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Shillitoe B, Duque JSR, Lai SHY, Lau TM, Chan JCH, Bourne H, Stroud C, Flood T, Buckland M, Ip W, Worth A, Hackett S, Herwadkar A, Coulter T, Blaney C, Jolles S, Garcez T, Moya E, Faust S, Pearce MS, Lau YL, Gennery AR. Outcomes of X-Linked Agammaglobulinaemia Patients. J Clin Immunol 2024; 45:40. [PMID: 39541002 DOI: 10.1007/s10875-024-01829-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND X-linked agammaglobulinaemia (XLA), caused by mutations in BTK, is characterised by low or absent peripheral CD19 + B lymphocytes and agammaglobulinaemia. The mainstay of treatment consists of immunoglobulin replacement therapy (IgRT). As this cannot fully compensate for the immune defects in XLA, patients may therefore continue to be at risk of complications. OBJECTIVES To describe the clinical outcomes of XLA patients in the United Kingdom and Hong Kong and evaluate current treatment strategies. METHODS Patients with a definitive diagnosis of XLA were included in this cross-sectional and retrospective analysis of clinical health outcomes. Data pertaining to diagnosis, infection incidence, IgG trough levels and lung function were collected and analysed. RESULTS 99 patients with a median age of 29.02 years (IQR 12.83-37.41) and a total follow up of 1922 patient years, were included this study. The median age at diagnosis was 3.30 years (IQR 1.04-8.38) which decreased over time (p = 0.004). 40% of the cohort had radiological evidence of bronchiectasis. Risk of bronchiectasis was not significantly associated with clinical infection incidence (p = 0.880) or IgG trough levels (p = 0.407). Two patients demonstrated novel complications, namely persistent norovirus infection, leading to haemopoietic stem cell transplantation (HSCT). CONCLUSIONS Despite modern therapy, most XLA patients continue to experience complications, most notably bronchiectasis, likely due to absence of IgA/M in current therapies, but lack of B lymphocytes may also lead to additional sequalae. These data strongly support the need for further research, particularly that of curative modalities including HSCT and gene therapy.
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Affiliation(s)
- Ben Shillitoe
- Sheffield Children's NHS Foundation Trust, Sheffield, UK.
| | - Jaime S Rosa Duque
- Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Sophie H Y Lai
- Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Tsun Ming Lau
- Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Jeffery C H Chan
- Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Helen Bourne
- Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Catherine Stroud
- Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Terry Flood
- Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Matthew Buckland
- Institute of Child Health, UCL, London, UK
- University College London, London, UK
| | - Winnie Ip
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Austen Worth
- Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Scott Hackett
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Archana Herwadkar
- Salford Care Organisation, Northern Care Alliance NHS Trust, Manchester, UK
| | | | | | - Stephen Jolles
- Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, UK
| | - Tomaz Garcez
- Manchester University NHS Foundation Trust, Manchester, UK
| | - Eduardo Moya
- Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
| | - Saul Faust
- NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK
- Faculty of Medicine, Institute for Life Sciences, University of Southampton, Southampton, UK
| | - Mark S Pearce
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Yu Lung Lau
- Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
| | - Andrew R Gennery
- Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
- Newcastle University Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
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2
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Thangaraj A, Sil A, Goel S, Vignesh P, Rawat A, Jindal AK. Disseminated Aspergillosis in X-linked Agammaglobulinemia: Beyond the norm. J Clin Immunol 2024; 45:24. [PMID: 39404906 DOI: 10.1007/s10875-024-01815-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 09/26/2024] [Indexed: 12/06/2024]
Abstract
X-linked agammaglobulinemia (XLA) due to a mutation in Bruton's tyrosine kinase (BTK), leads to the arrested development of B cells at the pro-B cell stage. This results in absent B cells and severe hypogammaglobulinemia. XLA patients usually present with recurrent sinopulmonary infection. Bacterial infections are the commonest [2], fungal infections like Pneumocystis jirovecii, Aspergillus and Candida species are rarely reported and they are associated with mortality in XLA [3]. We report a 3.5-year-old boy with disseminated aspergillosis, an uncommon presentation of XLA. Despite treatment with antifungals, including voriconazole and amphotericin B, the patient succumbed to the illness. Genetic analysis revealed a pathogenic variant in the BTK gene (R28H), confirming XLA diagnosis. This case highlights the potential for severe fungal infections in XLA patients and suggests broader immune system dysregulation beyond B-cell defects.
