Pub Date : 2021-02-26DOI: 10.14785/LYMPHOSIGN-2021-0016
L. Vong
February 11, 2021 marked the sixth annual International Day of Women and Girls in Science – a day commemorating the global effort to increase the advancement and engagement of women and girls in sc...
{"title":"Spotlight on women in science","authors":"L. Vong","doi":"10.14785/LYMPHOSIGN-2021-0016","DOIUrl":"https://doi.org/10.14785/LYMPHOSIGN-2021-0016","url":null,"abstract":"February 11, 2021 marked the sixth annual International Day of Women and Girls in Science – a day commemorating the global effort to increase the advancement and engagement of women and girls in sc...","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2021-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46159504","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 : 2020-12-01DOI: 10.14785/lymphosign-2020-0011
{"title":"Abstracts from the Immunodeficiency Canada—8th SCID Symposium, 22 October 2020","authors":"","doi":"10.14785/lymphosign-2020-0011","DOIUrl":"https://doi.org/10.14785/lymphosign-2020-0011","url":null,"abstract":"","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2020-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48584378","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 : 2020-03-10DOI: 10.14785/lymphosign-2020-0001
Noreen Choe, Lauren Brick, M. Kozenko, P. Chakraborty, K. Kernohan, D. Bulman, R. Brager
Background: Artemis enzyme, encoded by the DCLRE1C gene, is essential to V(D)J recombination in both T and B lymphocytes. Artemis functions as an important component of the nonhomologous end-joining DNA double-strand break repair pathway. Artemis deficiency leads to a T-B-NK+ severe combined immune deficiency (SCID) associated with radiosensitivity. Clinical presentation: We present a case of a positive newborn screen for SCID in a patient who was subsequently shown to have a T-B-NK+ phenotype. Further immune evaluation showed profound T and B lymphopenia, near-absent response to mitogen stimulation, and absent immunoglobulins A and M. Genetic investigation demonstrated a novel and putative pathogenic variant in the DCLRE1C gene. Conclusion: This case identifies a novel variant in the DCLRE1C gene in a patient with SCID identified by newborn screening. Statement of novelty: This case report identifies a novel variant in the DCLRE1C gene in a patient with T-B-NK+ SCID.
{"title":"Positive newborn screen: a case of a novel variant in DCLRE1C in a patient with SCID","authors":"Noreen Choe, Lauren Brick, M. Kozenko, P. Chakraborty, K. Kernohan, D. Bulman, R. Brager","doi":"10.14785/lymphosign-2020-0001","DOIUrl":"https://doi.org/10.14785/lymphosign-2020-0001","url":null,"abstract":"Background: Artemis enzyme, encoded by the DCLRE1C gene, is essential to V(D)J recombination in both T and B lymphocytes. Artemis functions as an important component of the nonhomologous end-joining DNA double-strand break repair pathway. Artemis deficiency leads to a T-B-NK+ severe combined immune deficiency (SCID) associated with radiosensitivity. Clinical presentation: We present a case of a positive newborn screen for SCID in a patient who was subsequently shown to have a T-B-NK+ phenotype. Further immune evaluation showed profound T and B lymphopenia, near-absent response to mitogen stimulation, and absent immunoglobulins A and M. Genetic investigation demonstrated a novel and putative pathogenic variant in the DCLRE1C gene. Conclusion: This case identifies a novel variant in the DCLRE1C gene in a patient with SCID identified by newborn screening. Statement of novelty: This case report identifies a novel variant in the DCLRE1C gene in a patient with T-B-NK+ SCID.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":"1 1","pages":""},"PeriodicalIF":0.8,"publicationDate":"2020-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46510672","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 : 2019-08-27DOI: 10.14785/lymphosign-2019-0011
Nufar Marcus
Pioneered in 1968, hematopoietic stem cell transplantation (HSCT) first cured a patient with severe combined immune deficiency (SCID) transplanted from a matched sibling, bringing hope for this previously fatal disease. Since then, HSCT has become the standard of care treatment for SCID with thousands of patients transplanted successfully worldwide. Initially successful mainly in patients with a matched sibling donor and in specific easier to transplant types of SCID, nowadays, most patients with SCID undergo successful transplantation due to HSCT technique advances. These include refined human leukocyte antigen (HLA)-tissue typing, use of alternative donors, availability of new stem cell sources such as umbilical cord blood, less toxic chemotherapeutic conditioning, as well as improved graft-versus-host disease (GvHD) prophylaxis. Other factors contributing to the success of transplantation include the improvement of supportive care by molecular detection of viral infections, enabling preemptive antiviral treatment before organ damage occurs. Increased awareness for primary immunodeficiency disorders (PID), leading to earlier diagnosis and referral to specialist centers, has been another important factor in successfully transplanting SCID patients. A major game changer in the last decade has been the implementation of neonatal screening for SCID. This increased early diagnosis, allowing for this disease to be almost universally diagnosed soon after birth in countries which included this test in their newborn screening program. As a result, early and optimal transplant timing and conditions could be achieved. However, very early diagnosis also raised new questions regarding SCID patients with a “leaky” phenotype, as well as dilemmas regarding transplant and conditioning regimens in very young infants. With improved diagnosis and treatment options, overall survival has increased to over 90% for SCID babies with a genoidentical donor and similar results are emerging for matched unrelated donor HSCT. Due to new advances, we hope to achieve similar results for those given HSCT from haploidentical donors as well. This review will focus on the new considerations in HSCT seen in recent years, and examines the effect they have had on treatment options and outcomes for SCID patients. Statement of novelty: The field of HSCT has advanced considerably since the first successful SCID bone marrow transplant in 1968. However, success rates have been limited due to delayed diagnosis and poor outcome of patients for which a HLA-matched donor could not be found. This review will discuss recent advances occurring in the last decade in HSCT for SCID, and our hopes to bring cure to this once fatal disease.
{"title":"New considerations in hematopoietic stem cell transplantation for severe combined immunodeficiency: how did newborn screening change our field, and can we finally brake the glass ceiling for haploidentical transplantation?","authors":"Nufar Marcus","doi":"10.14785/lymphosign-2019-0011","DOIUrl":"https://doi.org/10.14785/lymphosign-2019-0011","url":null,"abstract":"Pioneered in 1968, hematopoietic stem cell transplantation (HSCT) first cured a patient with severe combined immune deficiency (SCID) transplanted from a matched sibling, bringing hope for this previously fatal disease. Since then, HSCT has become the standard of care treatment for SCID with thousands of patients transplanted successfully worldwide. Initially successful mainly in patients with a matched sibling donor and in specific easier to transplant types of SCID, nowadays, most patients with SCID undergo successful transplantation due to HSCT technique advances. These include refined human leukocyte antigen (HLA)-tissue typing, use of alternative donors, availability of new stem cell sources such as umbilical cord blood, less toxic chemotherapeutic conditioning, as well as improved graft-versus-host disease (GvHD) prophylaxis. Other factors contributing to the success of transplantation include the improvement of supportive care by molecular detection of viral infections, enabling preemptive antiviral treatment before organ damage occurs. Increased awareness for primary immunodeficiency disorders (PID), leading to earlier diagnosis and referral to specialist centers, has been another important factor in successfully transplanting SCID patients. A major game changer in the last decade has been the implementation of neonatal screening for SCID. This increased early diagnosis, allowing for this disease to be almost universally diagnosed soon after birth in countries which included this test in their newborn screening program. As a result, early and optimal transplant timing and conditions could be achieved. However, very early diagnosis also raised new questions regarding SCID patients with a “leaky” phenotype, as well as dilemmas regarding transplant and conditioning regimens in very young infants. With improved diagnosis and treatment options, overall survival has increased to over 90% for SCID babies with a genoidentical donor and similar results are emerging for matched unrelated donor HSCT. Due to new advances, we hope to achieve similar results for those given HSCT from haploidentical donors as well. This review will focus on the new considerations in HSCT seen in recent years, and examines the effect they have had on treatment options and outcomes for SCID patients. Statement of novelty: The field of HSCT has advanced considerably since the first successful SCID bone marrow transplant in 1968. However, success rates have been limited due to delayed diagnosis and poor outcome of patients for which a HLA-matched donor could not be found. This review will discuss recent advances occurring in the last decade in HSCT for SCID, and our hopes to bring cure to this once fatal disease.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2019-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43198352","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 : 2019-08-21DOI: 10.14785/LYMPHOSIGN-2019-0012
