Case Report: p40 phox deficiency underlying pediatric-onset systemic lupus erythematosus.

Introduction: Systemic lupus erythematosus is a multi-faceted autoimmune disorder of complex etiology. Pre-pubertal onset of pediatric systemic lupus erythematosus (pSLE) is uncommon and should raise suspicion for a genetic driver of disease. Autosomal recessive p40 phox deficiency is a rare immunologic disorder characterized by defective but not abolished NADPH oxidase activity with residual production of reactive oxygen species (ROS) by phagocytic cells. Case presentation: We report the case of a now 18-year-old female with pSLE onset at 7 years of age. She presented with recurrent fever and malar rash. Aspects of her immune dysregulation over time have included typical pSLE features including production of autoantibodies, hematologic manifestations, and hypocomplementemia, as well as chronic suppurative skin lesions and recurrent infections. Genetic analysis revealed biallelic pathogenic variants in NCF4 resulting in p40 phox deficiency. Comprehensive NADPH oxidase activity studies confirmed significantly decreased production of reactive oxygen species, confirming the cellular phenotype seen in p40 phox deficient patients. Conclusions: Here, we present a patient with pSLE harboring biallelic variants in NCF4. Our patient represents a unique clinical presentation of severe onset autoimmunity in the setting of a rare inborn error of immunity affecting NADPH oxidase activity. This case underscores the need to consider genetic causes of pSLE in cases of pre-pubertal onset and atypical disease.

Unraveling the unphosphorylated STAT3-unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome.

Background: Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES. Objective: This study aims to elucidate the role of unphosphorylated STAT3-unphosphorylated NF-κB (uSTAT3-uNF-κB) activation pathway in LOF STAT3 HIES patients. Methodology: The mRNA expression of downstream molecules of unphosphorylated STAT3-unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter. Results: A reduced expression of the downstream signaling molecules of the uSTAT3-uNF-κB complex pathway, viz., RANTES, STAT3, IL-6, IL-8, ICAM1, IL-8, ZFP36L2, CSF1, MRAS, and SOCS3, in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients. Conclusion: The reduced expression of downstream signaling molecules, specially RANTES and STAT3, confirmed the impaired uSTAT3-uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.

Case Report: Aplastic anemia related to a novel CTLA4 variant.

A 20-year-old male patient with a history of celiac disease came to medical attention after developing profound fatigue and pancytopenia. Evaluation demonstrated pan-hypogammaglobulinemia. There was no history of significant clinical infections. Bone marrow biopsy confirmed hypocellular marrow consistent with aplastic anemia. Oncologic and hematologic evaluations were unremarkable for iron deficiency, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes, T-cell clonality, and leukemia. A next generation genetic sequencing immunodeficiency panel revealed a heterozygous variant of uncertain significance in CTLA4 c.385T >A, p.Cys129Ser (C129S). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor important in maintaining immunologic homeostasis. To determine the functional significance of the C129S variant, additional testing was pursued to assess for diminished protein expression, as described in other pathogenic CTLA4 variants. The results demonstrated severely impaired CTLA-4 expression and CD80 transendocytosis, consistent with other variants causing CTLA-4 haploinsufficiency. He was initially treated with IVIG and cyclosporine, and became transfusion independent for few months, but relapsed. Treatment with CTLA-4-Ig fusion protein (abatacept) was considered, however the patient opted for definitive therapy through reduced-intensity haploidentical hematopoietic stem cell transplant, which was curative.

Evaluation of recurrent and recalcitrant warts in a deaf adolescent male reveals GATA2 deficiency.

Prompt evaluation and genetic testing of patients who present with recurrent and recalcitrant warts, before onset of severe infection or myelodysplastic syndrome, leads to improved outcomes in patients with GATA2 deficiency.

Inborn Errors of Immunity and Cytokine Storm Syndromes.

