Research

Genes (Basel). 2025 Oct 22;16(11):1247. doi: 10.3390/genes16111247.

ABSTRACT

BACKGROUND/OBJECTIVES: Inborn errors of immunity (IEIs), formerly known as primary immunodeficiency disorders, are a heterogeneous group of genetic diseases characterized by recurrent infections and multisystem involvement. Although more than 500 distinct entities have been identified, reports from Central Asia remain scarce. This study describes two rare pediatric IEI cases from Kazakhstan, highlighting the importance of genomic diagnostics in underrepresented regions.

METHODS: Two unrelated male patients with early-onset recurrent infections and systemic complications were evaluated at the University Medical Center, Astana. Clinical and laboratory assessments included immunophenotyping, imaging, and histopathology. Whole-genome sequencing (WGS) was performed, followed by Sanger confirmation and segregation analysis when feasible. Variants were classified according to ACMG/AMP guidelines.

RESULTS: The first case involved a child with recurrent bronchopulmonary disease, pulmonary fibrosis, and connective tissue abnormalities, found to carry a novel homozygous FBLN5:c.53del frameshift variant consistent with autosomal recessive cutis laxa type 1A. The second case concerned an adolescent with progressive neurodegeneration, granulomatous skin lesions, and chronic pancreatitis, who was identified with a heterozygous pathogenic ATM:c.4828dup variant, confirming ataxia-telangiectasia. Both patients required lifelong subcutaneous immunoglobulin therapy. Consanguinity contributed to the genetic risk in the first case, while the second case demonstrated diagnostic delays that emphasized the value of genetic testing.

CONCLUSIONS: These cases underscore the clinical heterogeneity of IEIs and illustrate the essential role of genomic diagnostics in elucidating atypical presentations. Documenting rare variants and unconventional phenotypes enhances global knowledge, elevates awareness in resource-limited regions, and emphasizes the necessity for early, multidisciplinary care and the enhancement of national registries for rare immunogenetic disorders.

PMID:41300699 | DOI:10.3390/genes16111247

Medicina (Kaunas). 2025 Oct 23;61(11):1897. doi: 10.3390/medicina61111897.

ABSTRACT

Background and Objectives: Hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH) is a rare genetic condition characterized by recurrent, potentially life-threatening episodes of angioedema. Long-term prophylaxis (LTP) is essential for decreasing the frequency and severity of attacks. This study aims to compare the safety profiles of two first-line LTP therapies, both of which inhibit kallikrein: berotralstat (oral) and lanadelumab (subcutaneous), using data from the WHO’s VigiBase pharmacovigilance database. Materials and Methods: The study employed a retrospective quantitative design, utilizing the World Health Organization’s pharmacovigilance database, VigiAccess, which contains individual case safety reports of adverse drug reactions (ADRs) to identify cases of ADRs associated with HAE-C1-INH long-term prophylaxis. Results: A total of 644 reports for berotralstat and 3432 reports for lanadelumab were analyzed. Berotralstat was mainly associated with gastrointestinal adverse events (47.9%), while lanadelumab was linked to injection site reactions (45.9%), infections (23.3%), musculoskeletal and connective tissue disorders (10%), immune system disorders (5.3%), vascular disorders (4.7%), and metabolic issues (3.9%). Female patients were more frequently affected in both groups. Statistically significant differences were observed, reflecting the differences in administration methods and pharmacological profiles between the two drugs. Limitations include the self-reported nature of the data and the absence of detailed clinical information. Conclusions: The results confirmed the literature’s data on the gastrointestinal adverse effects of berotralstat, as well as site reactions and infections associated with lanadelumab. Notably, musculoskeletal and connective tissue disorders, immune system disorders, vascular disorders, and metabolic issues occurred more frequently in patients using lanadelumab.

PMID:41303734 | DOI:10.3390/medicina61111897

Front Immunol. 2025 Nov 10;16:1629876. doi: 10.3389/fimmu.2025.1629876. eCollection 2025.

ABSTRACT

Antibody deficiency may be primary, because of an underlying inborn error of immunity, or secondary, due to another disease process or medication, leading to decreased antibody production or increased antibody loss. Secondary antibody deficiency is much more common than primary. It can, however, be difficult to distinguish primary from secondary, and both should be considered when assessing patients with hypogammaglobulinaemia. The case presented highlights the importance of confirming the underlying pathophysiology in patients presenting with antibody deficiency, the contribution of genetic assessment to the care of patients with complex phenotypes, and the impact this can have on long-term patient management.

PMID:41293159 | PMC:PMC12640896 | DOI:10.3389/fimmu.2025.1629876

Immunol Lett. 2025 Nov 23:107112. doi: 10.1016/j.imlet.2025.107112. Online ahead of print.

NO ABSTRACT

PMID:41290118 | DOI:10.1016/j.imlet.2025.107112

Blood Adv. 2025 Nov 25:bloodadvances.2025016812. doi: 10.1182/bloodadvances.2025016812. Online ahead of print.

ABSTRACT

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 133 patients with severe combined immunodeficiency (SCID) receiving matched sibling donor (MSD) hematopoietic cell transplantation (HCT) between 1980 and 2023 at 30 North American institutions. In this largest cohort of MSD outcomes in SCID patients to date, we examined the impact of conditioning regimen and graft-versus-host disease (GVHD) prophylaxis on survival and immune recovery. Outcomes after MSD HCT for SCID were excellent. Patients without an active infection or failure to thrive (FTT) at the time of HCT had 5-year overall survival (OS) superior to those with infection or FTT. Acute and chronic GVHD outcomes were independent of GVHD prophylaxis, conditioning regimen, SCID type, or presence of maternal engraftment. Patients without active infection at the time of HCT had superior chronic GVHD free event-free survival vs. those with infection. T cell reconstitution at 6 months was less likely achieved with use of GVHD prophylaxis or serotherapy, and in leaky SCID or Omenn syndrome patients. At 6 months, 1 year, and 2-5 years T cell reconstitution was less likely with ADA, DCLRE1C or RAG genotype. B cell reconstitution at 1 year and 2-5 years was negatively impacted by development of grade II-IV or III-IV acute GVHD. Conditioning did not impact T or B cell reconstitution. Our data suggest omitting conditioning and GVHD prophylaxis for patients with typical SCID did not negatively impact 5-year outcomes following MSD HCT, but the data are insufficient to recommend this approach for best long-term outcomes. (ClinicalTrials.gov NCT01186913).

PMID:41289158 | DOI:10.1182/bloodadvances.2025016812

J Med Virol. 2025 Dec;97(12):e70704. doi: 10.1002/jmv.70704.

ABSTRACT

Oral polio vaccine (OPV) from attenuated Sabin strains widely used for poliomyelitis prevention and eradication along with undeniable advantages has significant disadvantages, one of which is the ability to cause cases of vaccine-associated paralytic poliomyelitis (VAPP). Inactivated poliovirus vaccine (IPV) introduction into the national immunization schedules of countries that continue to use OPV allows effective prevention of VAPP cases and simultaneously forms immunity to PV type 2. The present study presents an example of VAPP development in a child with Bruton’s disease, born by in vitro fertilization, vaccinated with four IPV doses followed by one bOPV dose, and paralysis onset 52 days bOPV vaccination. Despite objective clinical, laboratory and instrumental signs of anterior corneal myelitis, the isolation of Sabin-like poliovirus, and contradictory results of serological investigation, diagnostics caused significant difficulties for the treating physicians. The case was associated with a recombinant poliovirus of vaccine Sabin strains types 3 and 1 with a recombination point in 2C-encoding genome region, containing known neurovirulence reverse mutations and some unique ones. The introduction of IPV doses for primary immunization increases the safety of immunization against polio; however, while OPV is in use there is still a VAPP threat for immunocompromised children and unvaccinated contacts.

PMID:41288257 | DOI:10.1002/jmv.70704

Blood. 2025 Nov 25:blood.2025031100. doi: 10.1182/blood.2025031100. Online ahead of print.

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder characterized by unchecked immune activation and hyperinflammation, resulting in end-organ tissue damage and high mortality rates in untreated patients. Since the first description of this condition in 1939, our understanding of HLH has continued to deepen, with increasing appreciation of the differences and similarities between primary (familial) HLH and secondary (acquired) HLH. While primary HLH presents in the early years of life on the backdrop of inherited genetic mutations affecting cytotoxic immune cell function, secondary HLH more commonly presents in adults and is a heterogenous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. Yet, they converge in a common pathway of widespread systemic inflammation, which clinically manifests with fevers, organomegaly, cytopenias, laboratory derangements, and rapid development of multiorgan failure. As such, early recognition and intervention is critical to prevent irreversible organ damage and death in both primary and secondary HLH. In this review, we focus our attention on adult secondary HLH and explore the latest updates on the pathophysiology, precipitants, clinical presentation, diagnosis and management of this life-threatening condition. Note that primary HLH is reviewed separately as a companion article in this review series.

PMID:41288529 | DOI:10.1182/blood.2025031100

J Clin Immunol. 2025 Nov 25;45(1):166. doi: 10.1007/s10875-025-01945-4.