B. Reid
The continued demand for immunoglobulin treatment for multiple indications has placed considerable strain on the supply of immunoglobulin product. Reliance on a few manufacturers can significantly impact the availability of product. In addition, patient tolerability may vary from one product to another necessitating a choice of products to find the best treatment for an individual patient. Therefore, it is important to conduct clinical trials with new immunoglobulin products to ensure that there is adequate supply and choice of products available on the market. This is particularly important for immunodeficient patients who require treatment with immunoglobulins for life. A requirement for licensing by the Federal Food and Drug Administration and Health Canada is that every immunoglobulin licensing study includes some paediatric patients. Enrolling paediatric subjects in immunoglobulin clinical trials can be challenging due to the need for both consent and assent for enrolment, as well as the increased demands that the study protocol places on the child and family over their usual clinical care. Therefore, it is necessary to utilize strategies that make the demands of the protocol more tolerable for children, and to ensure that the study documentation reflects the unique needs of paediatric patients (Denhoff et al. 2015). Statement of novelty: This paper discusses strategies to facilitate enrolment and adherence to immunoglobulin study protocols that are unique to paediatric patients.
{"title":"Strategies for managing paediatric patients in immunoglobulin clinical trials","authors":"B. Reid","doi":"10.14785/LYMPHOSIGN-2019-0012","DOIUrl":"https://doi.org/10.14785/LYMPHOSIGN-2019-0012","url":null,"abstract":"The continued demand for immunoglobulin treatment for multiple indications has placed considerable strain on the supply of immunoglobulin product. Reliance on a few manufacturers can significantly impact the availability of product. In addition, patient tolerability may vary from one product to another necessitating a choice of products to find the best treatment for an individual patient. Therefore, it is important to conduct clinical trials with new immunoglobulin products to ensure that there is adequate supply and choice of products available on the market. This is particularly important for immunodeficient patients who require treatment with immunoglobulins for life. A requirement for licensing by the Federal Food and Drug Administration and Health Canada is that every immunoglobulin licensing study includes some paediatric patients. Enrolling paediatric subjects in immunoglobulin clinical trials can be challenging due to the need for both consent and assent for enrolment, as well as the increased demands that the study protocol places on the child and family over their usual clinical care. Therefore, it is necessary to utilize strategies that make the demands of the protocol more tolerable for children, and to ensure that the study documentation reflects the unique needs of paediatric patients (Denhoff et al. 2015). Statement of novelty: This paper discusses strategies to facilitate enrolment and adherence to immunoglobulin study protocols that are unique to paediatric patients.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2019-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41616441","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 : 2019-08-20DOI: 10.14785/LYMPHOSIGN-2019-0010
Amarilla B. Mandola, N. Sharfe
Background: Common variable immunodeficiency (CVID) is a term used to define a heterogeneous group of patients who commonly have hypogammaglobulinemia and variable degrees of modest T cell dysfunction. Recent advances made in next generation sequencing technologies have accelerated the identification of CVID disease-causing genes, including NFKB1, a component of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Objective: We sought to identify the genetic defect in a 3-generation family of patients with CVID who presented with cytopenias, eczema, and recurrent sinopulmonary infections. Methods: Whole exome sequencing and Sanger confirmation was performed, and a combination of molecular and cellular techniques used to assess the variant impact on B and T cell function. Results: A novel heterozygous frameshift mutation in NFKB1, encoding the transcriptional regulator protein p50/p105, was identified. This resulted in c.1584dupG (p.M528fs). We demonstrate that c.1584dupG is a loss-of-function variant, responsible for reduced p105/p50 protein expression in affected individuals as well as variable increased CD21low B cell numbers. Conclusion: This novel mutation affecting NFKB1 causes a CVID phenotype with variable clinical manifestations. Given the wide spectrum of age in this kindred, this may reflect diversity of phenotype expression, or more probably, age-related expression of typical features. Statement of novelty: We report here a novel loss-of-function frameshift mutation in NFKB1.
