Manish Butte

Clin Genet. 2026 Feb 13. doi: 10.1111/cge.70147. Online ahead of print.

ABSTRACT

Pathogenic variants in GINS1 are believed to cause a primary combined immunodeficiency and growth retardation syndrome with natural killer cell deficiency and chronic neutropenia. To date, however, very few cases have been reported. Thus, the role of GINS1 in disease, as well as the spectrum of variants and their associated phenotype, remains unclear. We present a 2-year-old female with growth retardation, chronic neutropenia, distinctive facial features, and glaucoma. Exome sequencing revealed two likely pathogenic variants in GINS1, c.-48C>G p.? and c.247C>T p.Arg83Cys, conferring a diagnosis of GINS1 deficiency. She has overlapping features with the previously reported individuals, cementing growth retardation, neutropenia, and natural killer cell deficiency as core features. We additionally present a review of all nine individuals reported to date. We highlight that our proband, unlike the others, has no history of infections, and that glaucoma has now been observed in multiple unrelated individuals, pointing toward possible phenotypic expansion. Efforts to identify affected individuals, including those with different variants and phenotypes, are needed to understand ways in which GINS1 may be implicated in disease and the phenotypic spectrum of this ultrarare inborn error of immunity.

PMID:41689265 | DOI:10.1111/cge.70147

Orphanet J Rare Dis. 2026 Feb 12;21(1):55. doi: 10.1186/s13023-025-04123-2.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE), a rare autosomal dominant disorder characterized by recurrent, potentially life-threatening attacks of cutaneous or submucosal swelling, affects patients’ everyday activities and psychological well-being. Although caregivers are instrumental in helping patients cope with HAE, its impact on the caregivers’ quality of life is poorly documented. Using web-based surveys (July 2022‒February 2023), this international study (Argentina, Brazil, Colombia, Croatia, Denmark, Germany, Hungary, Ireland, Norway, Poland, Portugal, Romania, and Sweden) assessed the humanistic and psychosocial burden of caregivers (≥ 18 years old) of pediatric (< 18 years) and adult (≥ 18 years) patients with diagnosed HAE.

RESULTS: In total, 120 caregivers completed the surveys: 54 caregivers of pediatric patients (CoPs; mean age 40.6 years; 79.6% female) and 66 caregivers of adult patients (CoAs; mean age 42.7 years; 48.5% female). CoPs and CoAs reported 5.6 and 13.1 HAE attacks (mean) in the past 6 months for individuals receiving their care, respectively. CoPs provided care for 23.5 days (mean) per month on average; in the past 4 weeks, CoPs missed (mean) 2.6 days (mean) of work, while the children missed 3.9 days (mean) of school. CoPs cited a lack of understanding of their caregiving duties from schools (20.4%), employers/coworkers (16.7%), family (13.0%), friends (13.0%), and partner/spouse (13.0%). CoPs reported impacts on their work (37.0%), sleep (37.0%), and household chores (31.5%), and restricted time with family (29.6%), spouses/partners (27.8%), and friends (24.1%). Emotional impacts on the CoPs included worry about the child’s health (90.7%) and future (68.5%); CoPs themselves reported having sleep problems (24.1%), migraine (22.2%), gastrointestinal disorders (22.2%), and anxiety (20.4%). CoAs reported impacts on their work (28.8%), sleep (28.8%), and recreational activities (27.3%), leading to missing time of work (mean 0.94 days in past 4 weeks). Emotional impacts on the CoAs included worry about the health of individual they provide care for (92.4%) and future (40.9%); CoAs themselves reported having anxiety (13.6%), migraines (13.6%), and sleep problems (12.1%).

CONCLUSION: Results of this caregiver survey revealed that the caregiver role in HAE is time-demanding and adversely impacts various aspects of the caregiver’s life, particularly their emotional wellbeing.

PMID:41680909 | DOI:10.1186/s13023-025-04123-2

Gastroenterology. 2026 Feb 13:S0016-5085(25)06151-7. doi: 10.1053/j.gastro.2025.10.022. Online ahead of print.

NO ABSTRACT

PMID:41686101 | DOI:10.1053/j.gastro.2025.10.022

Immunol Med. 2026 Feb 13:1-13. doi: 10.1080/25785826.2025.2607878. Online ahead of print.

ABSTRACT

This phase 3 open-label study (jRCT2031210457; NCT05150340; January 2022-August 2023) evaluated pharmacokinetics, safety and tolerability, and efficacy of recombinant hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in Japanese patients with primary immunodeficiency diseases (PID) transitioning from intravenous immunoglobulin (IVIG) or conventional SCIG (cSCIG). Patients received fSCIG 10% (HyQvia^®) with dose ramp-up (Epoch 1) and 3- or 4-week dosing intervals (Epoch 2; 24 weeks). Assessments included IgG trough levels, infusion-related tolerability, validated acute serious bacterial infections (VASBIs), and treatment-emergent adverse events (TEAEs). Sixteen patients completed the study (median age: 21 years; range: 5-62). Prior treatments included cSCIG (62.5%), IVIG (31.3%), and SCIG (human) 20% solution (Ig20Gly; Cuvitru^®) (6.3%). Geometric mean IgG trough levels during the evaluation period (Epoch 2) remained stable across all visits (1254-1351 mg/dL, 3-week dosing; 874-937 mg/dL, 4-week dosing). No tolerability events or VASBIs were observed. Annual infection rate was 2.74 per patient-year. TEAEs related to fSCIG 10% occurred in 68.8% of patients, all mild or moderate. No serious TEAEs related to fSCIG 10% or deaths occurred. No TEAEs led to study discontinuation. fSCIG 10% effectively maintained IgG levels, prevented infections, and was well tolerated in Japanese patients with PID transitioning from IVIG or cSCIG.

PMID:41685940 | DOI:10.1080/25785826.2025.2607878

Front Immunol. 2026 Jan 28;17:1723142. doi: 10.3389/fimmu.2026.1723142. eCollection 2026.

ABSTRACT

RAC2-related immunodeficiency is a rare inborn error of immunity with a broad clinical spectrum ranging from neonatal severe combined immunodeficiency to atypical combined immunodeficiency diagnosed later in life. We describe two unrelated French-Canadian patients carrying a rare, homozygous RAC2 variant (c.202C>T; p.R68W), both presenting with combined immunodeficiency. The first patient developed recurrent bacterial respiratory infections and early bronchiectasis that initially responded to immunoglobulin replacement therapy. She subsequently experienced severe, treatment-refractory cutaneous viral infections. In adulthood, she developed gynecologic and anal neoplasms associated with chronic viral disease, requiring long-term multidisciplinary management. The second patient presented in early childhood with recurrent respiratory infections, marked lymphoproliferation, and generalized lymphadenopathy. He then developed kidney dysfunction due to light-chain deposition disease. Management included immunoglobulin therapy, and ultimately hematopoietic cell transplantation (HCT), after which he achieved sustained clinical improvement. Genetic testing identified the same homozygous p.R68W substitution in both patients. Despite significantly reduced RAC2 protein expression, patient-derived cells exhibited increased effector signaling in the homozygous state, producing a phenotype that phenocopies dominant gain-of-function RAC2 variants. Functional hyperactivation was not observed in heterozygous cells, supporting a dosage-dependent mechanism. These cases expand the clinical and functional spectrum of RAC2 deficiency and have immediate implications for clinical care. Persistent viral disease with oncogenic complications, bronchiectasis, lymphoproliferation, or progressive organ involvement should prompt consideration of RAC2 testing even beyond infancy. From a diagnostic standpoint, reliance on expression alone may be misleading; incorporating targeted signaling assays is essential for accurate variant interpretation. Therapeutically, HCT can be effective in progressive disease with organ damage, while others may require long-term medical management of chronic viral complications. Recognizing this rare, homozygous p.R68W variant and its functional consequences supports a precision-diagnosis approach to RAC2-related immunodeficiency and refines surveillance and treatment strategies for affected patients.

