Pub Date : 2024-06-10DOI: 10.14785/lymphosign-2024-0005
Abdulrahman Al Ghamdi, Linda Vong, C. Roifman, Bo Ngan
Background: X-linked Moesin Associated Immunodeficiency (X-MAID) is a combined immunodeficiency caused by deficiency in the moesin protein. Moesin, which is encoded by the MSN gene, is part of the ezrin-radixin-moesin (ERM) family of transmembrane proteins that interact with the actin cytoskeleton and regulate the shape and migration of cells. Deficiency of moesin is associated with aberrant T cell migration and inadequate immune synapse formation, leading to significant immunodeficiency and recurrent infections. While the clinical presentation of XMAID is diverse, to date, no thymus histopathology findings have been reported. Aim: Describe the thymus histopathology of a patient with X-MAID. Results: Our patient is a 10-year-old male who presented early in life with recurrent infections, dysmorphic features, and severe pulmonary venous stenosis which required a double lung transplant at the age of 4 years. Prior to transplant, he was referred to Immunology for assessment and was subsequently found to harbour a hemizygous variant in the MSN gene (c.278dupT; L93FfsX21). Thymus histophathology findings showed significant cortical atrophy and dysplasia, and was accompanied by reduction in CD3+ cells in the cortex. Abnormally low numbers of suppressor T cells and T helper cells in the thymic cortex and medulla were noted. Conclusion: Thymic findings in X-MAID can include cortical atrophy, dysplasia, and decreased cellularity. This provides further evidence for the importance of moesin on T cell development and migration in the thymus. Statement of Novelty: Description of thymus histopathology in a patient with X-MAID
背景X-连锁莫司蛋白相关免疫缺陷症（X-MAID）是一种因缺乏莫司蛋白而导致的联合免疫缺陷症。Moesin由MSN基因编码，是ezrin-radixin-moesin（ERM）跨膜蛋白家族的一员，与肌动蛋白细胞骨架相互作用，调节细胞的形状和迁移。缺乏 moesin 会导致 T 细胞迁移异常和免疫突触形成不足，从而导致严重的免疫缺陷和反复感染。虽然 XMAID 的临床表现多种多样，但迄今为止，尚未有胸腺组织病理学发现的报道。目的：描述一名X-MAID患者的胸腺组织病理学。结果：我们的患者是一名10岁的男性，早年出现反复感染、畸形特征和严重的肺静脉狭窄，4岁时需要进行双肺移植。移植前，他被转诊到免疫科进行评估，随后发现他携带 MSN 基因半杂合子变异（c.278dupT; L93FfsX21）。胸腺组织病理学检查结果显示，皮质明显萎缩和发育不良，同时皮质中的 CD3+ 细胞减少。胸腺皮质和髓质中的抑制性T细胞和T辅助细胞数量异常低。结论X-MAID患者的胸腺发现可包括皮质萎缩、发育不良和细胞减少。这进一步证明了 Moesin 对胸腺中 T 细胞发育和迁移的重要性。新颖性声明：X-MAID 患者胸腺组织病理学描述
{"title":"Characterization of thymic architecture and lymphocyte populations in X-MAID due to an underlying pathogenic moesin mutation","authors":"Abdulrahman Al Ghamdi, Linda Vong, C. Roifman, Bo Ngan","doi":"10.14785/lymphosign-2024-0005","DOIUrl":"https://doi.org/10.14785/lymphosign-2024-0005","url":null,"abstract":"Background: X-linked Moesin Associated Immunodeficiency (X-MAID) is a combined immunodeficiency caused by deficiency in the moesin protein. Moesin, which is encoded by the MSN gene, is part of the ezrin-radixin-moesin (ERM) family of transmembrane proteins that interact with the actin cytoskeleton and regulate the shape and migration of cells. Deficiency of moesin is associated with aberrant T cell migration and inadequate immune synapse formation, leading to significant immunodeficiency and recurrent infections. While the clinical presentation of XMAID is diverse, to date, no thymus histopathology findings have been reported. Aim: Describe the thymus histopathology of a patient with X-MAID. Results: Our patient is a 10-year-old male who presented early in life with recurrent infections, dysmorphic features, and severe pulmonary venous stenosis which required a double lung transplant at the age of 4 years. Prior to transplant, he was referred to Immunology for assessment and was subsequently found to harbour a hemizygous variant in the MSN gene (c.278dupT; L93FfsX21). Thymus histophathology findings showed significant cortical atrophy and dysplasia, and was accompanied by reduction in CD3+ cells in the cortex. Abnormally low numbers of suppressor T cells and T helper cells in the thymic cortex and medulla were noted. Conclusion: Thymic findings in X-MAID can include cortical atrophy, dysplasia, and decreased cellularity. This provides further evidence for the importance of moesin on T cell development and migration in the thymus. Statement of Novelty: Description of thymus histopathology in a patient with X-MAID","PeriodicalId":515640,"journal":{"name":"LymphoSign Journal","volume":" 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141365362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-19DOI: 10.14785/lymphosign-2024-0002
