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Endocrinol Diabetes Metab Case Rep. 2025 Jul 24;2025(3):e250054. doi: 10.1530/EDM-25-0054. Print 2025 Jul 1.

ABSTRACT

SUMMARY: This case report describes a 54-year-old woman with multiple endocrine autoimmune pathologies and recurrent mucocutaneous Candida spp. infections that were inappropriately attributed to her glycemic control. Following an allergic reaction over four decades later, the patient was referred to clinical immunology. The combination of persistent Candida infections, autoimmune endocrinopathies, and a positive family history prompted investigation for an inborn error of immunity (IEI). Genetic testing revealed a novel, missense mutation in STAT1. Functional analysis confirmed enhanced STAT1 protein phosphorylation, confirming a gain-of-function phenotype that explained her infectious and autoimmune manifestations. She was started on the JAK inhibitor, ruxolitinib, with clinical improvement. This case underscores the shared molecular mechanisms between IEIs and autoimmune endocrinopathies and highlights the importance of early recognition of IEI in patients with unusual or treatment-refractory infections alongside autoimmune disease. Endocrinologists and primary care providers may be the first to encounter such patients and should consider referral for immunologic and genetic evaluation. Early diagnosis can reduce long-term morbidity and open the door to targeted therapies that address the root cause of immune dysregulation.

LEARNING POINTS: Persistent mucocutaneous candidiasis in patients with autoimmune endocrinopathies warrants evaluation for underlying IEI: while candidiasis is common in individuals with diabetes, recurrent or treatment-refractory infections – particularly in the presence of additional autoimmune conditions – should prompt consideration of IEI, including STAT1 gain-of-function mutations. Autoimmunity and immunodeficiency represent overlapping spectra of immune dysregulation: genetic syndromes such as STAT1 GOF may manifest with both autoimmune endocrinopathies and increased susceptibility to fungal infections, underscoring the importance of a unifying diagnostic approach to seemingly disparate clinical features. Early referral to clinical immunology and genetic testing can enable timely diagnosis and targeted therapy: early recognition of IEI allows for disease-modifying treatment, such as JAK inhibition, which may alleviate infectious susceptibility and autoimmune manifestations, ultimately reducing morbidity and improving the quality of life. A thorough family history can provide critical diagnostic clues in cases of immune dysregulation: subtle patterns of autoimmunity or recurrent infections in family members – particularly in non-consanguineous pedigrees – may indicate heritable immunologic disorders and should inform the clinical threshold for pursuing genetic evaluation.

PMID:40704637 | DOI:10.1530/EDM-25-0054

Expert Rev Hematol. 2025 Jul 22. doi: 10.1080/17474086.2025.2538543. Online ahead of print.

ABSTRACT

INTRODUCTION: Leukocyte adhesion deficiency (LAD) is a rare genetic disorder that impairs leukocyte migration, leading to severe immune dysfunction and recurrent infections. Although allogeneic hematopoietic cell transplantation (HCT) remains the primary curative treatment for severe LAD, it is complicated by a high incidence of graft-versus-host-disease (GVHD).

AREAS COVERED: This narrative review outlines the key factors influencing GVHD development in patients with LAD-I, the most common LAD subtype, undergoing HCT. It explores established and emerging strategies for preventing GVHD, focusing on their effectiveness and outcomes. The literature search was conducted using PubMed to identify studies reporting HCT for LAD published 1989-2025.

EXPERT OPINION: Conventional GVHD prophylaxis regimens, primarily involving calcineurin inhibitors, have proven insufficient in preventing GVHD in high-risk populations. Among patients undergoing haploidentical HCT, post-transplantation cyclophosphamide has shown efficacy in preventing GVHD, although these results were based on limited cases. Graft manipulation techniques such as CD34⁺ selection have also been explored. However, these approaches are often associated with high graft failure rate and poor survival. Alemtuzumab, which is used in conditioning regimens, has shown promise in lowering GVHD incidence. Further studies are essential to optimize GVHD prophylaxis and improve survival outcomes in patients with LAD undergoing HCT.

PMID:40693940 | DOI:10.1080/17474086.2025.2538543

Curr Issues Mol Biol. 2025 Apr 18;47(4):290. doi: 10.3390/cimb47040290.