Inborn errors of immunity (IEI) are a diverse and growing category of more than 430 chronic disorders that share susceptibilities to infections. Whether the result of a genetic lesion that causes defective granule-dependent cytotoxicity, excessive lymphoproliferation, or an overwhelming infection represents a unique antigenic challenge, IEIs can display a proclivity for cytokine storm syndrome (CSS) development. This chapter provides an overview of CSS pathophysiology as it relates to IEIs. For each IEI, the immunologic defect and how it promotes or discourages CSS phenomena are reviewed. The IEI-associated molecular defects in pathways that are postulated to be critical to CSS physiology (i.e., toll-like receptors, T regulatory cells, the IL-12/IFNγ axis, IL-6) and, whenever possible, review strategies for treating CSS in IEI patients with molecularly directed therapies are highlighted.

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Inborn errors of immunity (IEI) are a diverse group of disorders caused by defects in immune system structure or function, involving both innate and adaptive immunity. The 2022 update of the IEI classification includes 485 distinct disorders, categorized into ten major disease groups. With the rapid development of molecular biology, the specific pathogenesis of many IEI has been revealed, making gene therapy possible in preclinical and clinical research of this type of disease. This article reviews the advancements in gene therapy for IEI, aiming to increase awareness and understanding of these disorders.

Sweet syndrome associated with moderate leukocyte adhesion deficiency type I: a case report and review of the literature.

Sweet syndrome is an acute febrile neutrophilic dermatosis characterized by the infiltration of neutrophils into the skin. It may occur idiopathically or be linked to malignancies, inflammatory or autoimmune diseases. Leukocyte adhesion deficiency type I (LAD-I) is an inborn error immunity wherein leukocytes lack adhesion molecules necessary for migration to infection sites due to mutations in the CD18 gene encoding ß2 integrins. We present a case of a 16-month-old female initially diagnosed and treated for Sweet syndrome based on histopathological findings with recurrent flare episodes. Subsequent workup revealed LAD-I, making this case the first documented association between Sweet syndrome and LAD-I. Moreover, we reviewed the pertinent literatures detailing the concurrence of neutrophilic dermatosis and immunodeficiency disorders. This case underscores the significance of comprehensive evaluation for Sweet syndrome patients who are refractory to conventional treatments.

Biallelic Loss of Function Variants in SENP7 Cause Immunodeficiency with Neurologic and Muscular Phenotypes.

To evaluate a novel candidate disease gene, we engaged international collaborators and identified rare, biallelic, specifically homozygous, loss of function variants in SENP7 in 4 children from 3 unrelated families presenting with neurodevelopmental abnormalities, dysmorphism, and immunodeficiency. Their clinical presentations were characterized by hypogammaglobulinemia, intermittent neutropenia, and ultimately death in infancy for all 4 patients. SENP7 is a sentrin-specific protease involved in posttranslational modification of proteins essential for cell regulation, via a process referred to as deSUMOylation. We propose that deficiency of deSUMOylation may represent a novel mechanism of primary immunodeficiency.

Analysis of LRBA pathogenic variants and the association with functional protein domains and clinical presentation.

LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early-onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X-linked-like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease.

Combined therapy with IL-1 and JAK inhibitors in a patient with the NLRP1 gene mutation and a complex inflammatory phenotype.

A patient presented with overlapping clinical and laboratory features of 2 rare autoinflammatory diseases, NLRP1-associated autoinflammation with arthritis and dyskeratosis and familial multiple self-healing palmoplantar carcinoma. Her severe inflammatory attack was treated with the IL-1 receptor-α inhibitor anakinra along with the Janus kinase inhibitor ruxolitinib. Three years into the treatment, the patient's inflammatory symptoms are completely in remission.

Analysis of Clinical, Immunological and Molecular Features of Leukocyte Adhesion Deficiency Type I in Egyptian Children.

PURPOSE: Leukocyte adhesion deficiency (LAD) represents a rare group of inherited inborn errors of immunity (IEI) characterized by bacterial infections, delayed umbilical stump separation, and autoimmunity. This single-center study aimed at describing the clinical, immunological, and molecular characterizations of 34 LAD-I Egyptian pediatric patients. METHODS: Details of 34 patients' personal medical history, clinical and laboratory findings were recorded; Genetic material from 28 patients was studied. Mutational analysis was done by Sanger sequencing. RESULTS: Omphalitis, skin and soft tissue infections with poorly healing ulcers, delayed falling of the umbilical stump, and recurrent or un-resolving pneumonia were the most common presentations, followed by chronic otitis media, enteropathy, periodontitis; and recurrent oral thrush. Persistent leukocytosis and neutrophilia were reported in all patients, as well as CD18 and CD11b deficiency. CD18 expression was < 2% in around 90% of patients. Sixteen different pathological gene variants were detected in 28 patients who underwent ITGß2 gene sequencing, of those, ten were novel and six were previously reported. Three families received a prenatal diagnosis. Patients were on antimicrobials according to culture's results whenever available, and on prophylactic Trimethoprim-Sulfamethoxazole 5 mg/kg once daily, with regular clinical follow up. Hematopoietic stem cell transplantation (HSCT) was offered for 4 patients. However due to severity of the disease and delay in diagnosis, 58% of the patients passed away in the first 2 years of life. CONCLUSION: This study highlights the importance of early diagnosis and distribution of ITGß2 gene mutation in Egyptian children. Further molecular studies, however, remain a challenging necessity for better disease characterization in the region.

Inborn Errors of Immunity in Jordan: First Report from a Tertiary Referral Center.

PURPOSE: Inborn errors of immunity (IEI) are a heterogeneous group of diseases with variable clinical phenotypes. This study was conducted to describe the epidemiology, clinical presentations, treatment, and outcome of IEI in Jordanian children. METHODS: A retrospective data analysis was conducted for children under 15 years diagnosed with IEI from the pediatric Allergy, Immunology, and Rheumatology Division-based registry at Queen Rania Children's Hospital, Amman, Jordan, between 2010 and 2022. RESULTS: A total of 467 patients, 263 (56.3%) males and 204 (43.7%) females, were diagnosed with IEI. The mean age at symptom onset was 18 months (1 week to 144 months), a positive family history of IEI was reported in 43.5%, and the consanguinity rate was 47.9%. The most common IEI category was immunodeficiencies affecting cellular and humoral immunity at 33.2%, followed by predominantly antibody deficiencies at 16.9%. The overall median diagnostic delay (range) was 6 (0-135) months; patients with a positive family history of IEI had a statistically significant shorter diagnostic delay. Pulmonary and gastrointestinal clinical features were the most common at 55.2% and 45.6%, respectively. The overall mortality was 33.2%; the highest rate was reported in severe combined immunodeficiency at 56.2%. CONCLUSIONS: The high minimal estimated IEI prevalence at 16.2/100,000 Jordanian children compared to the regional and worldwide data, with the diversities in clinical presentation and distribution of IEI categories in our cohort point to unique features of IEI in Jordanian children, call for national registry establishment, regional and international collaborative networks.

Genomic testing identifies monogenic causes in patients with very early-onset inflammatory bowel disease: a multicenter survey in an Iranian cohort.

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multicenter study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in 1 patient, respectively. In 3 patients (18.7%), no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD.

Case Report: Profound newborn leukopenia related to a novel RAC2 variant.

We report the case of a 1-week-old male born full-term, who had two inconclusive severe combined immunodeficiency (SCID) newborn screens and developed scalp cellulitis and Escherichia coli bacteremia. He did not pass early confirmatory hearing screens. Initial blood counts and lymphocyte flow cytometry revealed profound neutropenia and lymphopenia with a T-/B-/NK- phenotype. Red blood cell adenosine deaminase 1 activity was within normal limits. A presumptive diagnosis of reticular dysgenesis was considered. Granulocyte colony-stimulating factor was started, but there was no improvement in neutrophil counts. Subsequent lymphocyte flow cytometry at around 4 weeks of age demonstrated an increase in T-, B- and NK-cell numbers, eliminating suspicion for SCID and raising concern for congenital neutropenia and bone marrow failure syndromes. Genetic testing revealed a novel variant in RAC2 [c.181C>A (p.Gln61Lys)] (Q61K). RAC2, a Ras-related GTPase, is the dominant RAC protein expressed in hematopoietic cells and is involved with various downstream immune-mediated responses. Pathogenic RAC2 variants show significant phenotypic heterogeneity (spanning from neutrophil defects to combined immunodeficiency) across dominant, constitutively activating, dominant activating, dominant negative, and autosomal recessive subtypes. Given the identification of a novel variant, functional testing was pursued to evaluate aberrant pathways described in other RAC2 pathogenic variants. In comparison to wild-type RAC2, the Q61K variant supported elevated superoxide production under both basal and PMA-stimulated conditions, increased PAK1 binding, and enhanced plasma membrane ruffling, consistent with other dominant, constitutively active mutations. This case highlights the diagnostic challenge associated with genetic variants identified via next-generation sequencing panels and the importance of functional assays to confirm variant pathogenicity.

Experience of pediatric to adult transition in immunology services: patient experience questionnaire and micro-costing analysis.

The effective transition from pediatric to adult care for individuals with chronic medical conditions should address the medical, psychosocial and educational needs of the cohort. The views and experiences of service users and their families are an integral component of service development. This study sought to evaluate the current provision of transition services from pediatric immunology services to adult immunology services for patients with a diagnosis of an inborn error of immunity at St. James's Hospital, Dublin. We gathered patient perspectives on the experience of the transition process using a structured survey. In addition, we adopted a micro-costing technique to estimate the cost of implementing the current standard of care for these patients. Results of a micro-costing analysis suggest that the most significant component of cost in assessing these patients is on laboratory investigation, an area where there is likely significant duplication between pediatric and adult care. Perspectives from patients suggested that the transition period went well for the majority of the cohort and that they felt ready to move to adult services, but the transition was not without complications in areas such as self-advocacy and medication management. The transition process may benefit from enhanced communication and collaboration between pediatric and adult services.

The Complexity of Being A20: From Biological Functions to Genetic Associations.

A20, encoded by TNFAIP3, is a critical negative regulator of immune activation. A20 is a ubiquitin editing enzyme with multiple domains, each of which mediates or stabilizes a key ubiquitin modification. A20 targets diverse proteins that are involved in pleiotropic immunologic pathways. The complexity of A20-mediated immunomodulation is illustrated by the varied effects of A20 deletion in different cell types and disease models. Clinically, the importance of A20 is highlighted by its extensive associations with human disease. A20 germline variants are associated with a wide range of inflammatory diseases, while somatic mutations promote development of B cell lymphomas. More recently, the discovery of A20 haploinsufficiency (HA20) has provided real world evidence for the role of A20 in immune cell function. Originally described as an autosomal dominant form of Behcet's disease, HA20 is now considered a complex inborn error of immunity with a broad spectrum of immunologic and clinical phenotypes.

Autoinflammatory Diseases Due to Defects in Degradation or Transport of Intracellular Proteins.

The number of human inborn errors of immunity has now gone beyond 430. The responsible gene variants themselves are apparently the cause for the disorders, but the underlying molecular or cellular mechanisms for the pathogenesis are often unclear. In order to clarify the pathogenesis, the mutant mice carrying the gene variants are apparently useful and important. Extensive analysis of those mice should contribute to the clarification of novel immunoregulatory mechanisms or development of novel therapeutic maneuvers critical not only for the rare monogenic diseases themselves but also for related common polygenic diseases. We have recently generated novel model mice in which complicated manifestations of human inborn errors of immunity affecting degradation or transport of intracellular proteins were recapitulated. Here, we review outline of these disorders, mainly based on the phenotype of the mutant mice we have generated.