Pub Date : 2023-09-01DOI: 10.14785/lymphosign-2023-0009
Immunodeficiency Canada
Abstracts of the Immunodeficiency Canada 10th PID Symposium, 19 October 2023, Ottawa
2023年10月19日，渥太华，加拿大免疫缺陷第10届PID研讨会摘要
{"title":"Abstracts of the Immunodeficiency Canada 10th PID Symposium, 19 October 2023, Ottawa","authors":"Immunodeficiency Canada","doi":"10.14785/lymphosign-2023-0009","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0009","url":null,"abstract":"Abstracts of the Immunodeficiency Canada 10th PID Symposium, 19 October 2023, Ottawa","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":"41 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134994428","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 : 2023-08-30DOI: 10.14785/lymphosign-2023-0008
C. Roifman, L. Vong
Background: Neurodevelopment is closely entwined with immune maturation and function during embryogenesis. While haematopoietic-derived microglia have recognized roles in a number of neurodevelopmental processes, the contribution of molecules classically involved in the immune system (including complement, toll-like receptors, and cytokines) are also emerging. To date, approximately 11% of genes known to cause primary immunodeficiency also confer varying degrees of neurological abnormalities. These can range from intellectual disability, cognitive and behavioural disorders, through to seizures, spasticity, and motor development delay. However, very rarely are sensory processing defects associated with aberrations of the immune system. Aims: To define the clinical presentation and immune phenotype of a novel syndrome encompassing immunodeficiency, neurodevelopmental abnormalities, and altered pain sensitivity in two siblings. Methods: Comprehensive retrospective review of the patient’s charts were performed, in accordance with local research ethics board approval. Results: We describe two teenage sisters who presented with recurrent sinopulmonary infections, lymphopenia affecting both B and T cells, developmental delay, learning and processing disorder, seizures, and reduced sensitivity to pain. Other features include bronchogenic cyst, microscopic hematuria, oral ulcers, popular urticaria and keratosis pilaris. Conclusion: An underlying defect in genes known to cause primary immunodeficiency was not identified, suggesting the role of an as-yet undefined molecule at the crossroads of immunity, neurodevelopment, and sensory processing. Statement of novelty: We report on two patients, siblings, with a novel phenotype of combined immunodeficiency, neurodevelopmental delay, and reduced sensitivity to painful stimuli.
{"title":"Neurodevelopmental disorder and immunodeficiency","authors":"C. Roifman, L. Vong","doi":"10.14785/lymphosign-2023-0008","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0008","url":null,"abstract":"Background: Neurodevelopment is closely entwined with immune maturation and function during embryogenesis. While haematopoietic-derived microglia have recognized roles in a number of neurodevelopmental processes, the contribution of molecules classically involved in the immune system (including complement, toll-like receptors, and cytokines) are also emerging. To date, approximately 11% of genes known to cause primary immunodeficiency also confer varying degrees of neurological abnormalities. These can range from intellectual disability, cognitive and behavioural disorders, through to seizures, spasticity, and motor development delay. However, very rarely are sensory processing defects associated with aberrations of the immune system. Aims: To define the clinical presentation and immune phenotype of a novel syndrome encompassing immunodeficiency, neurodevelopmental abnormalities, and altered pain sensitivity in two siblings. Methods: Comprehensive retrospective review of the patient’s charts were performed, in accordance with local research ethics board approval. Results: We describe two teenage sisters who presented with recurrent sinopulmonary infections, lymphopenia affecting both B and T cells, developmental delay, learning and processing disorder, seizures, and reduced sensitivity to pain. Other features include bronchogenic cyst, microscopic hematuria, oral ulcers, popular urticaria and keratosis pilaris. Conclusion: An underlying defect in genes known to cause primary immunodeficiency was not identified, suggesting the role of an as-yet undefined molecule at the crossroads of immunity, neurodevelopment, and sensory processing. Statement of novelty: We report on two patients, siblings, with a novel phenotype of combined immunodeficiency, neurodevelopmental delay, and reduced sensitivity to painful stimuli.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41978344","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 : 2023-06-23DOI: 10.14785/lymphosign-2023-0007
