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Turk J Haematol. 2025 Dec 24. doi: 10.4274/tjh.galenos.2025.2025.0221. Online ahead of print.

ABSTRACT

OBJECTIVES: Inborn errors of immunity (IEI) 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 (NK) 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 HSCT as approach 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.

MATHERIAL AND METHODS: From 2000 to 2025, 30 HLH cases with primary HLH/IEI who were diagnosed and treated at the departments of pediatric hematology, immunology and oncology of Ankara University School of Medicine Children Hospital and Bone Marrow Transplantation Unit were included in this study.

RESULTS: Of the 30 patients, 18 were boys and 12 were girls. The mean age at the onset of the first symptom was 10 months (range: 0.5-204 months), while the mean 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 five 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 patients (83%). Anemia was observed in 27 patients (90%), neutropenia in 23 patients (76.6%), and thrombocytopenia in 30 patients (100%). Genetic evaluation was performed in all patients, and a causative gene was identified in 19 out of 30 cases (63%). The most common genetic diagnosis was perforin deficiency (FHLH2), detected in 8 patients (26,6%), followed by UNC13D gene defect (FHLH3) in 4 patients (13,3%). HSCT was performed in 17 patients (56,6%), with 6 receiving transplants from matched related donors (MRD), 4 from matched sibling donors (MSD), 5 from matched unrelated donors (MURD), and 2 from mismatched related donors (MMRD). 13 patients remain alive, with a mean survival of 119.89 months. 17 patients (56.6%) died, primarily from mortality included multi-organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), HLH reactivation, septic shock, and heart failure. HSCT patients had a significantly longer survival (mean 165.6 months) compared to non-HSCT patients (45.36 months, p <0.01). PICU admission, 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 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.

PMID:41437329 | DOI:10.4274/tjh.galenos.2025.2025.0221

BMJ Case Rep. 2025 Dec 23;18(12):e270684. doi: 10.1136/bcr-2025-270684.

ABSTRACT

Primary immunodeficiencies are genetic disorders that impair immune function, increasing the risk of infections, autoimmune diseases and cancer. Patients with severe viral infections are often not thoroughly evaluated for immunodeficiencies. This case presents a young infant with human parvovirus B-19 meningitis and persistent lymphocytopenia, whose immunophenotyping revealed low absolute counts of T, B and natural killer cells, leading to a diagnosis of underlying immunodeficiency. This case underscores the necessity for vigilant diagnosis when standard presentation is complicated by recurrent illness or risk factors, highlighting the ‘Think Zebra’ analogy in paediatric practice.

PMID:41436218 | DOI:10.1136/bcr-2025-270684

Front Public Health. 2025 Dec 5;13:1695162. doi: 10.3389/fpubh.2025.1695162. eCollection 2025.

ABSTRACT

Live attenuated vaccines may cause life-threatening complications in infants with undiagnosed severe combined immunodeficiency (SCID). We describe a fatal case of disseminated Bacillus Calmette-Guérin infection and rotavirus enteritis in an infant with SCID to evaluate vaccine-adverse event causality and discuss implications for immunization policy. A multidisciplinary team retrospectively reviewed clinical records, microbiological and immunological tests, genetic analysis, and vaccination history. Causality was assessed using the WHO-UMC system and the revised WHO classification for adverse events following immunization. The infant received BCG at birth and oral pentavalent rotavirus vaccine at 8 weeks, then developed disseminated BCG infection and persistent rotavirus enteritis. A frameshift variant in TNFRSF13B, consistent with a combined immunodeficiency phenotype, was identified; SCID was diagnosed by integrating this genetic result with the patient’s clinical and immunologic findings. Despite intensive anti-tuberculosis therapy and hematopoietic stem cell transplantation, she died at 13 months. Both BCG dissemination and rotavirus enteritis were considered vaccine-associated in the setting of an underlying, undiagnosed SCID; the SCID was not attributable to vaccination. To the best of our knowledge, this is the only case identified in Chaoyang District surveillance in which live attenuated vaccination was temporally associated with a fatal severe adverse outcome. This case underscores that live vaccines administered to neonates with unrecognized immune disorders-later confirmed as SCID-can result in fatal complications. Therefore, integrating newborn screening for severe combined immunodeficiency with comprehensive pre-vaccination assessment is essential to identify high-risk infants and tailor vaccine schedules. We propose that these approaches be evaluated in prospective pilot studies. We further suggest that public-health authorities consider pilot-testing tuberculosis surveillance and household exposure assessment as components of risk-stratified immunization strategies for vulnerable populations.