PMID:41685306 | PMC:PMC12891230 | DOI:10.3389/fimmu.2026.1723142

Int J Mol Sci. 2026 Feb 3;27(3):1518. doi: 10.3390/ijms27031518.

ABSTRACT

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency or inborn error of immunity (IEI) encountered in clinical practice. Characterized by a remarkably broad clinical spectrum, CVID presents with phenotypes spanning from “infection only” to significant non-infectious complications. The frequent overlap between these classifications underscores that their distinction is more accurately viewed as a continuous spectrum, rather than a binary categorization. CVID-associated liver disease is a significant source of morbidity, yet often poses diagnostic challenges due to its insidious and clinically silent nature, typically becoming apparent only upon the development of complications. Manifestations range from abnormal liver tests to irreversible organ damage, with reports including granulomas, autoimmune hepatitis, fibrosis, and porto-sinusoidal vascular disorder (PSVD). Regenerative nodular hyperplasia (RNH), commonly associated with PSVD, is a frequent histopathological finding. Management requires a multidisciplinary approach, including cause-directed immunosuppression and supportive treatment for non-cirrhotic portal hypertension. Despite significant advances in comprehending CVID-associated liver involvement, substantial gaps persist concerning its pathogenesis, its optimal management, and the correlation between histological findings and clinical outcomes. A heightened awareness of CVID-associated liver disease is paramount for multidisciplinary teams across IEI centers. Furthermore, given its prevalence, its insidious clinical phenotype until advanced complications, and the significant diagnostic delay and underdiagnosis, such awareness is critical across a broader range of medical specialties. In this paper, we aim to consolidate current knowledge regarding CVID-related liver disease, examining its clinical presentation, recent genetic and pathogenetic advancements along with current diagnostic methodologies, and therapeutic strategies.

PMID:41683939 | DOI:10.3390/ijms27031518

J Thromb Haemost. 2026 Feb 9:S1538-7836(26)00066-8. doi: 10.1016/j.jtha.2026.01.011. Online ahead of print.

ABSTRACT

Immune thrombocytopenia (ITP) is an acquired bleeding disorder caused by complex immune dysregulation. ITP is a rare disorder with significant morbidity; patients can suffer from bleeding symptoms and reduced quality of life. The pathogenesis of ITP can be observed at several levels: the mechanisms of thrombocytopenia, the loss of tolerance mechanisms, and underlying factors that drive its occurrence. Several mechanisms of platelet destruction and impaired platelet production are recognized as driving the disease. These mechanisms range from autoantibody-mediated platelet destruction, T cell-mediated cytotoxicity, complement-mediated destruction, and platelet desialylation leading to platelet clearance, to thrombopoietin consumption. These alterations are driven by a loss of tolerance with impaired T regulatory and myeloid derived suppressor cell surveillance. Several underlying factors may contribute to ITP pathogenesis by promoting this loss of tolerance, including genetic susceptibility, infections, the gut microbiome, and environmental influences. The numerous alterations described may be heterogeneous across patients with ITP, contributing to disease heterogeneity. Many patients will require treatment of ITP, which may target one or more of these mechanisms, with new therapies being developed to focus on specific pathways. Ultimately, identifying the main mechanism(s) driving ITP in a patient may allow individualized management. This review will highlight the major mechanisms of ITP immunopathology to deepen understanding of important pathways and therapies modulating these pathways.

PMID:41672375 | DOI:10.1016/j.jtha.2026.01.011

Tidsskr Nor Laegeforen. 2025 Dec 22;145(2). doi: 10.4045/tidsskr.25.0487. Print 2026 Feb 10.

ABSTRACT

BACKGROUND: Major causes of elevated liver enzymes are toxic, infectious, neoplastic and autoimmune disease. In immunocompromised patients, the spectrum of infectious pathogens causing hepatitis is broader and the immune response is blunted, making diagnosis more challenging.