{"title":"Novel heterozygous NFKB1 mutation—variable penetrance in a family cohort","authors":"Amarilla B. Mandola, N. Sharfe","doi":"10.14785/LYMPHOSIGN-2019-0010","DOIUrl":"https://doi.org/10.14785/LYMPHOSIGN-2019-0010","url":null,"abstract":"Background: Common variable immunodeficiency (CVID) is a term used to define a heterogeneous group of patients who commonly have hypogammaglobulinemia and variable degrees of modest T cell dysfunction. Recent advances made in next generation sequencing technologies have accelerated the identification of CVID disease-causing genes, including NFKB1, a component of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Objective: We sought to identify the genetic defect in a 3-generation family of patients with CVID who presented with cytopenias, eczema, and recurrent sinopulmonary infections. Methods: Whole exome sequencing and Sanger confirmation was performed, and a combination of molecular and cellular techniques used to assess the variant impact on B and T cell function. Results: A novel heterozygous frameshift mutation in NFKB1, encoding the transcriptional regulator protein p50/p105, was identified. This resulted in c.1584dupG (p.M528fs). We demonstrate that c.1584dupG is a loss-of-function variant, responsible for reduced p105/p50 protein expression in affected individuals as well as variable increased CD21low B cell numbers. Conclusion: This novel mutation affecting NFKB1 causes a CVID phenotype with variable clinical manifestations. Given the wide spectrum of age in this kindred, this may reflect diversity of phenotype expression, or more probably, age-related expression of typical features. Statement of novelty: We report here a novel loss-of-function frameshift mutation in NFKB1.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2019-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45039590","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 : 2019-08-20DOI: 10.14785/LYMPHOSIGN-2019-0009
P. Kashani, Haiying Chen
Introduction: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Affected patients suffer recurrent life-threatening infections due to phagocyte dysfunction and dysregulation of the immune system. Histopathological assessment is important to help identify the extent and severity of infection and tissue injury. Aim: We present pathological findings in 5 patients with CGD who were followed at our centre. Methods: Patient information was reviewed retrospectively in accordance with local institutional guidelines. All patients had confirmed diagnosis of CGD with mutation in one of the 5 subunits of the NADPH oxidase. Results: Histopathological features of the gastrointestinal tract, liver, and spleen are noted, and include the presence of granulomatous inflammation and pigmented macrophages. Discussion: It is essential for clinicians to keep primary immunodeficiency as one of the differential diagnoses in patients with severe infection or inflammation, whether in the absence or presence of granuloma formation. The detection of PAS-positive macrophages, diffuse granulomatous inflammation, and hepatic abscesses should raise strong suspicion of CGD. Statement of novelty: We describe the histopathological findings of a paediatric cohort of patients with CGD.
{"title":"Histopathological features of patients with chronic granulomatous disease","authors":"P. Kashani, Haiying Chen","doi":"10.14785/LYMPHOSIGN-2019-0009","DOIUrl":"https://doi.org/10.14785/LYMPHOSIGN-2019-0009","url":null,"abstract":"Introduction: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Affected patients suffer recurrent life-threatening infections due to phagocyte dysfunction and dysregulation of the immune system. Histopathological assessment is important to help identify the extent and severity of infection and tissue injury. Aim: We present pathological findings in 5 patients with CGD who were followed at our centre. Methods: Patient information was reviewed retrospectively in accordance with local institutional guidelines. All patients had confirmed diagnosis of CGD with mutation in one of the 5 subunits of the NADPH oxidase. Results: Histopathological features of the gastrointestinal tract, liver, and spleen are noted, and include the presence of granulomatous inflammation and pigmented macrophages. Discussion: It is essential for clinicians to keep primary immunodeficiency as one of the differential diagnoses in patients with severe infection or inflammation, whether in the absence or presence of granuloma formation. The detection of PAS-positive macrophages, diffuse granulomatous inflammation, and hepatic abscesses should raise strong suspicion of CGD. Statement of novelty: We describe the histopathological findings of a paediatric cohort of patients with CGD.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2019-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48974185","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 : 2019-05-27DOI: 10.14785/LYMPHOSIGN-2019-0007
A. Aujnarain, H. Dadi, Amarilla B. Mandola
Background: 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.
{"title":"Chronic mucocutaneous candidiasis associated with a novel frameshift mutation in IL-17 receptor alpha","authors":"A. Aujnarain, H. Dadi, Amarilla B. Mandola","doi":"10.14785/LYMPHOSIGN-2019-0007","DOIUrl":"https://doi.org/10.14785/LYMPHOSIGN-2019-0007","url":null,"abstract":"Background: 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.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2019-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46117677","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 : 2019-05-24DOI: 10.14785/LYMPHOSIGN-2019-0004
A. Ovadia, V. Kim, B. Reid, H. Dadi, Anne Pham-Huy, C. Roifman
Introduction: Coronin 1A is part of a family of highly conserved actin regulatory proteins with key roles in T cell homeostasis and T cell receptor signaling. Null mutations in coronin 1A result in severe combined immunodeficiency, whereas hypomorphic mutations have been associated with a somewhat milder immunological phenotype. Nevertheless, all patients described so far have markedly reduced naïve peripheral T cells, impaired T cell responses to mitogens, and limited T cell receptor diversity. Interestingly, despite poor thymic output, thymus architecture appears normal. To date, only 2 cases of hematopoietic stem cell transplantation (HSCT) have been reported in coronin 1A deficiency. Aim: To describe the identification, transplantation course, and long term outcome of a Canadian Inuit patient diagnosed with coronin 1A deficiency. Methods: Patient chart review was performed in accordance with institutional research ethics approval. A combination of immunological investigations and molecular genetic analyses were utilized to identify a novel mutation in the tryptophan-aspartate repeat region of coronin 1A. Based on the patient’s profound T cell dysfunction, the decision was made to proceed with HSCT. Results: The patient presented with a history of recurrent urinary tract infections, otitis media, and developmental delay involving poor axial and peripheral muscle tone. Axillary lymphadenopathy was noted and subsequent thymus biopsy revealed aberrant CD7+ T cell deficiency. Lymphocyte responses to mitogens and T cell receptor excision circle levels were markedly reduced, consistent with the diagnosis of severe combined immunodeficiency. Whole exome sequencing and Sanger confirmation revealed a novel mutation in coronin 1A. HSCT using a HLA-matched unrelated donor resulted in long term engraftment and solid immune reconstitution. Conclusion: Very few patients with coronin 1A deficiency have been described to date, making it difficult to evaluate its natural history and management. Here, we describe the presentation, identification, transplantation, and outcome in our patient. Statement of novelty: We describe the successful hematopoietic stem cell transplantation course and outcome in a patient with a novel mutation in coronin 1A.
{"title":"Successful hematopoietic stem cell transplantation in a patient with a novel mutation in coronin 1A","authors":"A. Ovadia, V. Kim, B. Reid, H. Dadi, Anne Pham-Huy, C. Roifman","doi":"10.14785/LYMPHOSIGN-2019-0004","DOIUrl":"https://doi.org/10.14785/LYMPHOSIGN-2019-0004","url":null,"abstract":"Introduction: Coronin 1A is part of a family of highly conserved actin regulatory proteins with key roles in T cell homeostasis and T cell receptor signaling. Null mutations in coronin 1A result in severe combined immunodeficiency, whereas hypomorphic mutations have been associated with a somewhat milder immunological phenotype. Nevertheless, all patients described so far have markedly reduced naïve peripheral T cells, impaired T cell responses to mitogens, and limited T cell receptor diversity. Interestingly, despite poor thymic output, thymus architecture appears normal. To date, only 2 cases of hematopoietic stem cell transplantation (HSCT) have been reported in coronin 1A deficiency. Aim: To describe the identification, transplantation course, and long term outcome of a Canadian Inuit patient diagnosed with coronin 1A deficiency. Methods: Patient chart review was performed in accordance with institutional research ethics approval. A combination of immunological investigations and molecular genetic analyses were utilized to identify a novel mutation in the tryptophan-aspartate repeat region of coronin 1A. Based on the patient’s profound T cell dysfunction, the decision was made to proceed with HSCT. Results: The patient presented with a history of recurrent urinary tract infections, otitis media, and developmental delay involving poor axial and peripheral muscle tone. Axillary lymphadenopathy was noted and subsequent thymus biopsy revealed aberrant CD7+ T cell deficiency. Lymphocyte responses to mitogens and T cell receptor excision circle levels were markedly reduced, consistent with the diagnosis of severe combined immunodeficiency. Whole exome sequencing and Sanger confirmation revealed a novel mutation in coronin 1A. HSCT using a HLA-matched unrelated donor resulted in long term engraftment and solid immune reconstitution. Conclusion: Very few patients with coronin 1A deficiency have been described to date, making it difficult to evaluate its natural history and management. Here, we describe the presentation, identification, transplantation, and outcome in our patient. Statement of novelty: We describe the successful hematopoietic stem cell transplantation course and outcome in a patient with a novel mutation in coronin 1A.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2019-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44494336","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 : 2019-05-24DOI: 10.14785/LYMPHOSIGN-2019-0006
L. Duan, S. Feanny
Background: The nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) signaling pathway is a critical regulator of many important adaptive and innate immune responses. The NF-κB transcription factor family consists of 5 structurally related core proteins, one of which is NFKB1. Mutations in the NFKB1 gene has been reported in patients with common variable immune deficiency (CVID) as well as with a large spectrum of clinical features including recurrent viral, bacterial, and fungal infections, autoimmunity, inflammation, and malignancy. Aim: We describe the clinical characteristics of a pediatric patient with a novel mutation in NFKB1. Methods: Patient informed consent was obtained in accordance with approved protocols from the Research Ethics Board at the Hospital for Sick Children. Gene panel testing was employed to identify the immune aberration. Results: Our patient, a previously well 18-month-old boy of Philippines descent, presented with multi-lineage cytopenias (thrombocytopenia, hemolytic anemia, neutropenia), splenomegaly, and lymphadenopathy. He did not have prior history of recurrent infections. Immunological work-up showed normal numbers of T and B cells, normal quantitative immunoglobulins, and adequate vaccination titres. Gene panel testing revealed a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene. Due to persistent cytopenias unresponsive to steroids and IVIG, he was started on Sirolimus with improvement in symptoms. Conclusion: NFKB1 encodes for p105, which is processed to generate the active p50 transcription factor that can interact with different proteins to activate or inhibit downstream signaling. Our patient was found to have a missense mutation in the Rel homology domain (RHD) of p50, which has distinct functions including DNA binding, protein dimerization, and inhibitory protein binding. The clinical presentation described here broadens the scope of characteristics associated with heterozygous NFKB1 mutations. Statement of novelty: We report a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene in a pediatric patient with cytopenias, lymphadenopathy, and splenomegaly. To the best of our knowledge, this variant has not been previously reported.
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