Jason ZX Chen, Anahita Dehmoobad Sharifabadi, Jenny Garkaby
Introduction: Hyper IgM (HIGM) syndrome is an inborn error of immunity (IEI) that occurs due to defects in immunoglobulin class switch recombination (Ig-CSR). HIGM syndrome typically presents with recurrent infections in early childhood, and is often characterized on investigation with decreased IgG, IgA, and IgE titres, alongside normal or elevated IgM. A common cause of HIGM syndrome is a disruption to the CD40-CD40L interaction that triggers Ig-CSR, of which variants in CD40 are much rarer than in CD40L. We present a case of an 11-year-old female with HIGM syndrome caused by two novel variants of in CD40. Aim: To describe a case report of an eleven-year-old female with HIGM syndrome presenting with recurrent pneumonia. Methods: Data was collected retrospectively from the patient’s medical records. Laboratory investigations included quantitative immunoglobulins, quantitative B and T cell subsets, genetic testing using a primary immunodeficiency panel, and a functional assay for CD40 expression. Results: The proband is an 11-year-old female, who presented with recurrent pneumonia, otitis and septic arthritis. Investigations revealed neutropenia, low IgA, elevated IgM and normal IgG, along with absent vaccine responses. She was identified to harbour two novel variants in CD40: an intronic variant c.52-13A>G p.(?) and a missense variant c.466T>C p.(Ser156Pro). Functional assay indicated low expression of CD40 compared to healthy control, confirming the diagnosis of CD40 deficiency. Conclusion: Class switch defects, such as CD40 deficiency, are rare but significant diagnoses within the spectrum of IEI. This case demonstrates that despite the absence of some clinical red flags for immunodeficiency in infancy, IEIs remain an important consideration in pediatric patients regardless of age. Increasing clinical awareness of IEI will lead to earlier diagnoses, initiation of appropriate treatment, and prevention of potential complications. Statement of Novelty: We describe a patient with a late presentation of hyper IgM syndrome due to two novel variants in the CD40 gene, thus expanding the spectrum of CD40 gene variants.
{"title":"Dual novel variants in CD40 leading to hyper IgM syndrome: A case report of a school-aged female with new-onset recurrent pneumonia.","authors":"Jason ZX Chen, Anahita Dehmoobad Sharifabadi, Jenny Garkaby","doi":"10.14785/lymphosign-2024-0002","DOIUrl":"https://doi.org/10.14785/lymphosign-2024-0002","url":null,"abstract":"Introduction: Hyper IgM (HIGM) syndrome is an inborn error of immunity (IEI) that occurs due to defects in immunoglobulin class switch recombination (Ig-CSR). HIGM syndrome typically presents with recurrent infections in early childhood, and is often characterized on investigation with decreased IgG, IgA, and IgE titres, alongside normal or elevated IgM. A common cause of HIGM syndrome is a disruption to the CD40-CD40L interaction that triggers Ig-CSR, of which variants in CD40 are much rarer than in CD40L. We present a case of an 11-year-old female with HIGM syndrome caused by two novel variants of in CD40. Aim: To describe a case report of an eleven-year-old female with HIGM syndrome presenting with recurrent pneumonia. Methods: Data was collected retrospectively from the patient’s medical records. Laboratory investigations included quantitative immunoglobulins, quantitative B and T cell subsets, genetic testing using a primary immunodeficiency panel, and a functional assay for CD40 expression. Results: The proband is an 11-year-old female, who presented with recurrent pneumonia, otitis and septic arthritis. Investigations revealed neutropenia, low IgA, elevated IgM and normal IgG, along with absent vaccine responses. She was identified to harbour two novel variants in CD40: an intronic variant c.52-13A>G p.(?) and a missense variant c.466T>C p.(Ser156Pro). Functional assay indicated low expression of CD40 compared to healthy control, confirming the diagnosis of CD40 deficiency. Conclusion: Class switch defects, such as CD40 deficiency, are rare but significant diagnoses within the spectrum of IEI. This case demonstrates that despite the absence of some clinical red flags for immunodeficiency in infancy, IEIs remain an important consideration in pediatric patients regardless of age. Increasing clinical awareness of IEI will lead to earlier diagnoses, initiation of appropriate treatment, and prevention of potential complications. Statement of Novelty: We describe a patient with a late presentation of hyper IgM syndrome due to two novel variants in the CD40 gene, thus expanding the spectrum of CD40 gene variants.","PeriodicalId":515640,"journal":{"name":"LymphoSign Journal","volume":" April","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140682674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-12DOI: 10.14785/lymphosign-2024-0001