PMID:41426715 | PMC:PMC12714996 | DOI:10.3389/fpubh.2025.1695162

JCI Insight. 2025 Dec 22;10(24):e197359. doi: 10.1172/jci.insight.197359. eCollection 2025 Dec 22.

ABSTRACT

The transcription factor IKAROS, encoded by IKZF1, is crucial for lymphocyte development and differentiation. Germline heterozygous IKZF1 mutations cause B cell immunodeficiency, but also affect T cells. Patients with IKZF1 haploinsufficiency (HI) or dimerization-defective (DD) variants show reduced naive and increased memory T cells, while dominant-negative (DN) mutations result in the opposite phenotype. Gain-of-function patients display variable patterns. To investigate IKAROS’s role in shaping the human naive/memory T cell phenotype, we performed IKAROS immunomodulation and knockdown experiments and analyzed early T cell development in an artificial thymic organoid (ATO) system using CD34+ cells from patients with representative IKZF1 variants. IKAROS inhibition by lenalidomide or silencing by small hairpin RNA directly altered expression of HNRNPLL, the master regulator of CD45 isoform splicing that defines CD45RA+/naive and CD45RO+/memory phenotypes. In the ATO system, IKAROS-DN precursor cells were blocked at the CD4-CD8-/double-negative stage and retained a CD45RA+ phenotype, whereas IKAROS-HI cells inefficiently reached the CD4+CD8+/double-positive stage and partially transitioned from CD45RA to CD45RO. Analysis of public gene expression data showed high HNRNPLL expression in double-positive thymic cells, beyond the stages affected by IKZF1 DN and HI mutations. Collectively, these findings indicate that IKAROS regulates early and late T cell development by mechanisms, including HNRNPLL modulation.

PMID:41424385 | DOI:10.1172/jci.insight.197359

Rev Alerg Mex. 2025 Dec 31;72(4):376-381. doi: 10.29262/ram.v72i4.1541.

ABSTRACT

BACKGROUND: Congenital neutropenia is a primary immunodeficiency characterized by a low neutrophil count, which predisposes to recurrent infections. A mutation in the ELANE gene is the most common cause of this disorder.

CASE REPORT: A 3-month-old infant with a history of recurrent bacterial infections since birth. The patient had presented with omphalitis and preseptal cellulitis, associated with a low blood neutrophil count. Suspecting congenital neutropenia, a genetic panel was performed, identifying a pathogenic mutation in the ELANE gene (c.164G>A, p.Cys55Tyr). Treatment with granulocyte colony-stimulating factor (G-CSF) was initiated, resulting in a significant improvement in the neutrophil count and resolution of the recurrent infections. The patient showed significant clinical improvement and is currently on a therapeutic protocol and receiving regular follow-up.

CONCLUSION: This case illustrates the importance of early diagnosis of congenital neutropenia. In every case where a pediatric patient with recurrent and difficult-to-manage bacterial infections is studied.

PMID:41420588 | DOI:10.29262/ram.v72i4.1541

Clin Immunol. 2025 Dec 17:110658. doi: 10.1016/j.clim.2025.110658. Online ahead of print.

