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[Paper Type: Novel mutation and VUS] AND [Author: Mandola, Amarilla] (3) | 21 May 2024 |
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- OPEN ACCESSBackground: Chronic mucocutaneous candidiasis (CMCC) has traditionally encompassed endocrinopathy, autoimmunity, and infection of the skin, nails, oral and genital mucosa. It is typically caused by Candida albicans, an organism that is found to be commensal in healthy individuals. To date, most patients with CMCC have mutations in AIRE or STAT1. While chronic Candida spp. infection is a feature of multiple profound T cell deficiencies, it has also been identified in rare cases involving selective immune defects, including interleukin-17 receptor A (IL-17RA) deficiency. An association between Staphylococcus aureus infections and candidiasis due to IL-17RA deficiency has recently been proposed.Aim: We sought to identify the genetic defect in a patient presenting with recurrent oral thrush and S. aureus infections, but otherwise unremarkable immune workup.Methods: Whole exome sequencing and Sanger confirmation was performed, and protein expression analysis utilized to assess the impact of the genetic aberration. A comprehensive immune workup was completed to characterize any possible deficits in his immune system.Results: Next generation sequencing techniques identified a homozygous mutation in IL17RA, c.1696insAG, resulting in the frameshift mutation p.Q566fs. Western blot analysis confirmed the loss of IL-17RA expression.Conclusion: We describe here a novel frameshift mutation in IL17RA. Clinically, the patient was a diagnostic challenge as he did not present with a classic CMCC phenotype. This case emphasizes the importance of genetic analysis in patients presenting with recurrent infections.Statement of novelty: We identify a novel frameshift mutation in IL17RA in a patient presenting with recurrent bacterial and fungal mucocutaneous infections.
- OPEN ACCESSIntroduction: Coronin 1A belongs to a large family of actin regulatory proteins with a role in T cell homeostasis. A role for coronin 1A was also observed in macrophages, NK, and neuronal cells. To date, coronin 1A deficiency has been described in relatively few patients with combined immunodeficiency.Aim: We studied here the molecular and genetic basis of immunodeficiency detected by newborn screening for severe combined immunodeficiency.Methods: Patient data was collected in accordance with REB approved protocols. Immune work up, including T and B cell proliferative responses and serum concentrations of immunoglobulins, was performed. Next generation sequencing techniques and cellular analyses were also utilized.Results: The patient presented with T cell lymphopenia, reduction in CD4+CD45Ra+ cells and hypogammaglobulinemia. Uniquely, she also had persistent severe neutropenia. Whole exome sequencing and Sanger confirmation revealed a novel homozygous mutation in coronin 1A.Conclusion: Coronin 1A deficiency can be detected after birth by T cell receptor excision circle-based newborn screening.Statement of novelty: We report here a patient with a novel mutation in coronin 1A, identified during newborn screening with low T cell receptor excision circle levels and neutropenia, which is a unique finding in this condition.
- OPEN ACCESSIntroduction: Major histocompatibility (MHC) class II deficiency is a rare autosomal recessive primary immunodeficiency with fewer than 200 patients reported worldwide. Patients usually present within their first year of life with severe and recurrent infections, failure to thrive, and chronic diarrhea. The disorder is caused by absent or reduced MHC class II expression on cell surfaces, leading to defective cellular and humoral immune responses. The disease is associated with a poor prognosis, with most patients dying in early childhood due to infectious complications.Aim: To report the clinical, immunological, and genetic features of an adult patient with MHC class II deficiency who did not undergo hematopoietic stem cell transplant (HSCT). We also explore proposed theories as to why some patients with MHC class II deficiency survive to adulthood, beyond the typical life expectancy.Results: We present a 23-year-old gentleman who was diagnosed with MHC class II deficiency at the age of 6 months based on a near complete absence of Human Leukocyte Antigen - DR isotype on peripheral blood mononuclear cells and CD4+ lymphopenia. He is one of a few patients with the condition reported in the literature to have survived to adulthood despite not having undergone HSCT. Next generation sequencing revealed a novel homozygous mutation in the CIITA gene, 1 of 4 genes involved in the regulation of MHC class II transcription.Discussion: MHC class II deficiency is considered a single entity phenotypic condition where the main problem lies in reduced or absent MHC class II expression and results in downstream immunologic effects, including CD4+ lymphopenia and impaired antigen specific responses. However, phenotypic differences between patients are emerging as more cases are described in the literature. Our patient, now 23 years old, has survived significantly beyond life expectancy despite not having HSCT.Statement of novelty: We describe a case of an adult patient diagnosed with MHC class II deficiency due to a novel homozygous intronic splice site variant in the CIITA gene.