Azhar Abdullah Al Shaqaq, Lucydx Li, Daniele Merico, Julia Upton
ABSTRACT Background: The prevalence of atopic disease, which consists of conditions such as atopic dermatitis, allergies, and asthma, has been on the rise in recent decades. In children, atopic dermatitis often acts as an initial manifestation of atopic disease and frequently precedes the development of food allergies, asthma, and allergic rhinitis. Mutations in the FLG gene, encoding the fillagrin precursor profillagrin, serve as a genetic risk factor for these diseases. Approximately 25-50% of individuals with atopic dermatitis carry FLG mutations. It has been proposed that FLG mutations exhibit variations specific to different populations, indicating distinct patterns within each population. Severe allergic symptoms could indicate the presence of an underlying immunodeficiency or immune dysregulation and in patients with severe, early-onset, or simultaneous allergic conditions, these could be suggestive of an underlying Primary Atopic Disorder. Specifically, the allergic triad characterized by elevated IgE levels, eosinophilia, and eczema is a common feature in various inborn error of immunity that could be mistakenly diagnosed as severe allergic conditions. Method: Our patient's medical record was analyzed retrospectively, including her medical history, as well as results from immune laboratory tests and genetic analyses. Results: We present a 9-year-old female of mixed ethnicity with a history severe eczematous rash diagnosed with atopic dermatitis. Whole exome sequencing analysis revealed a novel heterozygous variant in the FLG gene (NM_002016: EXON3:c.C2218T: p.R740X). Conclusion: Healthcare providers caring for patients with atopic dermatitis and recurrent staphlococcus infections should be aware of the significant link between filaggrin gene mutations and the development of severe, persistent atopic dermatitis that begins in childhood, as well as its association with recurring staphlococcus infections. Additionally, they should keep in mind that certain inborn errors of immunity may predominantly manifest as severe and treatment-resistant atopic disorders.
{"title":"Novel FLG mutation associated with severe atopy","authors":"Azhar Abdullah Al Shaqaq, Lucydx Li, Daniele Merico, Julia Upton","doi":"10.14785/lymphosign-2024-0001","DOIUrl":"https://doi.org/10.14785/lymphosign-2024-0001","url":null,"abstract":"ABSTRACT Background: The prevalence of atopic disease, which consists of conditions such as atopic dermatitis, allergies, and asthma, has been on the rise in recent decades. In children, atopic dermatitis often acts as an initial manifestation of atopic disease and frequently precedes the development of food allergies, asthma, and allergic rhinitis. Mutations in the FLG gene, encoding the fillagrin precursor profillagrin, serve as a genetic risk factor for these diseases. Approximately 25-50% of individuals with atopic dermatitis carry FLG mutations. It has been proposed that FLG mutations exhibit variations specific to different populations, indicating distinct patterns within each population. Severe allergic symptoms could indicate the presence of an underlying immunodeficiency or immune dysregulation and in patients with severe, early-onset, or simultaneous allergic conditions, these could be suggestive of an underlying Primary Atopic Disorder. Specifically, the allergic triad characterized by elevated IgE levels, eosinophilia, and eczema is a common feature in various inborn error of immunity that could be mistakenly diagnosed as severe allergic conditions. Method: Our patient's medical record was analyzed retrospectively, including her medical history, as well as results from immune laboratory tests and genetic analyses. Results: We present a 9-year-old female of mixed ethnicity with a history severe eczematous rash diagnosed with atopic dermatitis. Whole exome sequencing analysis revealed a novel heterozygous variant in the FLG gene (NM_002016: EXON3:c.C2218T: p.R740X). Conclusion: Healthcare