ABSTRACT

Folliculin-interacting protein 1 (FNIP1) is a key regulator of cellular metabolism and immune homeostasis, integrating nutrient signaling with proteostasis. FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for RagC/D. Additionally, FNIP1 interacts with heat shock protein 90 (HSP90) and undergoes phosphorylation, glycosylation, and ubiquitination, which dynamically regulate its stability and function. Evidence from murine models suggests that FNIP1 loss disrupts immune cell development and mitochondrial homeostasis. However, FNIP1 deficiency in humans remains incompletely characterized, and its full phenotypic spectrum is likely underestimated. Notably, FNIP1-deficient patients exhibit immunological and hematological abnormalities, immune dysregulation, and metabolic perturbations, emphasizing its role in cellular adaptation to stress. Understanding the mechanistic basis of FNIP1 dysfunction in human tissues will be critical for delineating its contributions to immune and metabolic disorders and identifying targeted interventions.

PMID:40699689 | DOI:10.3390/cimb47040290

Cureus. 2025 Jun 22;17(6):e86516. doi: 10.7759/cureus.86516. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: Non-cystic fibrosis bronchiectasis (NCFB) remains underdiagnosed in pediatric populations, particularly in the Middle East.

OBJECTIVE: To characterize the high-resolution computed tomography (HRCT) features of NCFB in pediatric patients, including extent, morphological subtype, and lobar distribution, and to evaluate their associations with underlying clinical diagnoses at a tertiary care center in Oman.

METHODS: We conducted a retrospective cross-sectional study at Sultan Qaboos University Hospital (SQUH), a tertiary center in Oman, reviewing pediatric patients ≤18 years diagnosed with NCFB between January 2000 and December 2022. High-resolution computed tomography (HRCT) reports prepared by pediatric radiologists were reviewed. Data on clinical features, radiological patterns, lobar involvement, and etiologies were analyzed descriptively using IBM SPSS Statistics for Macintosh, Version 19.0 (IBM Corp., Armonk, NY).

RESULTS: Of the 150 patients reviewed, 61 met the inclusion criteria. The mean age at diagnosis was 7.3 years, with 35 (57.4%) being male. Diffuse bronchiectasis was predominant, observed in 48 patients (78.7%), and involved more than two lobes in 40 cases (65.6%). The left lower lobe was the most frequently affected, seen in 13 patients (21.6%). Cylindrical bronchiectasis was present in all patients, while cystic in 25 patients (41.0%) and varicose in 19 patients (31.1%) forms were more common in those with systemic disorders, such as primary immunodeficiency (PID, 18 patients; 37.5%) and primary ciliary dyskinesia (PCD, 8 patients; 16.7%). Patients diagnosed at age ≥5 years had a significantly higher prevalence of diffuse disease.

CONCLUSION: HRCT is a crucial diagnostic tool for pediatric NCFB, particularly in children with recurrent infections or systemic comorbidities, such as PID or PCD. Early imaging may prevent irreversible damage and guide targeted treatment. Establishing national guidelines for pediatric chest CT utilization and incorporating multidisciplinary assessments may improve diagnostic timeliness and outcomes.

PMID:40698238 | PMC:PMC12281239 | DOI:10.7759/cureus.86516

Cureus. 2025 Jun 22;17(6):e86531. doi: 10.7759/cureus.86531. eCollection 2025 Jun.

ABSTRACT

Phosphoglucomutase 3 (PGM3) deficiency (OMIM (Online Mendelian Inheritance in Man) #615816) is a rare autosomal recessive congenital disorder of glycosylation that disrupts multiple glycosylation pathways, with few cases reported in the literature. It leads to a broad clinical spectrum ranging from hyper-IgE syndrome (HIES)-like features to severe combined immunodeficiency (SCID). We report a case of a 17-year-old female of Brazilian origin, referred to our center in Portugal for investigation of persistent neutropenia. Her medical history included recurrent infections in early childhood, severe eczema, and autism spectrum disorder. She exhibited persistent neutropenia and T-cell lymphopenia, with elevated IgE levels. Genetic analysis using a next-generation sequencing panel for primary immunodeficiencies identified compound heterozygous likely pathogenic variants in PGM3: a missense variant (c.1475C>T, p.(Thr492Ile)) and a complete gene deletion in the other allele, confirming the diagnosis of PGM3 deficiency. Chronic neutropenia was the main finding that prompted the genetic investigation. Although it is not a defining feature of PGM3 deficiency, it has been reported in nearly half of the cases. In this patient, the clinical presentation has been comparatively milder than the severe phenotypes described in the literature, which highlights the phenotypic variability of this condition and the need for clinical suspicion, even when classical features are absent. The genetic diagnosis has important implications for clinical follow-up and enables appropriate genetic counseling. This case illustrates the clinical variability of PGM3 deficiency and reinforces the role of genetic testing in clarifying the diagnosis, guiding management, and informing long-term follow-up in rare inborn errors of immunity.

