediatric diagnosis is associated with improved outcomes. The genetic spectrum of CXCR4 expands beyond the canonical C-terminal hotspot, with N-terminal p.D84H variant. Recent trials of oral CXCR4 antagonist demonstrated increased circulating mature neutrophils and lymphocytes, reduced infection burden, and, in some cases, wart regression. Mechanistic studies in human and murine models contribute to the understanding of the combined immunodeficiency phenotype and highlight how CXCR4 hyperactivation impairs hematopoietic stem/progenitor cell egress, leukocyte trafficking and disrupts stromal niches critical for lymphocyte development and survival.

SUMMARY: Increased awareness, opportunities for screening at birth, improved pathological and genetic diagnostics, and 2024 FDA approval of the first oral CXCR4 antagonist create practical advance in targeting WHIM syndrome. As a CID with lifetime risk for humoral deficiency, impaired antiviral defense and malignancy, WHIM warrants long-term monitoring and further investigation into broader applications of CXCR4 antagonism.

PMID:41451822 | DOI:10.1097/ACI.0000000000001128

Balkan Med J. 2025 Dec 26. doi: 10.4274/balkanmedj.galenos.2025.2025-10-42. Online ahead of print.

ABSTRACT

BACKGROUND: Childhood interstitial lung diseases (chILD) and immunodeficiencies are rare, heterogeneous, and clinically challenging disorders.

AIMS: This study aimed to evaluate the clinical and radiological characteristics of immunodeficiency-related chILD using data from the Türkiye chILD Registry (chILD-TR).

STUDY DESIGN: We conducted a retrospective cohort study using data collected from the chILD-TR in 2023.

METHODS: Patients registered with the B3 code, according to the chILD-European classification, from 18 participating centers were included. Patients were classified into primary immunodeficiency (PID) and secondary immunodeficiency (SID) groups. Demographic, clinical, and radiological variables were compared between the two groups.

RESULTS: Among 667 patients registered in the chILD-TR, 114 (17%) had immunodeficiency-related chILD, including 53 (47%) females. The median current age was 156 months (range: 23-357), the age at symptom onset was 60 months (range: 0-215), and the age at chILD diagnosis was 85 months (range: 2-217). PID was identified in 77 patients (67.6%) and SID in 37 patients (32.4%). The PID group had significantly lower median current age, age at first symptom, and age at chILD diagnosis compared with the SID group (p < 0.05). No significant differences were observed in growth z-scores between the groups (p > 0.05). A history of hematopoietic stem cell transplantation (HSCT) and a diagnosis of bronchiolitis obliterans (BO) were more frequent in the SID group (p < 0.05). The most common computed tomography findings were ground-glass opacities in PID and mosaic perfusion in SID. During follow-up, 14 patients (12.3%) died.

CONCLUSION: Immunodeficiency-associated chILD encompasses a heterogeneous spectrum of disorders and is associated with increased mortality. Distinct clinical and radiological patterns were observed between PID and SID. These findings underscore the importance of early detection, individualized diagnostic strategies, and ongoing follow-up to improve outcomes in this high-risk population. Recognition of post-infectious BO and following HSCT is critical for timely intervention.

PMID:41452243 | DOI:10.4274/balkanmedj.galenos.2025.2025-10-42

J Clin Immunol. 2025 Dec 26. doi: 10.1007/s10875-025-01955-2. Online ahead of print.

ABSTRACT

Type II interferon (IFN) immunity is crucial for controlling intramacrophagic infections, driven by the interaction between innate immunity (macrophage-derived IL-12) and adaptive immunity (Th-derived IFN-γ). This study examines the maturation of type II IFN immunity in 55 healthy children (ages 1-18) to enable proper identification of deficiencies as part of the diagnostic evaluation of Mendelian Susceptibility to Mycobacterial Diseases (MSMD). The IL-12/IFN-γ axis was assessed through: (1) cytokine production after mycobacterial stimulation (Luminex and ELISA for IFN-γ, IL-12p70, TNF, CXCL10, IL-1RA, IL-10, IL-1β and IL-6), (2) IFN-γR1/R2 expression on monocytes, and (3) STAT1 phosphorylation/dephosphorylation. T cell maturation (primary IFN-γ source) was evaluated via immunophenotyping (naïve/memory/activated, Th1; Th2; Th17; Th1/17; Tfh) and proliferation assays. Main findings: (1) stable expression/production of key components of the IL-12/IFN-γ axis (IFN-γ, IL-12, TNF, IFN-γR1/2, and STAT1 activity) across ages confirming the stability of innate immune function throughout childhood; (2) increasing responses to IFN-γ with age reflected by increased CXCL10 production, and increase in the IFN-γ counter-acting anti-inflammatory cytokines (IL-10, IL-1RA); and (3) progressive T cell maturation, including Th1, Th17 and Th1/17 subsets, with significant milestones between 6 and 8.6 years, while T cell proliferative capacity remained stable. These observations highlight the stability of IL-12/IFN-γ axis innate components with age, accompanied by enhanced downstream IFN-γ signaling, aligning with the maturation of Th cell compartment. These underscore the limited benefit of age-specific controls in the evaluation of IL-12/IFN-γ axis in MSMD diagnosis, while emphasizing the importance of T cell maturation in the overall type II IFN immunity.

PMID:41452432 | DOI:10.1007/s10875-025-01955-2