providers caring for patients with atopic dermatitis and recurrent staphlococcus infections should be aware of the significant link between filaggrin gene mutations and the development of severe, persistent atopic dermatitis that begins in childhood, as well as its association with recurring staphlococcus infections. Additionally, they should keep in mind that certain inborn errors of immunity may predominantly manifest as severe and treatment-resistant atopic disorders.","PeriodicalId":515640,"journal":{"name":"LymphoSign Journal","volume":"33 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140249195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-21DOI: 10.14785/lymphosign-2023-0013
Mohammadreza Shafiei, M. Jamee
Double-strand DNA breakage syndromes are rare monogenic inborn errors of immunity with a vast spectrum of manifestations. In addition to a high predisposition to malignancies, these patients are also at risk of recurrent, severe, or opportunistic infections. Therefore, monitoring of immunoglobulin levels and response to the vaccination, and interventions such as immunoglobulin replacement therapy should be considered to improve the patients’ outcomes. As DNA double-strand breakage (DSB) repair pathways have a great impact on lymphocyte development through involvement in the generation of B and T cell receptors, disruption in one of their components may lead to genomic instability, aberrant BCR/TCR development, impaired B-cell development and antibody production. The aim of this review is to describe the most common of DBSs, such as ataxia-telangiectasia (AT), ataxia-telangiectasia like disorder (ATLD), Nijmegen breakage syndrome (NBS), Nijmegen breakage syndrome-like disorder (NBSLD), Bloom syndrome (BS), Fanconi anemia (FA) and some others with a focus on the role of DNA repair proteins in the development of humoral immunity. We also describe the immunoglobulin profile, recommendations for diagnosis, screening, and interventions for the ideal management of these patients.
双链DNA断裂综合征是一种罕见的单基因先天性免疫错误，具有多种表现。除了极易罹患恶性肿瘤外，这些患者还面临反复感染、严重感染或机会性感染的风险。因此，应考虑监测免疫球蛋白水平和对疫苗接种的反应，并采取免疫球蛋白替代疗法等干预措施，以改善患者的预后。由于 DNA 双链断裂（DSB）修复途径参与 B 细胞和 T 细胞受体的生成，对淋巴细胞的发育有很大影响，因此，其中一个环节的破坏可能会导致基因组不稳定、BCR/TCR 发育异常、B 细胞发育受损和抗体产生。本综述旨在描述最常见的 DBSs，如共济失调-特朗基二病（AT）、共济失调-特朗基二病样障碍（ATLD）、奈梅亨断裂综合征（NBS）、奈梅亨断裂综合征样障碍（NBSLD）、布卢姆综合征（BS）、范可尼贫血（FA）和其他一些疾病，重点是 DNA 修复蛋白在体液免疫发育中的作用。我们还介绍了免疫球蛋白谱、诊断建议、筛查和干预措施，以便对这些患者进行理想的管理。
{"title":"Defective Antibody Production in Double-Strand DNA Breakage Syndromes: Insights and Implications","authors":"Mohammadreza Shafiei, M. Jamee","doi":"10.14785/lymphosign-2023-0013","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0013","url":null,"abstract":"Double-strand DNA breakage syndromes are rare monogenic inborn errors of immunity with a vast spectrum of manifestations. In addition to a high predisposition to malignancies, these patients are also at risk of recurrent, severe, or opportunistic infections. Therefore, monitoring of immunoglobulin levels and response to the vaccination, and interventions such as immunoglobulin replacement therapy should be considered to improve the patients’ outcomes. As DNA double-strand breakage (DSB) repair pathways have a great impact on lymphocyte development through involvement in the generation of B and T cell receptors, disruption in one of their components may lead to genomic instability, aberrant BCR/TCR development, impaired B-cell development and antibody production. The aim of this review is to describe the most common of DBSs, such as ataxia-telangiectasia (AT), ataxia-telangiectasia like disorder (ATLD), Nijmegen breakage syndrome (NBS), Nijmegen breakage syndrome-like disorder (NBSLD), Bloom syndrome (BS), Fanconi anemia (FA) and some others with a focus on the role of DNA repair proteins in the development of humoral immunity. We also describe the immunoglobulin profile, recommendations for diagnosis, screening, and interventions for the ideal management of these patients.","PeriodicalId":515640,"journal":{"name":"LymphoSign Journal","volume":"29 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140443416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-10DOI: 10.14785/lymphosign-2023-0011
Angela Hu, Omar Almatrafi, Vy HD Kim, Donna Wall, R. Brager