PMID:40698220 | PMC:PMC12282493 | DOI:10.7759/cureus.86531

J Allergy Clin Immunol Glob. 2025 Jun 23;4(3):100521. doi: 10.1016/j.jacig.2025.100521. eCollection 2025 Aug.

ABSTRACT

BACKGROUND: Autoantibodies against IFN-α (anti-IFN-α) have been reported in recombinase activating gene (RAG) deficiency, attributed to impaired central and peripheral T-cell/B-cell tolerance. However, the clinical features, especially viral infections, associated with these autoantibodies at baseline, their kinetics over time, and their response to hematopoietic cell transplantation are not well defined.

OBJECTIVE: We described the clinical and immunologic findings linked to anti-IFN-α IgG in RAG deficiency and tracked its kinetics longitudinally, including in those who underwent hematopoietic cell transplantation.

METHODS: We measured anti-IFN-α IgG by enzyme-linked immunosorbent assay in 80 RAG-deficient patients with curated clinical and immunologic data from a multinational collaboration.

RESULTS: Forty-eight patients (60.0%) had positive anti-IFN-α at baseline; these patients were typically older at time of testing, fulfilled the phenotype of delayed-onset combined immunodeficiency with granuloma and/or autoimmunity (70.8% vs 31.3%, P = .001), and had a history of more frequent viral infections, mainly from the Herpesviridae family (62.5% vs 21.9%, P < .001). These patients also showed higher levels of serum immunoglobulins and expanded populations of peripheral blood autoreactive-prone (CD19^hiCD21^lo) (14.3 vs 5.2%, P = .016) and double-negative (IgD^–CD27^–) B cells (12.8 vs 5.8%, P = .001). In cases with longitudinal evaluation, anti-IFN-α titers were largely stable, although an increase was observed with concurrent active cytomegalovirus infections. Despite some decline after transplantation, these autoantibodies persisted during follow-up.

CONCLUSIONS: Anti-IFN-α autoantibodies reflect immune dysregulation in partial RAG deficiency. Their production is likely aggravated by environmental factors, especially frequent viral infections. Further studies are needed to define their pathogenic role in RAG deficiency.

PMID:40697949 | PMC:PMC12281840 | DOI:10.1016/j.jacig.2025.100521

J Allergy Clin Immunol Glob. 2025 Jun 24;4(3):100525. doi: 10.1016/j.jacig.2025.100525. eCollection 2025 Aug.

ABSTRACT

Hyper-IgE syndrome (HIES) is a rare and sporadic primary immunodeficiency usually characterized by atopic dermatitis, recurrent skin staphylococcal infections, recurrent pulmonary infections, and elevated IgE levels. Due to the rarity of the syndrome and its nonspecific and wide presentation, the diagnosis is difficult and arises with other diagnoses including other types of primitive chronic granulomatous disease or acquired immunodeficiency, severe atopic dermatitis, or cystic fibrosis or chronic respiratory infection as tuberculosis. To date, there is no gold standard management and treatments aim to relieve symptoms and avoid complications. We report on a 30-year-old female with a long-time misdiagnosed HIES.

PMID:40697947 | PMC:PMC12281938 | DOI:10.1016/j.jacig.2025.100525

Front Oncol. 2025 Jul 8;15:1613864. doi: 10.3389/fonc.2025.1613864. eCollection 2025.

ABSTRACT

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is increasingly being utilized in pediatric patients with severe respiratory failure, extending its use to high-risk patients, including those who are immunocompromised. Despite its growing application, reports on outcomes and prognostic factors in this specific population are scarce, highlighting a gap in our understanding.

METHODS: This retrospective cohort study analyzed the outcomes of 19 immunocompromised pediatric patients who received ECMO for respiratory failure at our institution between 2006 and 2023. Patients were classified as immunocompromised due to conditions such as cancer, hematopoietic cell transplantation (HCT), primary immunodeficiency or receiving immunosuppression for a chronic (auto-) inflammatory disease. Data on patient demographics, baseline laboratory and ventilation parameters were collected and compared between survivors and non-survivors.