CASE PRESENTATION: A man in his sixties had received CAR-T therapy for multiple myeloma.

INTERPRETATION: The increasing number of immunocompromised patients means that more patients are at risk of developing chronic hepatitis E. Serologic tests may be unreliable for this patient population, and nucleic acid testing for HEV RNA should be the primary diagnostic approach. HEV can be contracted in Norway, and hepatitis E is an underdiagnosed infection.

PMID:41670322 | DOI:10.4045/tidsskr.25.0487

Prostate. 2026 Feb 10. doi: 10.1002/pros.70142. Online ahead of print.

ABSTRACT

BACKGROUND: Smoking is a modifiable risk factor for prostate cancer (PCa) diagnosis, recurrence, and mortality. While the mutagenic effects of tobacco are well-documented, the immunological consequences of smoking within the tumor microenvironment (TME) are poorly understood. This study investigates how smoking reshapes the PCa immune landscape and how the associated changes could potentially be associated with patient survival.

METHODS: Tumor tissues from smoker and nonsmoker prostate cancer patients were subjected to multiplex gene expression analysis of immune cell types using the nanoString nCounter® PanCancer immune profiling panel to examine the effect of smoking behavior on the immune landscape. Gene expression data were also analyzed using Enrichr to identify differentially activated pathways in smoker versus nonsmoker patients. Further, we surveyed public databases to examine the association between top differentially-expressed genes and altered immune cell abundance with patient survival.

RESULTS: Current-smokers exhibited significantly higher infiltration of tumor-associated macrophages (TAMs) (p = 0.036) and regulatory T cells (Tregs) (p = 0.045), compared to nonsmokers, with a trend for lower mast cell infiltration (p = 0.055). A significant positive correlation (r = 0.42; p = 0.036) was observed between TAMs with Tregs in all samples, with a stronger correlation in current-smokers (r = 0.88; p = 0.008) than nonsmokers (r = 0.26; p = 0.403). A total of 89 DEGs were identified between current-smokers and nonsmokers, associated with upregulation of immunosuppressive pathways including “primary immunodeficiency” and “PD-L1 expression and PD-1 checkpoint,” and downregulation of “antigen-processing and -presentation” and “NF-kappa-B signaling” pathways. Key upregulated genes, MAGEA3, POU2AF1, and SEMG1, correlated with immune suppression markers and poorer PCa patient survival. Concomitant high TAM and Treg infiltration also significantly correlated with reduced overall survival (p = 0.04). No significant differences were observed between current-smokers and former-smokers, who exhibited patterns similar to nonsmokers.

CONCLUSIONS: These findings suggest that active smoking creates an immunosuppressive TME, potentially facilitating rapid tumor growth and aggressive progression. Smoking cessation may reverse these changes, highlighting the clinical significance of smoking behavior in disease outcomes.

PMID:41664985 | DOI:10.1002/pros.70142

Cureus. 2026 Jan 9;18(1):e101159. doi: 10.7759/cureus.101159. eCollection 2026 Jan.

ABSTRACT

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder characterized by defective neutrophil oxidative burst function, leading to impaired host defense against pathogenic microorganisms. This condition significantly increases the risk of invasive infections in affected patients. However, the clinical manifestations of CGD are not limited to infection-related complications; non-infectious complications can also lead to a variety of clinical symptoms. The global occurrence rate of CGD varies, and its inheritance patterns include X-linked and autosomal recessive forms. Research indicates that CGD patients are predominantly children who frequently face life-threatening infections and related complications, with early diagnosis often being challenging. Currently, hematopoietic stem cell transplantation (HSCT) is the only widely applied curative treatment for CGD. Recent advances in gene therapy offer a promising, safer, and more directly suitable alternative. This review primarily focuses on the pathophysiology, molecular genetics, occurrence rate, clinical manifestations, laboratory diagnosis, and cellular therapies of pediatric CGD, aiming to offer ideas for its clinical diagnosis.

PMID:41664758 | PMC:PMC12883141 | DOI:10.7759/cureus.101159