Azhar Abdullah Al Shaqaq, Amarilla B. Mandola
Background: The Nuclear Factor-kappa B (NF-kB) pathway is a signaling pathway that plays a critical role in regulating a wide range of cellular processes among those such as immune function, inflammation and tumor regulation. There are two major pathways that play a role in NF-kB activation: the canonical NF-kB1 pathway and the non-canonical NF-kB2 pathway. Abnormalities in non-canonical NF-κB signaling are linked with significant impairments in the immune system, mainly B cell maturation, antibody production, impact on T helper and regulatory T cell function through its effect on germinal center regulation. Methods: 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 16-year-old female with a history of chronic cough complicated with episodes of hemoptysis and diagnosed with bronchiectasis secondary to common variable immunodeficiency disease. Whole exome sequence analysis revealed a novel heterozygous variant in the NFKB2 gene (NM_001077494.3), c.931C>T resulting in p. Arg567Cys. Conclusion: The presence of NFKB2 mutations can lead to the development of early-onset common variable immunodeficiency. Statement of Novelty: We have identified a novel variant in the NFKB2 gene associated with antibody deficiency.
{"title":"Novel heterozygous mutation in NFKB2 in a patient with predominantly antibody deficiency","authors":"Azhar Abdullah Al Shaqaq, Amarilla B. Mandola","doi":"10.14785/lymphosign-2023-0007","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0007","url":null,"abstract":"Background: The Nuclear Factor-kappa B (NF-kB) pathway is a signaling pathway that plays a critical role in regulating a wide range of cellular processes among those such as immune function, inflammation and tumor regulation. There are two major pathways that play a role in NF-kB activation: the canonical NF-kB1 pathway and the non-canonical NF-kB2 pathway. Abnormalities in non-canonical NF-κB signaling are linked with significant impairments in the immune system, mainly B cell maturation, antibody production, impact on T helper and regulatory T cell function through its effect on germinal center regulation. Methods: 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 16-year-old female with a history of chronic cough complicated with episodes of hemoptysis and diagnosed with bronchiectasis secondary to common variable immunodeficiency disease. Whole exome sequence analysis revealed a novel heterozygous variant in the NFKB2 gene (NM_001077494.3), c.931C>T resulting in p. Arg567Cys. Conclusion: The presence of NFKB2 mutations can lead to the development of early-onset common variable immunodeficiency. Statement of Novelty: We have identified a novel variant in the NFKB2 gene associated with antibody deficiency.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2023-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47406129","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 : 2023-06-12DOI: 10.14785/lymphosign-2023-0006
Jessica Willett-Pachul
Jessica Willett Pachul is a Clinical Nurse Specialist in the Division of Immunology & Allergy at the Hospital for Sick Children in Toronto, Canada. In this commentary, she discusses the implications that the collection and sharing of health data can have in the diagnosis and treatment of primary immunodeficiency (PID), as well as in research and development in the field.
{"title":"Perspectives of women in science: data sharing in primary immunodeficiency","authors":"Jessica Willett-Pachul","doi":"10.14785/lymphosign-2023-0006","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0006","url":null,"abstract":"Jessica Willett Pachul is a Clinical Nurse Specialist in the Division of Immunology & Allergy at the Hospital for Sick Children in Toronto, Canada. In this commentary, she discusses the implications that the collection and sharing of health data can have in the diagnosis and treatment of primary immunodeficiency (PID), as well as in research and development in the field.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44528343","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 : 2023-05-29DOI: 10.14785/lymphosign-2023-0005
C. Roifman, L. Vong
Severe combined immunodeficiency is caused by critical genetic defects affecting the immune system. Early diagnosis and intervention are essential for preventing life-threatening infections, end-organ damage, and complications. Newborn screening for severe combined immunodeficiency is currently rolled out across many provinces and territories across Canada. The SickKids Newborn Screening Centre in Toronto, Ontario, is a quaternary referral centre that has evaluated SCID newborn screen-positive infants since the program’s introduction in 2013. Here, we provide updated algorithms for clinical investigation and follow-up of infants with an initial positive screen.