Background: Severe Combined Immunodeficiency (SCID) is a category of inborn errors of immunity where there is impaired T and B cell development and/or function. Artemis SCID (Art-SCID) is characterized by dysfunctional Artemis protein, which is crucial for V(D)J recombination in T and B cell maturation. Art-SCID is fatal without management, and current definitive treatment involves hematopoietic stem cell transplantation (HSCT) or gene therapy. As the prognosis and survival of SCID patients improves, current research has begun unveiling long-term complications and morbidities. Previous literature has reported neurodevelopmental abnormalities in SCID patients, such as developmental delay and Autism Spectrum Disorder (ASD). However, it remains unknown whether these neurodevelopmental differences are linked to the SCID mutation, an adverse outcome of treatment and hospitalization, or comorbid social isolation and psychosocial challenges. Aims: In this case series, we discuss two cases of Art-SCID which presented with neurodevelopmental deficits following successful HSCT. Results: In both cases, SCID was detected on Newborn Screening (NBS), and Art-SCID was confirmed with genetic testing. Both patients were successfully treated with HSCT at 80 days of life, and followed up clinically well, with robust cell counts. Both patients later presented in toddlerhood with developmental, speech and language delay, however only one patient met diagnostic criteria for ASD. Conclusion: The definitive relationship between SCID, HSCT, and neurodevelopmental outcomes remain unclear, and warrants further study to allow for early intervention. We are currently working with colleagues across the country to further investigate and define this complex relationship. Statement of Novelty: We are investigating the complex relationship between SCID, HSCT, and potential neurodevelopmental outcomes. We present two cases of patients with Artemis SCID who were successfully treated with HSCT, and later presented in toddlerhood with developmental, speech, and language delay.
{"title":"Neurodevelopmental outcomes in two cases of artemis deficiency","authors":"Angela Hu, Omar Almatrafi, Vy HD Kim, Donna Wall, R. Brager","doi":"10.14785/lymphosign-2023-0011","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0011","url":null,"abstract":"Background: Severe Combined Immunodeficiency (SCID) is a category of inborn errors of immunity where there is impaired T and B cell development and/or function. Artemis SCID (Art-SCID) is characterized by dysfunctional Artemis protein, which is crucial for V(D)J recombination in T and B cell maturation. Art-SCID is fatal without management, and current definitive treatment involves hematopoietic stem cell transplantation (HSCT) or gene therapy. As the prognosis and survival of SCID patients improves, current research has begun unveiling long-term complications and morbidities. Previous literature has reported neurodevelopmental abnormalities in SCID patients, such as developmental delay and Autism Spectrum Disorder (ASD). However, it remains unknown whether these neurodevelopmental differences are linked to the SCID mutation, an adverse outcome of treatment and hospitalization, or comorbid social isolation and psychosocial challenges. Aims: In this case series, we discuss two cases of Art-SCID which presented with neurodevelopmental deficits following successful HSCT. Results: In both cases, SCID was detected on Newborn Screening (NBS), and Art-SCID was confirmed with genetic testing. Both patients were successfully treated with HSCT at 80 days of life, and followed up clinically well, with robust cell counts. Both patients later presented in toddlerhood with developmental, speech and language delay, however only one patient met diagnostic criteria for ASD. Conclusion: The definitive relationship between SCID, HSCT, and neurodevelopmental outcomes remain unclear, and warrants further study to allow for early intervention. We are currently working with colleagues across the country to further investigate and define this complex relationship. Statement of Novelty: We are investigating the complex relationship between SCID, HSCT, and potential neurodevelopmental outcomes. We present two cases of patients with Artemis SCID who were successfully treated with HSCT, and later presented in toddlerhood with developmental, speech, and language delay.","PeriodicalId":515640,"journal":{"name":"LymphoSign Journal","volume":"64 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139441168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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