ABSTRACT

BACKGROUND: Newborn screening (NBS) by quantification of T-cell receptor excision circles (TREC) identifies a considerable number of infants with T-cell lymphopenia (TCL) other than severe combined immunodeficiency (SCID). While some of these children have well-defined inborn errors of immunity (IEI), many lack a clear genetic diagnosis, complicating their management and causing prognostic uncertainty.

OBJECTIVE: To characterize the natural history of non-SCID TCL detected through NBS in Swiss infants between 2019 and 2023.

METHODS: Clinical, genetic and laboratory data from all non-SCID TCL cases were extracted from the national NBS registry and analyzed.

RESULTS: Out of 435 985 screened infants, 42 patients were identified with non-SCID, non-congenital athymia TCL, without an obvious secondary cause. A clear genetic diagnosis of IEI was established in 20 (48%) patients. Infants with confirmed IEI had significantly lower total T-cell, CD4 + T-cell and recent thymic emigrant (RTE) counts on initial lymphocyte phenotyping. In contrast, those with an unclear genetic diagnosis despite full investigations demonstrated faster normalization of total T-cell counts (hazard ratio 5.2, 95% CI 1.9 to 14.5, p = 0.001). All infants with initial CD4 + T-cell < 0.3 × 10⁹/L showed minimal recovery of T-cell counts and remained on long-term prophylactic measures. All infants with an unclear genetic diagnosis despite investigations were able to discontinue prophylaxis at median age 6 months without experiencing opportunistic or severe infections.

CONCLUSION: Infants with non-SCID TCL identified by NBS represent a heterogenous group, ranging from severe, persistent TCL to mild, transient lymphopenia. Management should be tailored based on individual immunological and genetic profiles.

PMID:41288825 | DOI:10.1007/s10875-025-01945-4

Ann Allergy Asthma Immunol. 2025 Nov 20:S1081-1206(25)01349-3. doi: 10.1016/j.anai.2025.11.009. Online ahead of print.

ABSTRACT

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency disorder seen in clinical medicine. The immune defect occurs in males and females equally, and is characterized by reduced serum levels of immunoglobulin G (IgG) along with deficient immunoglobulin A (IgA) and/ or immunoglobulin M (IgM) levels, along with poor to absent specific antibody responses to infection or vaccinations. Although CVID is considered a primary immune defect, most subjects are diagnosed between the ages of 20 to 40. However, due to the heterogeneous clinical appearance, a diagnostic delay of 5 to 8 years after the first cardinal symptom is common in all countries where this has been investigated. As the genetics of this immune defect have been further clarified, it is clear that the name “CVID” is an umbrella diagnosis, useful clinically for arranging treatment, but it actually includes a very large number of immune defects, many of which are not yet discovered. Due to prevalence, common inflammatory complications, and numbers of medical encounters, the awareness of CVID is critical for pediatricians, internists, and primary care physicians, as well as pulmonologists, otolaryngologists, hematologists and physicians in many other specialties. Here we outline the early history of CVID, the diagnostic criteria and standard workup of subjects, the clinical manifestations, emerging genetic understandings and current treatment modalities for patients with this immune defect.

PMID:41274495 | DOI:10.1016/j.anai.2025.11.009

Iran J Allergy Asthma Immunol. 2025 Oct 29;24(6):799-807. doi: 10.18502/ijaai.v24i6.20158.

ABSTRACT

The autosomal recessive form of hyperimmunoglobulin E syndrome (AR-HIES), caused by mutations in the DOCK8 (Dedicator of Cytokinesis 8) gene, presents a wide range of clinical manifestations and phenotypically overlaps with several types of combined immunodeficiency disorders characterized by elevated serum IgE levels. Due to the high rates of morbidity and mortality, as well as the potential curability through hematopoietic stem cell transplantation (HSCT), early and accurate differential diagnosis of this syndrome is crucial for optimal management and improved prognosis. Flow cytometry tests can be beneficial for early diagnosis of many inborn errors of immunity (IEIs), including this syndrome. This study, conducted for the first time on Iranian patients, investigated the expression of the DOCK8 protein. DOCK8 expression was assessed by flow cytometry in 14 patients (6 males and 8 females) with a clinical diagnosis of DOCK8 deficiency. The diagnosis was ultimately confirmed through genetic testing. The results showed that DOCK8 expression in patients was significantly lower compared to the healthy control group. Flow cytometric evaluation of DOCK8 protein expression offers a rapid and efficient diagnostic method with a sensitive detection range suitable for many cases. This approach can facilitate the diagnosis of DOCK8 deficiency, thereby enabling timely and effective disease management.

PMID:41266265 | DOI:10.18502/ijaai.v24i6.20158