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.

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.

B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both somatic hypermutation (SHM) of the immunoglobulin (Ig) variable region genes of the B-cell receptor and class switch recombination (CSR) which alters the Ig heavy chain constant region. Both of these processes are initiated by the enzyme activation-induced cytidine deaminase (AID), encoded by AICDA. Deleterious variants in AICDA are causal of hyper-IgM syndrome type 2 (HIGM2), a B-cell intrinsic primary immunodeficiency characterised by recurrent infections and low serum IgG and IgA levels. Biallelic variants affecting exons 2, 3 or 4 of AICDA have been identified that impair both CSR and SHM in patients with autosomal recessive HIGM2. Interestingly, B cells from patients with autosomal dominant HIGM2, caused by heterozygous variants (V186X, R190X) located in AICDA exon 5 encoding the nuclear export signal (NES) domain, show abolished CSR but variable SHM. We herein report the immunological and functional phenotype of two related patients presenting with common variable immunodeficiency who were found to have a novel heterozygous variant in AICDA (L189X). This variant led to a truncated AID protein lacking the last 10 amino acids of the NES at the C-terminal domain. Interestingly, patients' B cells carrying the L189X variant exhibited not only greatly impaired CSR but also SHM in vivo, as well as CSR and production of IgG and IgA in vitro. Our findings demonstrate that the NES domain of AID can be essential for SHM, as well as for CSR, thereby refining the correlation between AICDA genotype and SHM phenotype as well as broadening our understanding of the pathophysiology of HIGM disorders.

Waldenstrom's disease is characterized by the presence of pathological changes in the B lymphocytes that are in the last stages of maturation. One characteristic of WM is the production of an abnormal high amount of IgM and hyper viscosity syndrome. The MW gets worse, symptoms such as fatigue, weight loss, night sweats, fever, recurrent infections and swollen lymph nodes develop in patients who have a known history of MGUS. In this clinical case, our patient without history of MGUS, presents for the first time for medical observation only for ascites and the presence of an interportocaval lymph node package. An atypical presentation of the disease that makes us reflect on the difficulty of making a diagnosis in the elderly patient and on pathogenetic hypotheses of ascites not yet explored. Seventy-three-year-old patient, hospitalized for the onset of ascites with sloping edema, diffuse left pulmonary opacification. At the ultrasound check, cava and portal vessels patent and of regular caliber, however with inversion of flow in correspondence with the right branch and of the door to the hilum, with a subdiaphragmatic retrocaval focus with a maximum diameter of about 3 cm, which cannot be better viewed. CT scan of the abdomen with confirmation of the presence of an interportocaval lymph node package. After evidence of the electrophoretic protein picture of a double component, probably monoclonal with positive urinary immunofixation for free K chains. IgM dosage equal to 2190 mg. Serum immunofixation practice that confirms the diagnosis of type B lymphoproliferative syndrome as per Waldenstrom's disease, confirmed by bone marrow aspiration with morphological and flow cytometric study. Immediately begin chemotherapy with Bendamustine 120 mg. After 4 weeks of therapy with the reduction of IgM values, the patient no longer presented ascites. This case has an unusual presentation of this disease and we could shed a new light on the possible pathogenesis of portal hypertension in Waldenstrom'disease.