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Background: Purine nucleoside phosphorylase (PNP) deficiency is a rare, autosomal recessive, inborn error of immunity. It is characterized by progressive immune abnormalities ranging from severe combined immunodeficiency (SCID) to combined immunodeficiency less profound than SCID, neurological abnormalities and autoimmunity. Early detection and diagnosis before the development of life-threatening complications are crucial. Methods: Immune cell subsets were assessed by flow cytometry, serum immunoglobulins and uric acid levels were evaluated, and genetic testing was performed for all patients. Results: Herein, we present six Egyptian PNP deficiency patients from four different families. We describe the patients' clinical phenotypes, their immunological profile as well as their genetic results. Sequence analysis results detected 4 different variants in the PNP gene; 1 likely pathogenic frameshift deletion c.452del; p.Asn151MetfsTer20 was found in one family, 1 pathogenic nonsense variant c.172C > T; p.Arg58Ter, and 2 likely pathogenic missense variants c.682G > C; p.Ala228Pro and c.722T > C; pIle2241Thr. Conclusion: In conclusion, PNP deficiency is a variable immunodeficiency and should be considered in various clinical contexts, with or without neurological manifestations. Hematopoietic stem cell transplantation offers a good treatment option, with excellent clinical outcomes, when performed in a timely manner. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion 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. [ABSTRACT FROM AUTHOR]

Background: Caspase recruitment domain family, member 11 (CARD11) is an important protein which plays a fundamental role in the activation of NF-κβ pathway in lymphocytes. CARD11 deficiency can be inherited in either autosomal dominant or autosomal recessive forms and present with different phenotypes including combined immunodeficiency, atopic dermatitis, and other variable manifestations. The present report describes clinical phenotypes and immunological defects of two unrelated patients with missense homozygous variants in CARD11 presenting with combined immunodeficiency (CID) and atopic skin disease resembling that reported in dominant negative CARD11 deficiency. The patients underwent next generation sequencing, immunophenotyping of T and B subsets by flow cytometry, T cell stimulation, and evaluation of CARD11 expression. Results: Both patients had features suggesting CID including repeated pneumoniae with ICU admissions, chronic diarrhea, and itchy atopic skin disease. Patient-1 has homozygous missense variant in the C terminal domain (c.2839G > A, p.Glu947Lys), and patient-2 has homozygous variant in the inhibitory domain (c.1073C > G, p.Pro568Arg). Both have profound defects in Tregs with normal recent thymic emigrants, memory, and naïve CD4+ T cells. However, in response to stimulation, T cells failed to upregulate the expression of CD25. CARD11 expression by flow cytometry was decreased rather than abolished as previously described in patients with autosomal recessive CARD11 deficiency. B cells showed marked deficiency of switched memory and increase in transitional B cells. Conclusion: Missense variants causing CARD11 deficiency may affect the protein function rather than the expression and can result in a phenotype combining the atopic skin disease and the features of CID. [ABSTRACT FROM AUTHOR]