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Affiliation(s)
- Abarna Thangaraj
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Archan Sil
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Sumit Goel
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Pandiarajan Vignesh
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Amit Rawat
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Ankur Kumar Jindal
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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3
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Desai JV, Zarakas MA, Wishart AL, Roschewski M, Aufiero MA, Donkò A, Wigerblad G, Shlezinger N, Plate M, James MR, Lim JK, Uzel G, Bergerson JR, Fuss I, Cramer RA, Franco LM, Clark ES, Khan WN, Yamanaka D, Chamilos G, El-Benna J, Kaplan MJ, Staudt LM, Leto TL, Holland SM, Wilson WH, Hohl TM, Lionakis MS. BTK drives neutrophil activation for sterilizing antifungal immunity. J Clin Invest 2024; 134:e176142. [PMID: 38696257 PMCID: PMC11178547 DOI: 10.1172/jci176142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 04/22/2024] [Indexed: 05/04/2024] Open
Abstract
We describe a previously unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, patients who were treated with BTKi, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in patients who are susceptible.
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Affiliation(s)
- Jigar V. Desai
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology (LCIM), National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Marissa A. Zarakas
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology (LCIM), National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Andrew L. Wishart
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology (LCIM), National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Mark Roschewski
- Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Mariano A. Aufiero
- Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Agnes Donkò
- Molecular Defenses Section, LCIM, NIAID, NIH, Bethesda, Maryland, USA
| | - Gustaf Wigerblad
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland, USA
| | - Neta Shlezinger
- Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Markus Plate
- Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Matthew R. James
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Jean K. Lim
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Gulbu Uzel
- Immunopathogenesis Section, LCIM, NIAID, NIH, Bethesda, Maryland, USA
| | | | - Ivan Fuss
- Mucosal Immunity Section, LCIM, NIAID, NIH, Bethesda, Maryland, USA
| | - Robert A. Cramer
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
| | - Luis M. Franco
- Functional Immunogenomics Section, NIAMS, NIH, Bethesda, Maryland, USA
| | - Emily S. Clark
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Wasif N. Khan
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Daisuke Yamanaka
- Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Georgios Chamilos
- Department of Clinical Microbiology and Microbial Pathogenesis, University Hospital of Heraklion, Heraklion, Crete, Greece
| | - Jamel El-Benna
- Centre de Recherche sur l’Inflammation, Laboratoire d’Excellence Inflamex, Faculté de Médecine Xavier Bichat, Université de Paris-Cité, INSERM-U1149, CNRS-ERL8252, Paris, France
| | - Mariana J. Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, Maryland, USA
| | - Louis M. Staudt
- Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Thomas L. Leto
- Molecular Defenses Section, LCIM, NIAID, NIH, Bethesda, Maryland, USA
| | - Steven M. Holland
- Immunopathogenesis Section, LCIM, NIAID, NIH, Bethesda, Maryland, USA
| | - Wyndham H. Wilson
- Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Tobias M. Hohl
- Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Michail S. Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology (LCIM), National Institute of Allergy & Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA
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Chear CT, Ismail IH, Chan KC, Noh LM, Kassim A, Latiff AHA, Gill SS, Ramly NH, Tan KK, Sundaraj C, Choo CM, Mohamed SAS, Baharin MF, Zamri AS, Yahya SNHS, Mohamad SB, Ripen AM. Clinical features and mutational analysis of X-linked agammaglobulinemia patients in Malaysia. Front Immunol 2023; 14:1252765. [PMID: 37809070 PMCID: PMC10560089 DOI: 10.3389/fimmu.2023.1252765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/05/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND Bruton's tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA. RESULTS Twenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients. CONCLUSION This report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.
