Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations.

WHIM syndrome is typically caused by C-terminal gain-of-function variants in , yet clinical heterogeneity suggests additional genetic modifiers. We investigated a family in which the 22-year-old proband harbored two heterozygous variants: a novel missense variant, c.1022C>A (p.

Factors associated with and kinetics of anti-IFN-α autoantibodies in deficiency.

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.

The c.64 + 2 T > A Founder Variant Hits Home: Report on 14 Patients Expands the Phenotypic Landscape of Inherited ARPC1B Deficiency - a Comparative Analysis.

Background: Inherited ARPC1B deficiency (ARPC1BD) is a rare autosomal recessive inborn error of immunity that manifests with allergic, infective, and autoimmune/inflammatory features. Only about three dozen patients with ARPC1BD have been reported in the literature thus far.

Methods: We describe 14 patients (ten families) with ARPC1BD from Nepal.

Loss of B cell tolerance at the T2/T3a B cell transition is a convergent pathogenic mechanism in common variable immunodeficiency.

Unlabelled: Many patients with common variable immunodeficiency (CVID), including those with CTLA4 deficiency, variants and activated PI3K-delta syndrome (APDS), develop autoimmunity that is refractory to treatment. Despite this shared clinical phenotype, a unifying mechanism for the breakdown of B cell tolerance across monogenic forms of CVID has not been established. Here, we demonstrate that patients with loss-of-function variants, like those with variants and APDS, exhibit dysregulated CD4 T cell expansion, accumulation of transitional B cells, and a relative lack of follicular B cells.

Facilitated Subcutaneous Immunoglobulin 10% Safety Among Pediatric Patients With Primary Immunodeficiency Diseases.

Immunoglobulin replacement therapy is a fundamental treatment option to protect against infection for most patients with a primary deficiency in antibody production. Facilitated subcutaneous immunoglobulin (fSCIG) 10% is an immunoglobulin replacement therapy that uses recombinant human hyaluronidase to enhance immunoglobulin dispersion and absorption. This review provides an overview of data published to date relating to the safety and tolerability of fSCIG 10% for the treatment of primary immunodeficiency diseases in pediatric patients.

Fatal HLH in patients with X-linked lymphoproliferative disease 1 due to a novel variant in : case report.

Introduction: X-linked lymphoproliferative disease type 1 (XLP1) is an inborn error of immunity (IEI) caused by pathogenic variants in the gene, leading to severe immune dysregulation, often triggered by Epstein-Barr virus (EBV) infection. Hemophagocytic lymphohistiocytosis (HLH) is one of the most severe manifestations of XLP1 with high mortality.

Objective: Present a clinical case of fatal HLH associated with a novel variant, highlighting the variability of clinical presentation and the potential role of co-infections.

Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency.

Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature.

Evolving Approach to Clinical Cytometry for Immunodeficiencies and Other Immune Disorders.

Primary immunodeficiencies were initially identified on the basis of recurrent, severe or unusual infections. Subsequently, it was noted that these diseases can also manifest with autoimmunity, autoinflammation, allergy, lymphoproliferation and malignancy, hence a conceptual change and their renaming as inborn errors of immunity. Ongoing advances in flow cytometry provide the opportunity to expand or modify the utility and scope of existing laboratory tests in this field to mirror this conceptual change.

Clinicopathologic Features and the Spectrum of Myelokathexis in Warts, Hypogammaglobulinemia, Infections, Myelokathexis Syndrome.

Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency disorder predominantly caused by germline CXCR4 variants. Bone marrow (BM) evaluation showing myelokathexis helps to establish the diagnosis of WHIM syndrome, but unfamiliarity with pertinent diagnostic features and variability in morphologic and clinical findings may result in disease underrecognition. We aimed to characterize the clinical, BM, and peripheral blood (PB) features of 30 patients with germline CXCR4 variants, including genotype-phenotype analysis and correlation between morphologic features and functional CXCR4 receptor internalization defect.

Multi-Year Registry Study of Elapegademase Treatment in Patients With Adenosine Deaminase Severe Combined Immunodeficiency (ADA-SCID) Requiring Enzyme Replacement Therapy.