{"title":"Management of newborn screening for severe combined immunodeficiency at a quaternary referral centre – an updated algorithm","authors":"C. Roifman, L. Vong","doi":"10.14785/lymphosign-2023-0005","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0005","url":null,"abstract":"Severe combined immunodeficiency is caused by critical genetic defects affecting the immune system. Early diagnosis and intervention are essential for preventing life-threatening infections, end-organ damage, and complications. Newborn screening for severe combined immunodeficiency is currently rolled out across many provinces and territories across Canada. The SickKids Newborn Screening Centre in Toronto, Ontario, is a quaternary referral centre that has evaluated SCID newborn screen-positive infants since the program’s introduction in 2013. Here, we provide updated algorithms for clinical investigation and follow-up of infants with an initial positive screen.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2023-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42140050","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 : 2023-03-30DOI: 10.14785/lymphosign-2023-0004
Marina Md Sham, Myra Pereira, C. Roifman
ABSTRACT Background: Lipopolysaccharide-responsive beige-like anchor (LRBA) is an intracellular protein that regulates the recycling of cytotoxic T lymphocyte-associated protein 4 (CTLA4), an immune checkpoint molecule which prevents ongoing activation of T cells. Deficiency of LRBA results in increased trafficking and degradation of CTLA4, and consequently, uncontrolled T cell responses. The phenotypic spectrum of LRBA deficiency arising from biallelic loss-of-function typically includes recurrent infections, autoimmunity, lymphoproliferation, chronic diarrhoea, hypogammaglobulinemia and cytopenia. Aim: To report an atypical presentation of LRBA deficiency arising from a set of compound heterozygous LRBA variants, encompassing recurrent hemophagocytic lymphocytosis (HLH) and neurological manifestations. Methods: Clinical data was gathered through retrospective chart review. Expanded genetic analysis including whole exome sequencing was performed. Results: Our patient initially presented at age 15 months with fever, seizures, and encephalopathy. HLH-work-up showed bicytopenia, elevated ferritin and triglyceride, and low fibrinogen, however, he did not yet meet the diagnostic criteria for HLH. MRI brain and EEG at diagnosis was suggestive of acute necrotizing encephalopathy of childhood. He responded to pulsed IV methylprednisolone treatment with minimal residual neurological deficit on follow-up. At 36 months old, he had a repeat presentation and rapidly deteriorated. He developed severe encephalopathy with fixed dilated pupils. Whole exome sequencing revealed a set of compound heterozygous missense variants in the LRBA gene, c.2206A>T (p.R736W) and c.5989C>T (p.R1997C). Conclusion: Compound heterozygous mutations in the LRBA gene caused an atypical presentation of recurrent HLH with CNS manifestations in our patient. Statement of Novelty: We herein report a set of compound heterozygous mutations in LRBA with atypical presentation of recurrent HLH with CNS manifestations, thus expanding the known phenotypic spectrum of LRBA deficiency.
{"title":"Identification of novel compound heterozygous LRBA mutations associated with recurrent HLH and CNS manifestations","authors":"Marina Md Sham, Myra Pereira, C. Roifman","doi":"10.14785/lymphosign-2023-0004","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0004","url":null,"abstract":"ABSTRACT Background: Lipopolysaccharide-responsive beige-like anchor (LRBA) is an intracellular protein that regulates the recycling of cytotoxic T lymphocyte-associated protein 4 (CTLA4), an immune checkpoint molecule which prevents ongoing activation of T cells. Deficiency of LRBA results in increased trafficking and degradation of CTLA4, and consequently, uncontrolled T cell responses. The phenotypic spectrum of LRBA deficiency arising from biallelic loss-of-function typically includes recurrent infections, autoimmunity, lymphoproliferation, chronic diarrhoea, hypogammaglobulinemia and cytopenia. Aim: To report an atypical presentation of LRBA deficiency arising from a set of compound heterozygous LRBA variants, encompassing recurrent hemophagocytic lymphocytosis (HLH) and neurological manifestations. Methods: Clinical data was gathered through retrospective chart review. Expanded genetic analysis including whole exome sequencing was performed. Results: Our patient initially presented at age 15 months with fever, seizures, and encephalopathy. HLH-work-up showed bicytopenia, elevated ferritin and triglyceride, and low fibrinogen, however, he did not yet meet the diagnostic criteria for HLH. MRI brain and EEG at diagnosis was suggestive of acute necrotizing encephalopathy of childhood. He responded to pulsed IV methylprednisolone treatment with minimal residual neurological deficit on follow-up. At 36 months old, he had a repeat presentation and rapidly deteriorated. He developed severe encephalopathy with fixed dilated pupils. Whole exome sequencing revealed a set of compound heterozygous missense variants in the LRBA gene, c.2206A>T (p.R736W) and c.5989C>T (p.R1997C). Conclusion: Compound heterozygous mutations in the LRBA gene caused an atypical presentation of recurrent HLH with CNS manifestations in our patient. Statement of Novelty: We herein report a set of compound heterozygous mutations in LRBA with atypical presentation of recurrent HLH with CNS manifestations, thus expanding the known phenotypic spectrum of LRBA deficiency.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2023-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48166985","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 : 2023-03-29DOI: 10.14785/lymphosign-2023-0003
Laura Abrego Fuentes, Amarilla B. Mandola, B. Ngan
Background: The cell cytoskeleton is regulated by the ezrin-radixin-moesin (ERM) family of proteins, forming links between transmembrane proteins and the underlying actin cytoskeleton. Phosphorylation and activation of these proteins enable interactions with partners critically involved in shape regulation, such as actin filaments, transmembrane proteins, and scaffolding proteins. The MSN gene encodes moesin, which is ubiquitously expressed in lungs, spleen, kidney, endothelial cells of vessels, lymphocytes, and neutrophils. Deficiency or dysregulation of moesin, called X-linked moesin-associated immunodeficiency (X-MAID), is characterized by severe leukopenia affecting T cells, B cells, and neutrophils. To date, the clinical picture of patients with X-MAID is variable. Aim: We describe the presentation, immune-workup, and lung histopathology findings of a young male patient with X-MAID and multi-organ involvement, whose severe pulmonary vein stenosis necessitated a double lung transplant. Methods: A thorough review of the patient’s chart was performed. Results: The patient presented with a history of recurrent respiratory tract infections, oral thrush, and 3 major bacterial infections requiring admission and antibiotic therapy. His immune evaluation was remarkable for low T cells, and normal numbers of B and NK cells. At age 4 years he underwent a double lung transplant due to severe pulmonary vein stenosis, and pulmonary hypertension, developing chronic kidney injury post-transplant. Clinical trio whole exome sequencing revealed a novel hemizygous variant in the MSN gene (c.278dupT; p.L93FfsX21), predicted to cause loss-of-function in moesin. Histologic evaluation of the lung tissue before transplantation identified profound abnormalities in alveoli formation. Conclusion: Patients with moesin deficiency may present during infancy or childhood with a severe form of the disease, including combined immunodeficiency with lymphopenia and neutropenia, while adults may have a milder clinical picture. The novel MSN mutation described here adds to the known spectrum of disease and highlights the non-redundant functions of moesin, particularly in the lung. Statement of Novelty: We report the first lung histopathological description of an X-MAID case, in a pediatric patient with recurrent infections, cytopenia, and autoimmunity who underwent a double lung transplant.
{"title":"Lung histopathology evaluation of an X-MAID patient with a novel mutation in MSN","authors":"Laura Abrego Fuentes, Amarilla B. Mandola, B. Ngan","doi":"10.14785/lymphosign-2023-0003","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0003","url":null,"abstract":"Background: The cell cytoskeleton is regulated by the ezrin-radixin-moesin (ERM) family of proteins, forming links between transmembrane proteins and the underlying actin cytoskeleton. Phosphorylation and activation of these proteins enable interactions with partners critically involved in shape regulation, such as actin filaments, transmembrane proteins, and scaffolding proteins. The MSN gene encodes moesin, which is ubiquitously expressed in lungs, spleen, kidney, endothelial cells of vessels, lymphocytes, and neutrophils. Deficiency or dysregulation of moesin, called X-linked moesin-associated immunodeficiency (X-MAID), is characterized by severe leukopenia affecting T cells, B cells, and neutrophils. To date, the clinical picture of patients with X-MAID is variable. Aim: We describe the presentation, immune-workup, and lung histopathology findings of a young male patient with X-MAID and multi-organ involvement, whose severe pulmonary vein stenosis necessitated a double lung transplant. Methods: A thorough review of the patient’s chart was performed. Results: The patient presented with a history of recurrent respiratory tract infections, oral thrush, and 3 major bacterial infections requiring admission and antibiotic therapy. His immune evaluation was remarkable for low T cells, and normal numbers of B and NK cells. At age 4 years he underwent a double lung transplant due to severe pulmonary vein stenosis, and pulmonary hypertension, developing chronic kidney injury post-transplant. Clinical trio whole exome sequencing revealed a novel hemizygous variant in the MSN gene (c.278dupT; p.L93FfsX21), predicted to cause loss-of-function in moesin. Histologic evaluation of the lung tissue before transplantation identified profound abnormalities in alveoli formation. Conclusion: Patients with moesin deficiency may present during infancy or childhood with a severe form of the disease, including combined immunodeficiency with lymphopenia and neutropenia, while adults may have a milder clinical picture. The novel MSN mutation described here adds to the known spectrum of disease and highlights the non-redundant functions of moesin, particularly in the lung. Statement of Novelty: We report the first lung histopathological description of an X-MAID case, in a pediatric patient with recurrent infections, cytopenia, and autoimmunity who underwent a double lung transplant.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2023-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47120194","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 : 2023-03-17DOI: 10.14785/lymphosign-2023-0002
O. Scott, Myra Pereira, Mar‐Har Sham
Background: Dominant negative STAT3 loss-of-function is the most common genetic cause of hyper-IgE syndrome (HIES). Patients may present with a host of both immune and non-immune manifestations, including connective tissue abnormalities, recurrent infections, malignant predisposition, and biochemical evidence of elevated serum IgE or eosinophilia. Aim: To describe a novel splice-site variant in STAT3 resulting in HIES. Methods: Case report of two family members with HIES. Results: A proband and his son presented with neonatal-onset pustular rash, recurrent skin and sinopulmonary infections and elevated serum IgE and were diagnosed with AD-HIES. They were identified to harbor a novel splice-site variant in the DNA-binding domain (DBD) of STAT3: c.1110-3C>G, predicted to result in defective splicing in exon 12. Interestingly, a number of other patients with AD-HIES with mutations affecting the same splice-site, suggesting this may be a hot-spot for mutagenesis. Conclusion: Splice-site mutations in the DBD of STAT3 are increasingly identified as a cause of AD-HIES. Future work is required to delineate whether patients with splice site mutations have unique clinical characteristics, supporting efforts for genotype-phenotype correlation in this disease.
{"title":"A Novel STAT3 Splice-Site Variant in A Kindred with Autosomal Dominant Hyper IgE Syndrome","authors":"O. Scott, Myra Pereira, Mar‐Har Sham","doi":"10.14785/lymphosign-2023-0002","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0002","url":null,"abstract":"Background: Dominant negative STAT3 loss-of-function is the most common genetic cause of hyper-IgE syndrome (HIES). Patients may present with a host of both immune and non-immune manifestations, including connective tissue abnormalities, recurrent infections, malignant predisposition, and biochemical evidence of elevated serum IgE or eosinophilia. Aim: To describe a novel splice-site variant in STAT3 resulting in HIES. Methods: Case report of two family members with HIES. Results: A proband and his son presented with neonatal-onset pustular rash, recurrent skin and sinopulmonary infections and elevated serum IgE and were diagnosed with AD-HIES. They were identified to harbor a novel splice-site variant in the DNA-binding domain (DBD) of STAT3: c.1110-3C>G, predicted to result in defective splicing in exon 12. Interestingly, a number of other patients with AD-HIES with mutations affecting the same splice-site, suggesting this may be a hot-spot for mutagenesis. Conclusion: Splice-site mutations in the DBD of STAT3 are increasingly identified as a cause of AD-HIES. Future work is required to delineate whether patients with splice site mutations have unique clinical characteristics, supporting efforts for genotype-phenotype correlation in this disease.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":"1 1","pages":""},"PeriodicalIF":0.8,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41286688","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 : 2023-03-08DOI: 10.14785/lymphosign-2023-0001
Abdulrahman Al Ghamdi, Mar‐Har Sham, Laura Abrego Fuentes, L. Vong
Introduction: NF-κB proteins are transcription factors that modulate various functions of the immune system. NF-κB2 (or p100/p52) has particularly important roles in B cell development and function. Primary immunodeficiency due to mutations in the NF-κB2 gene range from combined immunodeficiency with susceptibility to viral or opportunistic infections to a primarily antibody deficiency. Methods: We investigated a 19-year-old male with multiple autoimmune cytopenia resistant to treatment and generalized granulomatous lymphadenopathy. Results: We identified a novel pathogenic variant in NF-κB2 via whole exome sequencing c.1700C>T (p.A567V) that is the cause of our patient’s presentation. Conclusion: We present a novel pathogenic variant in NF-κB2 with an unusual presentation that furthers our understanding of this disease.
{"title":"Identification of a novel NFKB2 mutation in a patient presenting with autoimmune cytopenia and generalized granulomatous lymphadenopathy","authors":"Abdulrahman Al Ghamdi, Mar‐Har Sham, Laura Abrego Fuentes, L. Vong","doi":"10.14785/lymphosign-2023-0001","DOIUrl":"https://doi.org/10.14785/lymphosign-2023-0001","url":null,"abstract":"Introduction: NF-κB proteins are transcription factors that modulate various functions of the immune system. NF-κB2 (or p100/p52) has particularly important roles in B cell development and function. Primary immunodeficiency due to mutations in the NF-κB2 gene range from combined immunodeficiency with susceptibility to viral or opportunistic infections to a primarily antibody deficiency. Methods: We investigated a 19-year-old male with multiple autoimmune cytopenia resistant to treatment and generalized granulomatous lymphadenopathy. Results: We identified a novel pathogenic variant in NF-κB2 via whole exome sequencing c.1700C>T (p.A567V) that is the cause of our patient’s presentation. Conclusion: We present a novel pathogenic variant in NF-κB2 with an unusual presentation that furthers our understanding of this disease.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2023-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42943505","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 : 2022-12-01DOI: 10.14785/lymphosign-2022-0014
Mar‐Har Sham, Rongbo Zhu, Y. Pasternak
Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease in which cells of the immune system are overactivated, leading to uncontrolled inflammation and tissue destruction. Inherited or familial forms of HLH (FHL) are further classified into FHL1 to 5, based on the underlying genetic etiology. The most common form, FHL2, is associated with mutations in the PRF1 gene encoding perforin, a pore-forming glycoprotein required for natural killer and cytotoxic T cell-mediated apoptosis. Importantly, diagnosis of FHL can be challenging, particularly in late-onset cases in which presentation is delayed beyond the first years of life. Aim: We report the essential role of whole exome sequencing in the diagnostic work-up of a patient with complex, late-onset FHL. Methods: A comprehensive retrospective chart review was performed. Results: Our patient presented at 11 years of age with recurrent fever, hepatosplenomegaly, and pancytopenia. In the following years, she was admitted to hospital on multiple occasions, including twice for febrile neutropenia, and once for febrile cytopenia. Serial immune evaluation revealed features of immune dysregulation. While HLH was suspected, she did not fulfil the diagnostic criteria. Initial genetic work-up involving a targeted primary immunodeficiency gene panel identified only a single novel variant of uncertain significance, c.T374C (p.I125T) in PRF1. Subsequently, research-based whole exome sequencing was performed which revealed a second variant, c.C272T (p.A91V), in the same gene. The expanded genetic findings, a set of compound heterozygous missense mutations in PRF1, strengthened the diagnosis of FHL. She later fulfilled the diagnostic criteria for HLH. Conclusion: Whole exome sequencing identified compound heterozygous mutations in the PRF1 gene in a patient with late-onset FHL. Statement of Novelty: We report the use of whole exome sequencing to identify compound heterozygous mutations in PRF1, including a novel p.I125T variant not previously identified in FHL.
{"title":"Whole exome sequencing identifies causative compound heterozygous variants in PRF1 in late-onset familial hemophagocytic lymphohistiocytosis","authors":"Mar‐Har Sham, Rongbo Zhu, Y. Pasternak","doi":"10.14785/lymphosign-2022-0014","DOIUrl":"https://doi.org/10.14785/lymphosign-2022-0014","url":null,"abstract":"Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease in which cells of the immune system are overactivated, leading to uncontrolled inflammation and tissue destruction. Inherited or familial forms of HLH (FHL) are further classified into FHL1 to 5, based on the underlying genetic etiology. The most common form, FHL2, is associated with mutations in the PRF1 gene encoding perforin, a pore-forming glycoprotein required for natural killer and cytotoxic T cell-mediated apoptosis. Importantly, diagnosis of FHL can be challenging, particularly in late-onset cases in which presentation is delayed beyond the first years of life. Aim: We report the essential role of whole exome sequencing in the diagnostic work-up of a patient with complex, late-onset FHL. Methods: A comprehensive retrospective chart review was performed. Results: Our patient presented at 11 years of age with recurrent fever, hepatosplenomegaly, and pancytopenia. In the following years, she was admitted to hospital on multiple occasions, including twice for febrile neutropenia, and once for febrile cytopenia. Serial immune evaluation revealed features of immune dysregulation. While HLH was suspected, she did not fulfil the diagnostic criteria. Initial genetic work-up involving a targeted primary immunodeficiency gene panel identified only a single novel variant of uncertain significance, c.T374C (p.I125T) in PRF1. Subsequently, research-based whole exome sequencing was performed which revealed a second variant, c.C272T (p.A91V), in the same gene. The expanded genetic findings, a set of compound heterozygous missense mutations in PRF1, strengthened the diagnosis of FHL. She later fulfilled the diagnostic criteria for HLH. Conclusion: Whole exome sequencing identified compound heterozygous mutations in the PRF1 gene in a patient with late-onset FHL. Statement of Novelty: We report the use of whole exome sequencing to identify compound heterozygous mutations in PRF1, including a novel p.I125T variant not previously identified in FHL.","PeriodicalId":53881,"journal":{"name":"LymphoSign Journal-The Journal of Inherited Immune Disorders","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45107678","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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