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Affiliation(s)
- Chai Teng Chear
- Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Shah Alam, Selangor, Malaysia
| | - Intan Hakimah Ismail
- Clinical Immunology Unit, Department of Paediatrics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Kwai Cheng Chan
- Pediatric Department, Penang General Hospital, Ministry of Health, George Town, Penang, Malaysia
| | - Lokman Mohd Noh
- Pediatric Department, Tunku Azizah Hospital (Women and Children Hospital Kuala Lumpur), Ministry of Health, Kuala Lumpur, Malaysia
| | - Asiah Kassim
- Pediatric Department, Tunku Azizah Hospital (Women and Children Hospital Kuala Lumpur), Ministry of Health, Kuala Lumpur, Malaysia
| | | | - Sandeep Singh Gill
- Pediatric Department, Hospital Wanita Dan Kanak-Kanak Sabah, Ministry of Health, Kota Kinabalu, Sabah, Malaysia
| | - Nazatul Haslina Ramly
- Pediatric Department, Tunku Azizah Hospital (Women and Children Hospital Kuala Lumpur), Ministry of Health, Kuala Lumpur, Malaysia
| | - Kah Kee Tan
- Pediatric Department, Perdana University and Royal College of Surgeons in Ireland (PURCSI), School of Medicine, Perdana University, Kuala Lumpur, Malaysia
| | - Charlotte Sundaraj
- Pediatric Department, Hospital Putrajaya, Ministry of Health, Putrajaya, Malaysia
| | - Chong Ming Choo
- Pediatric Department, Hospital Sultan Abdul Halim, Ministry of Health, Sungai Petani, Kedah, Malaysia
| | | | - Mohd Farid Baharin
- Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Shah Alam, Selangor, Malaysia
| | - Amelia Suhana Zamri
- Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Shah Alam, Selangor, Malaysia
| | - Sharifah Nurul Husna Syed Yahya
- Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Shah Alam, Selangor, Malaysia
| | - Saharuddin Bin Mohamad
- Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur, Malaysia
- Centre of Research in Systems Biology, Structural Bioinformatics and Human Digital Imaging (CRYSTAL), Universiti Malaya, Kuala Lumpur, Malaysia
| | - Adiratna Mat Ripen
- Primary Immunodeficiency Unit, Allergy and Immunology Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health, Shah Alam, Selangor, Malaysia
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Schaafsma GCP, Väliaho J, Wang Q, Berglöf A, Zain R, Smith CIE, Vihinen M. BTKbase, Bruton Tyrosine Kinase Variant Database in X-Linked Agammaglobulinemia: Looking Back and Ahead. Hum Mutat 2023; 2023:5797541. [PMID: 40225173 PMCID: PMC11918983 DOI: 10.1155/2023/5797541] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/10/2023] [Accepted: 06/09/2023] [Indexed: 04/15/2025]
Abstract
BTKbase is an international database for disease-causing variants in Bruton tyrosine kinase (BTK) leading to X-linked agammaglobulinemia (XLA), a rare primary immunodeficiency of antibody production. BTKbase was established in 1994 as one of the first publicly available variation databases. The number of cases has more than doubled since the last update; it now contains information for 2310 DNA variants in 2291 individuals. 1025 of the DNA variants are unique. The human genome contains more than 500 protein kinases, among which BTK has the largest number of unique disease-causing variants. The current version of BTKbase has numerous novel features: the database has been reformatted, it has moved to LOVD database management system, it has been internally harmonized, etc. Systematics and standardization have been increased, including Variation Ontology annotations for variation types. There are some regions with lower than expected variation frequency and some hotspots for variations. BTKbase contains, in addition to variant descriptions at DNA, RNA and protein levels, also laboratory parameters and clinical features for many patients. BTKbase has served clinical and research communities in the diagnosis of XLA cases and provides general insight into effects of variations, especially in signalling pathways. Amino acid substitutions and their effects were investigated, predicted, and visualized at 3D level in the protein domains. BTKbase is freely available.