ABSTRACT

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with microthrombocytopenia, eczema, immunodeficiency, autoimmunity and malignancies resulting from WAS pathogenic variants. Prevalence of disease in heterozygous female carriers has not been described previously. An online Qualtrics survey was designed in collaboration with the Wiskott-Aldrich Foundation, the Immune Deficiency Foundation, the Primary Immune Deficiency Treatment Consortium and Emory University to describe the incidence of thrombocytopenia, eczema, infections, autoimmune disorders, malignancies, and psychosocial factors. 193 carriers with a median age of 39 years participated in this survey. Respondents were predominantly White and were mothers of WAS patients. We observed a high prevalence of thrombocytopenia (13 %), eczema (22 %), infections (33 %) and autoimmunity (24 %) in this self-reported survey. No hematological malignancies were reported. Guilt (91 %), anxiety (41 %) and depression (44 %) were very prevalent. Comprehensive clinical and immunologic studies of WAS carriers should be prioritized to define appropriate health screening, preventive approaches, and counselling for carriers. SUMMARY: This self-reported survey describes the disease burden in 193 carriers of X-linked Wiskott-Aldrich syndrome. It highlights the increased incidence of thrombocytopenia, eczema, infections and autoimmunity in WAS carriers and the need for more comprehensive studies of WAS carriers.

PMID:41419161 | DOI:10.1016/j.clim.2025.110658

Proc Natl Acad Sci U S A. 2025 Dec 30;122(52):e2518589122. doi: 10.1073/pnas.2518589122. Epub 2025 Dec 19.

ABSTRACT

Ataxia-telangiectasia (A-T), caused by biallelic mutations in the ATM gene, leads to multiple disease phenotypes, including cerebellar neurodegeneration, radiosensitivity, cancer predisposition, immunodeficiency, insulin resistance, and pulmonary inflammation. ATM plays a central role in regulating cellular responses to DNA breakage [M. B. Kastan, J. Bartek, Nature 432, 316-323 (2004)], but several cellular and physiologic abnormalities associated with ATM dysfunction suggest the possibility of noncanonical roles for ATM as well. Herein, we identified the HSP90 paralogue, GRP94, as an ATM interactor/substrate and found that ATM influences N-glycosylation of GRP94 and its subsequent activation/translocation to the plasma membrane, where it serves as a scaffold protein and stabilizer for several membrane proteins, including receptor tyrosine kinases (RTKs), such as EGFR and IGF1-R. In selected cell types, ATM loss/inhibition resulted in increased cell surface expression of RTKs and overactivation of RTK pathways, alterations that were rescued by specific inhibition of cell surface GRP94. This ATM/GRP94 pathway also regulated the activation of microglial cells, manifest as increased cytokine production and phagocytosis activity associated with ATM loss/inhibition and reversal of that activation with GRP94 inhibition. These results identified GRP94 as an ATM interactor and apparent substrate and demonstrated specific critical regulatory roles for ATM outside of DNA damage signaling. These insights provide potential explanations for several of the phenotypes associated with ATM dysfunction and potential opportunities for novel approaches to blunt clinical symptoms in A-T, and also suggest that other neurodegenerative and inflammatory disorders might benefit from selective inhibition of cell surface GRP94.

PMID:41417600 | DOI:10.1073/pnas.2518589122

Br J Dermatol. 2025 Dec 19;193(Supplement_3):ljaf465.021. doi: 10.1093/bjd/ljaf465.021.

ABSTRACT

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma of subcutaneous adipose tissue. It is exceptionally uncommon in children, with fewer than 100 cases reported worldwide and very few under five years. Clinically, it may mimic cellulitis, panniculitis, or lupus erythematosus profundus, leading to diagnostic delay. Diagnosis relies on clinicopathological correlation, as histological features overlap with reactive and autoimmune panniculitides, and confirmation often requires molecular studies and expert review. Paediatric cases generally have a more favourable prognosis than adults. We report a two-year-old girl who developed an erythematous, indurated nodule on her left forearm, initially resembling an insect bite. The whole arm soon became markedly swollen and firm, though she remained systemically well. It was treated as cellulitis but did not respond to antibiotics. Multidisciplinary assessment excluded autoimmune disease, atypical infection, and primary immunodeficiency. Histopathology showed a lymphohistiocytic panniculitis with atypical CD8-positive cytotoxic T-cells rimming adipocytes, high Ki-67, and absence of B-cells or plasma cells. T-cell clonality studies confirmed clonal TCR beta and gamma rearrangements, supporting a neoplastic process, although TCR-beta staining was repeatedly negative. Despite this, the findings favoured SPTCL. Staging investigations did not show systemic involvement. Treatment with high-dose prednisolone and ciclosporin led to complete remission. Both were successfully tapered without relapse. SPTCL should be considered in children with panniculitis nodules unresponsive to antibiotics, but distinction from lupus erythematosus profundus and infection remains a critical diagnostic pitfall. Accurate diagnosis and management require multidisciplinary input, highlighting the importance of an MDT approach in such complex paediatric cases.

PMID:41413007 | DOI:10.1093/bjd/ljaf465.021

Br J Dermatol. 2025 Dec 19;193(Supplement_3):ljaf465.014. doi: 10.1093/bjd/ljaf465.014.

ABSTRACT

Adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID) is an inborn error of immunity characterised by pan-lymphopenia, failure to thrive, severe infections, autoimmunity, and non-immunological organ dysfunction secondary to accumulated cytotoxic adenine metabolites (Kohn et al. 2019). ADA-SCID has been associated with an increased risk of tumour growth, including dermatofibrosarcoma protuberans (DFSP), a locally aggressive fibroblastic neoplasm associated with PDGFB or PDGFD fusions (Gardner et al. 2024). Here, we present a 6-year-old boy with ADA-SCID (treated with family-matched haematopoietic cell transplant (HCT) at age 5 months) with a six-month history of atrophic, roughened, hyperpigmented plaques over his abdomen, back, neck and right medial thigh. Post-transplant, he maintained high donor chimerism (94% donor myeloid and B-lymphocyte; 91% donor T-lymphocyte). Five excision biopsies were performed: all showed a spindle cell lesion in the dermis, with subcutaneous extension in four specimens. Immunohistochemistry revealed diffuse CD34 positivity of the spindle cells, consistent with multicentric DFSP. The tumours demonstrated reduced cellularity and more eosinophilic cytoplasm compared with typical DFSP, findings characteristic of DFSP arising in the context of ADA-SCID. This case highlights the increased incidence and distinct histological features of DFSP in ADA-SCID. Further reporting of cases of DFSP occurring in ADA-SCID is needed to raise clinical awareness and to better define any temporal relationship to enzyme-replacement therapy, HCT or gene therapy. Careful dermatological surveillance is warranted in this patient population. Any new or abnormal skin lesions should prompt early referral, histopathological assessment, and tailored surgical management, preferably with Mohs’ micrographic surgery or wide local excision.

PMID:41412989 | DOI:10.1093/bjd/ljaf465.014

Int J Mycobacteriol. 2025 Oct 1;14(4):407-411. doi: 10.4103/ijmy.ijmy_191_25. Epub 2025 Dec 18.

ABSTRACT

Interferon-γ serves as the pivotal cytokine for macrophage activation. Anti-interferon-γ autoantibody (AIGA)-mediated adult-onset immunodeficiency (AOID) represents a phenocopy of primary immunodeficiency, characterized by recurrent disseminated infections predominantly caused by Mycobacterium abscessus complex (MABC) and other nontuberculous mycobacteria. Disseminated MABC (dMABC) in AOID poses significant therapeutic challenges, requiring long-term multidrug antimicrobial therapy combined with AIGA-targeted immunotherapy. This report details three cases of AOID with dMABC. All patients exhibited recurrent fevers, widespread cutaneous erythema, nodules, pustules, and painful multifocal lymphadenopathy over several months to 2 years. Serum AIGA testing was positive in all cases. MABC was isolated from skin and lymph node specimens through culture or next-generation sequencing. Radiologic studies confirmed systemic involvement, including pulmonary, lymphatic, and osteoarticular sites. A therapeutic regimen of combined antibiotics and low-to-medium-dose oral glucocorticoids (prednisone 20-30 mg/day initiated, tapered to 5 mg/day maintenance) was instituted, leading to clinical resolution in all patients. All were discharged successfully and remained disease-free on long-term follow-up.

PMID:41411392 | DOI:10.4103/ijmy.ijmy_191_25