RESULTS: The median age of patients was 12.1 years, and the majority suffered from infectious pneumonia leading to respiratory failure. The median duration of ventilation before ECMO was 5 days, and ECMO support lasted a median of 19 days. The hospital mortality rate in this cohort was 74% (14/19). All patients who had undergone HCT or a primary immunodeficiency did not survive. Non-survivors exhibited significantly higher median C-reactive protein levels and more bleeding complications. Other laboratory and respiratory parameters, as well as vasopressor requirements, pSOFA, and P-PREP scores, were similar across survivors and non-survivors.

CONCLUSION: The treatment of immunocompromised pediatric patients with ECMO for respiratory failure presents notable challenges. This study highlights the complexity of predicting outcomes in this group, as traditional laboratory and respiratory parameters were not distinctly different between survivors and non-survivors. These findings indicate a need for continued research and nuanced clinical approaches to improve care and outcomes in this vulnerable population.

PMID:40697384 | PMC:PMC12279884 | DOI:10.3389/fonc.2025.1613864

Front Immunol. 2025 Jul 7;16:1598896. doi: 10.3389/fimmu.2025.1598896. eCollection 2025.

ABSTRACT

INTRODUCTION: Cardiofaciocutaneous syndrome (CFCS) is a rare syndromic disorder caused by germline mutations affecting the RAS/MAPK pathway. It is characterized by distinctive craniofacial dysmorphism, congenital heart defects, skin abnormalities, gastrointestinal dysfunction, neurocognitive impairment, and epilepsy. Emerging evidence suggests an association with hypogammaglobulinemia, but a comprehensive characterization of immunological abnormalities in CFCS is lacking.

METHODS: We conducted a retrospective, multicenter observational study to investigate the immunological phenotype of CFCS. Clinical features, immune-related manifestations, and laboratory parameters were analyzed to delineate the immunological profile of affected individuals.

RESULTS: A total of 56 patients with a confirmed clinical and molecular diagnosis of CFCS were included, with a median age at evaluation of 13 years (range: 1-39 years). Increased susceptibility to infections was reported in 18/56 patients (32%), while autoimmune manifestations were observed in 14/56 patients (25%). Common immunological findings included monocytosis (32%), lymphopenia (21%), and hypogammaglobulinemia, with decreased IgG, IgA, or IgM levels in 21%, 40%, and 35% of patients, respectively. Genotype-phenotype analysis revealed that BRAF mutations were predominantly associated with T-cell lymphopenia, whereas MAP2K1 mutations were linked to monocytosis, reduced naïve and switched-memory B cells, and hypogammaglobulinemia. Immunodeficiency-related treatments, including immunoglobulin replacement therapy, antibiotic prophylaxis, or immunosuppressive therapy, were administered to 6/56 patients (11%).

CONCLUSIONS: CFCS is associated with recurrent yet heterogeneous immunological abnormalities, including lymphopenia, hypogammaglobulinemia, and increased infection susceptibility. Given these findings, routine immunological assessment should be considered in CFCS patients to facilitate early detection and appropriate management of immune dysfunction.

PMID:40692796 | PMC:PMC12277328 | DOI:10.3389/fimmu.2025.1598896

Pan Afr Med J. 2025 Apr 1;50:88. doi: 10.11604/pamj.2025.50.88.46204. eCollection 2025.

ABSTRACT

Drug hypersensitivity reactions to essential antibiotics like vancomycin pose significant diagnostic and therapeutic challenges, particularly in vulnerable populations such as pediatric patients with immune deficiencies. We present the case of a 7-year-old girl with primary immunodeficiency who experienced immediate hypersensitivity reactions to vancomycin, including urticaria and angioedema, managed with corticoids and antihistamines. The Basophil Activation Test (BAT) conducted two years after the last allergic episode revealed significant basophil activation across all tested vancomycin dilutions, with CD63 and CD203c expression exceeding negative and positive controls. These findings confirm vancomycin hypersensitivity and underscore the BAT’s utility as a reliable in vitro diagnostic tool, especially in settings where skin testing or specific IgE assays are unavailable. This case highlights the BAT’s potential for broader adoption in clinical allergy practice, particularly in resource-limited environments. It emphasizes the importance of reliable diagnostic methods for managing drug hypersensitivity in high-risk patients.

PMID:40687172 | PMC:PMC12271878 | DOI:10.11604/pamj.2025.50.88.46204