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Affiliation(s)
- Gerard C. P. Schaafsma
- Protein Structure and Bioinformatics, Department of Experimental Medical Science, Lund University, BMC B13, 221 84 Lund, Sweden
| | - Jouni Väliaho
- Institute of Biomedical Technology, University of Tampere, Tampere, Finland
| | - Qing Wang
- Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden
| | - Anna Berglöf
- Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden
| | - Rula Zain
- Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden
- Centre for Rare Diseases, Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden
| | - C. I. Edvard Smith
- Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Mauno Vihinen
- Protein Structure and Bioinformatics, Department of Experimental Medical Science, Lund University, BMC B13, 221 84 Lund, Sweden
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Chan KW, Wong CY, Leung D, Yang X, Fok SFS, Mak PHS, Yao L, Ma W, Mao H, Zhao X, Liang W, Singh S, Barbouche MR, He JX, Jiang LP, Liew WK, Le MHT, Muktiarti D, Santos-Ocampo FJ, Djidjik R, Belaid B, Ismail IH, Abdul Latiff AH, Lee WS, Chen TX, Liu J, Jin R, Wang X, Chien YH, Yu HH, Raj D, Raj R, Vaughan J, Urban M, van den Berg S, Eley B, Lee ACW, Isa MS, Ang EY, Lee BW, Yeoh AEJ, Shek LP, Quynh Le NN, Nguyen VAT, Phan Nguyen Lien A, Capulong RD, Mallillin JM, Villanueva JCMM, Camonayan KAB, Vera MD, Casis-Hao RJ, Lobo RCM, Foronda R, Binas VWE, Boushaki S, Kechout N, Phongsamart G, Wongwaree S, Jiratchaya C, Lao-Araya M, Trakultivakorn M, Suratannon N, Jirapongsananuruk O, Chantveerawong T, Kamchaisatian W, Chan LL, Koh MT, Wong KJ, Fong SM, Thong MK, Latiff ZA, Noh LM, de Silva R, Jouhadi Z, Al-Saad K, Vignesh P, Jindal AK, Rawat A, Gupta A, Suri D, Yang J, Au EYL, Kwok JSY, Chan SY, Hui WYF, Chua GT, Duque JR, Cheong KN, Chong PCY, Ho MHK, Lee TL, Wong WHS, Yang W, Lee PP, Tu W, Yang XQ, Lau YL. Targeted Gene Sanger Sequencing Should Remain the First-Tier Genetic Test for Children Suspected to Have the Five Common X-Linked Inborn Errors of Immunity. Front Immunol 2022; 13:883446. [PMID: 35874699 PMCID: PMC9304939 DOI: 10.3389/fimmu.2022.883446] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/02/2022] [Indexed: 11/13/2022] Open
Abstract
To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott-Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.
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Affiliation(s)
- Koon-Wing Chan
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Chung-Yin Wong
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Daniel Leung
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Xingtian Yang
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Susanna F. S. Fok
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Priscilla H. S. Mak
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Lei Yao
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Wen Ma
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Huawei Mao
- Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Xiaodong Zhao
- Children’s Hospital, Chongqing Medical University, Chongqing, China
| | - Weiling Liang
- Shenzhen Primary Immunodeficiency Diagnostic and Therapeutic Laboratory, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Surjit Singh
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Jian-Xin He
- Department of Respiratory Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Li-Ping Jiang
- Children’s Hospital, Chongqing Medical University, Chongqing, China
| | - Woei-Kang Liew
- Department of Paediatric Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
| | - Minh Huong Thi Le
- Department of Immuno-Allergology and Rheumatology, National Hospital of Paediatrics, Hanoi, Vietnam
| | - Dina Muktiarti
- Department of Child Health, Faculty of Medicine Universitas Indonesia-Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | | | - Reda Djidjik
- Department of Medical Immunology, Beni Messous University Hospital Centre, University of Algiers 1, Algiers, Algeria
| | - Brahim Belaid
- Department of Medical Immunology, Beni Messous University Hospital Centre, University of Algiers 1, Algiers, Algeria
| | - Intan Hakimah Ismail
- Clinical Immunology Unit, Department of Paediatrics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia
| | | | - Way Seah Lee
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Tong-Xin Chen
- Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinrong Liu
- Department of Respiratory Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Runming Jin
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaochuan Wang
- Department of Clinical Immunology, Children’s Hospital of Fudan University, Shanghai, China
| | - Yin Hsiu Chien
- Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsin-Hui Yu
- Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, National Taiwan University Children’s Hospital, Taipei, Taiwan
| | - Dinesh Raj
- Department of Paediatrics, Holy Family Hospital, University of Delhi, New Delhi, India
| | - Revathi Raj
- Department of Paediatric Haematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Chennai, India
| | - Jenifer Vaughan
- Department of Molecular Medicine and Haematology, National Health Laboratory Services, University of the Witwatersrand, Johannesburg, South Africa
| | - Michael Urban
- Division of Molecular Biology and Human Genetics, University of Stellenbosch Western Cape, Pretoria, South Africa
| | - Sylvia van den Berg
- Department of Immunology, Ampath and Department of Paediatrics and Child Health, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa
| | - Brian Eley
- Department of Paediatrics and Child Health, University of Cape Town and Red Cross War Memorial Children’s Hospital, Cape Town, South Africa
| | - Anselm Chi-Wai Lee
- Children’s Haematology and Cancer Center, Mount Elizabeth Hospital, Singapore, Singapore
| | - Mas Suhaila Isa
- Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore, Singapore
| | - Elizabeth Y. Ang
- Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore, Singapore
| | - Bee Wah Lee
- Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Allen Eng Juh Yeoh
- Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Lynette P. Shek
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | | | - Van Anh Thi Nguyen
- Department of Rheumatology, Allergy, and Immunology, Vietnam National Children's Hospital, Hanoi, Vietnam
| | | | | | - Joanne Michelle Mallillin
- Child and Adult Allergy, Asthma and Immunology General Emilio Aguinaldo Memorial Hospital, Cavite, Philippines
| | - Jose Carlo Miguel M. Villanueva
- Section of Allergy and Clinical Immunology, Department of Pediatrics, University of Santo Tomas Hospital, Manila, Philippines
| | | | - Michelle De Vera
- Section of Allergy and Immunology, The Medical City, Pasig, Philippines
| | - Roxanne J. Casis-Hao
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Philippine General Hospital, Manila, Philippines
| | - Rommel Crisenio M. Lobo
- Section of Allergy Asthma and Immunology, Fe del Mundo Medical Center, Quezon City, Philippines
| | - Ruby Foronda
- Department of Pediatrics, University of the East Ramon Magsaysay Memorial Medical Center, Quezon City, Philippines
| | | | - Soraya Boushaki
- Department of Medical Immunology, Beni Messous University Hospital Centre, University of Algiers 1, Algiers, Algeria
- Unit of Genetics, Laboratory of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Sciences and Technology “HouariBoumediene”, Algiers, Algeria
| | - Nadia Kechout
- Department of Immunology, Pasteur Institute of Algeria/Faculty of Medicine, Algiers, Algeria
| | - Gun Phongsamart
- Department of Pediatrics, Queen Sirikit National Institute of Child Health, Bangkok, Thailand
| | - Siriporn Wongwaree
- Department of Pediatrics, Queen Sirikit National Institute of Child Health, Bangkok, Thailand
| | - Chamnanrua Jiratchaya
- Department of Pediatrics, Queen Sirikit National Institute of Child Health, Bangkok, Thailand
| | - Mongkol Lao-Araya
- Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Muthita Trakultivakorn
- Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Narissara Suratannon
- Center of Excellence for Allergy and Clinical Immunology, Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Orathai Jirapongsananuruk
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Teerapol Chantveerawong
- Division of Allergy and Clinical Immunology, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand
| | - Wasu Kamchaisatian
- Division of Pediatrics Allergy and Immunology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Lee Lee Chan
- Subang Jaya Medical Centre, Subang Jaya, Malaysia
| | - Mia Tuang Koh
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Ke Juin Wong
- Department of Paediatrics, Likas Hospital, Ministry of Health, Sabah, Malaysia
| | - Siew Moy Fong
- Department of Paediatrics, Likas Hospital, Ministry of Health, Sabah, Malaysia
| | - Meow-Keong Thong
- Genetics and Metabolism Unit, Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Zarina Abdul Latiff
- Department of Pediatrics, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Lokman Mohd Noh
- Department of Pediatrics, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
- Department of Paediatrics, Hospital Tunku Azizah, Ministry of Health Malaysia, Kuala Lumpur, Malaysia
| | - Rajiva de Silva
- Department of Immunology, Medical Research Institute, Colombo, Sri Lanka
| | - Zineb Jouhadi
- Department of Pediatric Infectious Diseases, Children’s Hospital CHU Ibn Rochd, University Hassan 2, Casablanca, Morocco
| | - Khulood Al-Saad
- Department of Pediatrics, Salmaniya Medical Complex, Manama, Bahrain
| | - Pandiarajan Vignesh
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ankur Kumar Jindal
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amit Rawat
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anju Gupta
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Deepti Suri
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jing Yang
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Elaine Yuen-Ling Au
- Division of Clinical Immunology, Department of Pathology, Queen Mary Hospital, Hong Kong, Hong Kong SAR, China
| | - Janette Siu-Yin Kwok
- Division of Transplantation and Immunogenetics, Department of Pathology, Queen Mary Hospital, Hong Kong, Hong Kong SAR, China
| | - Siu-Yuen Chan
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Wayland Yuk-Fun Hui
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Gilbert T. Chua
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jaime Rosa Duque
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Kai-Ning Cheong
- Hong Kong Children’s Hospital, Hong Kong, Hong Kong SAR, China
| | | | | | - Tsz-Leung Lee
- Hong Kong Children’s Hospital, Hong Kong, Hong Kong SAR, China
| | - Wilfred Hing-Sang Wong
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Wanling Yang
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Pamela P. Lee
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Wenwei Tu
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Xi-Qiang Yang
- Children’s Hospital, Chongqing Medical University, Chongqing, China
| | - Yu Lung Lau
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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7
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Qing-Qi R, Ya-Wen L, Huan C, Yu Z, Yun-Fei A, Xue-Mei T, Xiao-Dong Z, Zhi-Yong Z. Retrospective study of 98 patients with X-linked agammaglobulinemia complicated with arthritis. Clin Rheumatol 2022; 41:1889-1897. [PMID: 35171366 DOI: 10.1007/s10067-022-06095-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 01/19/2022] [Accepted: 01/30/2022] [Indexed: 11/28/2022]
Abstract
OBJECTIVE We preformed this retrospective study of clinical manifestation, imaging feature, and mutations to describe joint involvement in X-linked agammaglobulinemia (XLA) patients, aimed to provide recommendation for physicians. METHODS A total number of 98 XLA patients who have been diagnosed between January 2000 and February 2020 were enrolled and grouped based on whether they developed arthritis and analyzed for the clinical, imaging, and gene mutation data using the t test or the Mann-Whitney test. RESULTS Forty-five out of 98 patients (45.9%) had joint involvement, 40.8% had symptom prior to the diagnosis of XLA, and 54.1% had no articular symptom. Patients with joint involvement had a higher median diagnostic age of XLA and initial IgG level than patients without it, while their intravenous immunoglobulin was lower (p < 0.05). Knee, hip, and ankle were the most frequent joint, and oligoarthritis (≦ 4 joints) was more common than polyarthritis (88.9% vs 11.1%). Red and tenderness were the most frequent clinical symptoms (80%) with 24.4% reporting limited activity and 8.9% reporting deformity. Imaging data collected from 32 patients indicated that joint effusion (53.3%), synovitis (15.5%), and swollen soft tissue (15.5%) were the most common feature. Seventeen patients were treated by antibiotics plus intravenous immunoglobulin (IVIG) with an effective rate of 70.6%, and 28 patients only received IVIG with an effective rate of 67.9%. In comparison to patients without arthritis who have higher frequency nonsense and frameshift mutation, patients with arthritis had a higher incidence of missense mutation (p < 0.05). CONCLUSION High prevalence of arthritis among X-linked agammaglobulinemia patients and subsequent progression through IVIG replacement therapy highlight the importance of timely diagnosis and better management of these patients. Our finding indicated a potential correlation between genotype and phenotype, and further research on the mechanism of arthritis in XLA patients could increase physicians' awareness and improve patients' prognosis. Key Points • This study described the feature of arthritis in XLA patients and indicated a potential correlation between this complication and genotype.
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Affiliation(s)
- Ran Qing-Qi
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China
| | - Li Ya-Wen
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China
| | - Chen Huan
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China
| | - Zhang Yu
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China.,National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China
| | - An Yun-Fei
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China.,National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China
| | - Tang Xue-Mei
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China.,National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China
| | - Zhao Xiao-Dong
- National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China.,The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Zhang Zhi-Yong
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, 400015, China.,National Clinical Research Center for Child Health and Disorders, Chongqing, 40015, China.,Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 40015, China.,China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 40015, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, 40015, China
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8
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Clinical, immunological and genomic characteristics of children with X-linked agammaglobulinemia from Kerala, South India. Hum Immunol 2022; 83:335-345. [PMID: 35074268 DOI: 10.1016/j.humimm.2022.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 12/22/2021] [Accepted: 01/05/2022] [Indexed: 11/18/2022]
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9
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Rojas-Restrepo J, Caballero-Oteyza A, Huebscher K, Haberstroh H, Fliegauf M, Keller B, Kobbe R, Warnatz K, Ehl S, Proietti M, Grimbacher B. Establishing the Molecular Diagnoses in a Cohort of 291 Patients With Predominantly Antibody Deficiency by Targeted Next-Generation Sequencing: Experience From a Monocentric Study. Front Immunol 2021; 12:786516. [PMID: 34975878 PMCID: PMC8718408 DOI: 10.3389/fimmu.2021.786516] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/29/2021] [Indexed: 12/12/2022] Open
Abstract
Predominantly antibody deficiencies (PAD) are a heterogeneous group of disorders characterized by dysfunctional antibody production, low immunoglobulin levels in serum and impaired vaccine responses. The clinical picture is variable, ranging from mild symptoms to severe complications, which may include autoimmunity, gastrointestinal disease, allergy, and malignancies. If left untreated, PAD patients are at risk of enduring disease progression, irreversible organ damage, and reduced life expectancy. A timely diagnosis has been shown to significantly improve disease prognosis. Here, we report on our experience using targeted gene panel sequencing by employing Agilent's HaloPlex or SureSelect and Illumina's MiSeq technologies in a cohort of 291 individuals who presented with low or absent immunoglobulin levels in combination with or without other clinical features. In total, we have detected over 57 novel or previously reported relevant mutations in ADA, ADA2, BTK, CTLA4, LRBA, NFKB1, NFKB2, PIK3CD, STAT3, and TNFRSF13B. Overall, a genetic diagnosis could be made in 24.7% of the investigated patients. The percentage of coverage for the targeted regions ranged from 90% to 98% in this study. Moreover, functional assays were performed on a defined group of the patients carrying candidate variants in CTLA4, LRBA, NFKB1 and BTK, which confirmed their deleterious effect on protein expression and/or function. This study reiterates that the immunological heterogeneity of predominantly antibody deficiencies may have a diverse genetic origin, although certain clinical features may hint towards a specific group of defects. Employing targeted sequencing panels proves to be a very time- and cost-efficient, yet reliable, method for the establishment of a genetic diagnosis in individuals with PAD. However, in case of negative panel results, or if functional testing reveals inconspicuous observations in patients with a clear indication for genetic testing, further work-up including whole exome or whole genome sequencing should be considered.
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Affiliation(s)
- Jessica Rojas-Restrepo
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Andrés Caballero-Oteyza
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Resolving Infection Susceptibility (RESIST) – Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
| | - Katrin Huebscher
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - Hanna Haberstroh
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - Manfred Fliegauf
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Integrative Biological Signaling Studies (CIBSS), University of Freiburg, Freiburg, Germany
| | - Baerbel Keller
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany
| | - Robin Kobbe
- First Department of Medicine, Division of Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Warnatz
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany
| | - Stephan Ehl
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
| | - Michele Proietti
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany
- Department of Rheumatology and Immunology, Hannover Medical University, Hannover, Germany
| | - Bodo Grimbacher
- Institute for Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany
- Resolving Infection Susceptibility (RESIST) – Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
- Center for Integrative Biological Signaling Studies (CIBSS), University of Freiburg, Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany
- German Center for Infection Research (DZIF), Satellite Center Freiburg, Freiburg, Germany
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10
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Pac M, Mikutskaya I, Mulawka J. Knowledge Discovery from Medical Data and Development of an Expert System in Immunology. ENTROPY (BASEL, SWITZERLAND) 2021; 23:695. [PMID: 34073080 PMCID: PMC8228842 DOI: 10.3390/e23060695] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 11/21/2022]
Abstract
Artificial intelligence is one of the fastest-developing areas of science that covers a remarkably wide range of problems to be solved. It has found practical application in many areas of human activity, also in medicine. One of the directions of cooperation between computer science and medicine is to assist in diagnosing and proposing treatment methods with the use of IT tools. This study is the result of collaboration with the Children's Memorial Health Institute in Warsaw, from where a database containing information about patients suffering from Bruton's disease was made available. This is a rare disorder, difficult to detect in the first months of life. It is estimated that one in 70,000 to 90,000 children will develop Bruton's disease. But even these few cases need detailed attention from doctors. Based on the data contained in the database, data mining was performed. During this process, knowledge was discovered that was presented in a way that is understandable to the user, in the form of decision trees. The best models obtained were used for the implementation of expert systems. Based on the data introduced by the user, the system conducts expertise and determines the severity of the course of the disease or the severity of the mutation. The CLIPS language was used for developing the expert system. Then, using this language, software was developed producing six expert systems. In the next step, experimental verification was performed, which confirmed the correctness of the developed systems.