Purpose: The safety and tolerability of elapegademase (elapegademase-lvlr; Revcovi) a PEGylated recombinant adenosine deaminase (ADA), were demonstrated in two Phase 3 clinical trials in the U.S. and Japan in patients with ADA-deficient severe combined immunodeficiency (ADA-SCID).

Efficacy, Safety, Tolerability, and Serum IgG Trough Levels of Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% in US Pediatric Patients with Primary Immunodeficiency Diseases.

Purpose: To investigate the efficacy, safety, tolerability, and serum IgG trough levels of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in US pediatric patients with primary immunodeficiency diseases (PIDDs).

Methods: This phase 3, open-label, prospective study (NCT03277313) was conducted at 17 US centers. Eligible patients aged 2 to < 16 years had PIDDs and had received immunoglobulin G (IgG) at a consistent dose for ≥ 3 months before screening.

Piloting an automated query and scoring system to facilitate APDS patient identification from health systems.

Introduction: Patients with activated PI3Kδ syndrome (APDS) may elude diagnoses for nearly a decade. Methods to hasten the identification of these patients, and other patients with inborn errors of immunity (IEIs), are needed. We sought to demonstrate that querying electronic health record (EHR) systems by aggregating disparate signs into a risk score can identify these patients.

Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons.

Novel Inherited N-terminus TAP1 Variants and Severe Clinical Manifestations- Are Genotype-Phenotype Correlations Emerging?

Major histocompatibility complex class I deficiency results from deleterious biallelic variants in TAP1, TAP2, TAPBP, and B2M genes. Only a few patients with variant-curated TAP1 deficiency (TAP1D) have been reported in the literature and the clinical phenotype has been variable with an emphasis on autoimmune and inflammatory complications. We report TAP1D in a Nepalese girl with a severe clinical phenotype with serious viral infections at a very young age.

Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans.

Patients with cytotoxic T-lymphocyte-associated protein 4 (CTLA4) deficiency exhibit profound humoral immune dysfunction, yet the basis for the B-cell defect is not known. We observed a marked reduction in transitional-to-follicular (FO) B-cell development in patients with CTLA4 deficiency, correlating with decreased CTLA4 function in regulatory T cells, increased CD40L levels in effector CD4+ T cells, and increased mammalian target of rapamycin complex 1 (mTORC1) signaling in transitional B cells (TrBs). Treatment of TrBs with CD40L was sufficient to induce mTORC1 signaling and inhibit FO B-cell maturation in vitro.

Association of CD19-targeted chimeric antigen receptor (CAR) T-cell therapy with hypogammaglobulinemia, infection, and mortality.

Background: CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19 receptors on B cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse.

Expanding CXCR4 variant landscape in WHIM syndrome: integrating clinical and functional data for variant interpretation.

Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency disease predominantly caused by gain-of-function variants in the gene that typically results in truncation of the carboxyl terminus of C-X-C chemokine receptor type 4 (CXCR4) leading to impaired leukocyte egress from bone marrow to peripheral blood. Diagnosis of WHIM syndrome continues to be challenging and is often made through clinical observations and/or genetic testing. Detection of a pathogenic variant in an affected individual supports the diagnosis of WHIM syndrome but relies on an appropriate annotation of disease-causing variants.

Infant with diffuse large B-cell lymphoma identified postmortem with homozygous founder Slavic variant: a case report and literature review.

Background And Aims: There is an increased risk of lymphomas in inborn errors of immunity (IEI); however, germline genetic testing is rarely used in oncological patients, even in those with early onset of cancer. Our study focuses on a child with a recombination-activating gene 1 () deficiency who was identified through a screening program for Slavic founder genetic variants among patients who died with malignancy at an early age in Belarus.

Results: We identified one homozygous founder variant out of 24 available DNA samples from 71 patients who developed lymphoma aged <3 years from the Belarusian cancer registry between 1986 and 2023.

Clinical and Treatment History of Patients with Partial DiGeorge Syndrome and Autoimmune Cytopenia at Multiple Centers.

Background: Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation.