Immune dysregulation in children can lead to a variety of health issues, including infections, allergies and autoimmune diseases. However, the coexistence of autoimmune diseases and primary immunodeficiency disorders is extremely rare in clinical practice. A 4-year-old male patient was admitted in July 2017 with joint swelling and pain, alongside a history of recurrent respiratory infections and severe pneumonia. Physical examination revealed tenderness and swelling in multiple joints, and laboratory tests indicated elevated inflammatory markers. Imaging studies showed joint effusion and inflammatory lesions in the lungs. He was diagnosed with rheumatoid factor-negative polyarticular juvenile idiopathic arthritis (PJIA) and treatment was initiated with naproxen, methotrexate and etanercept, leading to significant symptom improvement. In July 2019, following a decline in immunoglobulin (Ig) M (IgM) levels (IgM 0.36 g/L) and recurrent infections, genetic testing was conducted, revealing a frameshift mutation in the CD40LG gene (c.621dup A, p.A208Sfs * 23), which confirmed the diagnosis of X-linked hyper IgM syndrome (XHIGM). The treatment regimen was adjusted to include monthly intravenous Ig infusions and prophylactic antibiotics, significantly reducing the frequency of respiratory infections. By January 2021, PJIA was in clinical remission, allowing for the discontinuation of immunosuppressive therapy, with follow-ups indicating continued recovery without discomfort. In conclusion, this case underscores the rare coexistence of XHIGM and PJIA in the field of pediatrics and identified a new pathogenic variant in CD40LG, enhancing our understanding of the clinical management of individuals with concurrent autoimmune and immunodeficiency disorders.

In children, hyper-IgM syndrome type 1 (HIGM1) is a type of severe antibody disorder, the pathogenesis of which remains unclear. The antibody diversity is partially determined by the alternative splicing (AS) in the germline, which is mainly regulated by RNA-binding proteins, including Breast cancer amplified sequence 2 (Bcas2). However, the effect of Bcas2 on AS and antibody production in activated B cells, the main immune cell type in the germline, remains unknown. To fill this gap, we created a conditional knockout (cKO, B cell-specific AID-Cre Bcas2 fl/fl) mouse model and performed integrated mechanistic analysis on alternative splicing (AS) and CSR in B cells through the RNA-sequencing approach, cross-linking immunoprecipitation and sequencing (CLIP-seq) analysis, and interactome proteomics. The results demonstrate that Bcas2-cKO significantly decreased CSR in activated B cells without inhibiting the B cell development. Mechanistically, Bcas2 interacts with SRSF7 at a conservative circular domain, forming a complex to regulate the AS of genes involved in the post-switch transcription, thereby causing broad-spectrum changes in antibody production. Importantly, we identified GAAGAA as the binding motif of Bcas2 to RNAs and revealed its essential role in the regulation of Bcas2-dependent AS and CSR. In addition, we detected a mutation of at the 3'UTR of Bcas2 gene in children with HIGM1 and observed similar patterns of AS events and CSR in the patient that were discovered in the Bcas2-cKO B cells. Combined, our study elucidates the mechanism by which Bcas2-mediated AS affects CSR, offering potential insights into the clinical implications of Bcas2 in HIGM1.

Hyper IgM syndrome (HIGM) is a rare immunodeficiency caused by impaired immunoglobulin class switching, leading to recurrent infections. The present report describes the case of an 18-year-old man initially diagnosed with common variable immunodeficiency at 3 years of age. Genetic analysis revealed a hemizygous CD40LG missense variant (p.Arg203Ile) associated with X-linked HIGM (XHIGM). Structural and flow cytometric analyses indicated normal CD40 ligand (CD40L) expression on activated CD4+ T-cells but impaired CD40 binding, indicating disrupted immune signaling. Notably, the patient experienced neither bacterial infections requiring hospitalization nor opportunistic infections during 15 years of immunoglobulin replacement therapy. These findings indicate that the p.Arg203Ile variant destabilizes CD40L-CD40 interactions without affecting CD40L expression, suggesting a hypomorphic phenotype. This report highlights the importance of combining genetic testing with functional analysis when evaluating atypical XHIGM presentations to predict clinical severity and provide a scientific basis for personalized treatment strategies. Additional studies are required to assess the long-term outcomes and potential curative therapies for similar cases.

Activation-induced cytidine deaminase (AID) deficiency is a rare autosomal recessive inborn error of immunity (IEI) characterized by increased susceptibility to infections, autoimmunity, and/or autoinflammation. AID plays an important role in immunoglobulin class switching and somatic hypermutation. AID deficiency patients have very low or absent levels of IgG, IgA, and IgE, while IgM level is elevated. The disease is designated as type 2 hyperimmunoglobulin M syndrome (HIGM-2). To date, around 130 patients with HIGM-2 have been reported, none from Egypt. Four patients from three different consanguineous families with elevated serum IgM and low IgG and IgA were included in the study. After the exclusion of CD40 and/or CD40L deficiency by flow cytometry, patients' samples were tested by a panel covering 452 genes (four bases PID-Pro) on the Illumina Miseq platform. All patients suffered repeated infections since childhood. Patients 1-3 had inflammatory bowel disease-like (IBD-like) symptoms, while patient 4 did not have autoimmune manifestations. Patient 1 is the first HIGM-2 patient to be reported to have renal amyloidosis as part of the autoinflammation. Patients 1-3 had the same pathogenic variant (NM_020661.4 (AID):c.406del, p.Ile136Ter), while patient 4 had another pathogenic variant (NM_020661.4 (AID):c.374G > A, p.Gly125Glu). The variant p.Ile136Ter was not reported before in any of the documented HIGM-2 patients. HIGM-2 is a rare IEI that can be overlooked; hence, patients' diagnosis is delayed. Autoimmune and autoinflammatory manifestations develop later in the disease course leading to significant morbidities. The diagnosis can be suspected after exclusion of CD40/CD40L deficiencies by flow cytometry, and the diagnosis can be confirmed by genetic testing.

Primary atopic disorders (PAD) are monogenic disorders caused by pathogenic gene variants encoding proteins that are key for the maintenance of a healthy skin barrier and a well-functioning immune system. Physicians face the challenge to find single, extremely rare PAD patients/families among the millions of individuals with common allergic diseases. We describe case scenarios with signature PAD. We review the literature and deduct specific clinical red flags for PAD detection. They include a positive family history and/or signs of pathological susceptibility to infections, immunodysregulation, or syndromic disease. Results of conventional laboratory and most immunological lab studies are not sufficient to make a definitive diagnosis of PAD. In the past, multistep narrowing of differential diagnoses by various immunological and other laboratory tests led to testing of single genes or gene panel analyses, which was a time-consuming and often unsuccessful approach. The implementation of whole-genomic analyses in the routine diagnostics has led to a paradigm shift. Upfront genome-wide analysis by whole genome sequencing (WGS) will shorten the time to diagnosis, save patients from unnecessary investigations, and reduce morbidity and mortality. We propose a rational, clinical landmark-based approach for deciding which cases pass the filter for carrying out early WGS. WGS result interpretation requires a great deal of caution regarding the causal relationship of variants in PAD phenotypes and absence of proof by adequate functional tests. In case of negative WGS results, a re-iteration attitude with re-analyses of the data (using the latest data base annotation)) may eventually lead to PAD diagnosis. PAD, like many other rare genetic diseases, will only be successfully managed, if physicians from different clinical specialties and geneticists interact regularly in multidisciplinary conferences.