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Affiliation(s)
- Małgorzata Pac
- The Department of Immunology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland
| | - Irina Mikutskaya
- Institute of Computer Science, Warsaw University of Technology, Nowowiejska 15/19, 00-665 Warsaw, Poland
| | - Jan Mulawka
- Institute of Computer Science, Warsaw University of Technology, Nowowiejska 15/19, 00-665 Warsaw, Poland
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11
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Seymour BJ, Singh S, Certo HM, Sommer K, Sather BD, Khim S, Clough C, Hale M, Pangallo J, Ryu BY, Khan IF, Adair JE, Rawlings DJ. Effective, safe, and sustained correction of murine XLA using a UCOE-BTK promoter-based lentiviral vector. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2021; 20:635-651. [PMID: 33718514 PMCID: PMC7907679 DOI: 10.1016/j.omtm.2021.01.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 01/14/2021] [Indexed: 02/06/2023]
Abstract
X-linked agammaglobulinemia (XLA) is an immune disorder caused by mutations in Bruton’s tyrosine kinase (BTK). BTK is expressed in B and myeloid cells, and its deficiency results in a lack of mature B cells and protective antibodies. We previously reported a lentivirus (LV) BTK replacement therapy that restored B cell development and function in Btk and Tec double knockout mice (a phenocopy of human XLA). In this study, with the goal of optimizing both the level and lineage specificity of BTK expression, we generated LV incorporating the proximal human BTK promoter. Hematopoietic stem cells from Btk−/−Tec−/− mice transduced with this vector rescued lineage-specific expression and restored B cell function in Btk−/−Tec−/− recipients. Next, we tested addition of candidate enhancers and/or ubiquitous chromatin opening elements (UCOEs), as well as codon optimization to improve BTK expression. An Eμ enhancer improved B cell rescue, but increased immunoglobulin G (IgG) autoantibodies. Addition of the UCOE avoided autoantibody generation while improving B cell development and function and reducing vector silencing. An optimized vector containing a truncated UCOE upstream of the BTK promoter and codon-optimized BTK cDNA resulted in stable, lineage-regulated BTK expression that mirrored endogenous BTK, making it a strong candidate for XLA therapy.
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Affiliation(s)
- Brenda J Seymour
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Swati Singh
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Hannah M Certo
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Karen Sommer
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Blythe D Sather
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Socheath Khim
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Courtnee Clough
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Malika Hale
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Joseph Pangallo
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Byoung Y Ryu
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Iram F Khan
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Jennifer E Adair
- Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.,Department of Medical Oncology, University of Washington, Seattle, WA 98195, USA
| | - David J Rawlings
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA.,Departments of Pediatrics and Immunology, University of Washington, Seattle, WA 98195, USA
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12
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Rawat A, Jindal AK, Suri D, Vignesh P, Gupta A, Saikia B, Minz RW, Banday AZ, Tyagi R, Arora K, Joshi V, Mondal S, Shandilya JK, Sharma M, Desai M, Taur P, Pandrowala A, Gowri V, Sawant-Desai S, Gupta M, Dalvi AD, Madkaikar M, Aggarwal A, Raj R, Uppuluri R, Bhattad S, Jayaram A, Lashkari HP, Rajasekhar L, Munirathnam D, Kalra M, Shukla A, Saka R, Sharma R, Garg R, Imai K, Nonoyama S, Ohara O, Lee PP, Chan KW, Lau YL, Singh S. Clinical and Genetic Profile of X-Linked Agammaglobulinemia: A Multicenter Experience From India. Front Immunol 2021; 11:612323. [PMID: 33584693 PMCID: PMC7873890 DOI: 10.3389/fimmu.2020.612323] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 12/01/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND There is paucity of literature on XLA from developing countries. Herein we report the clinical and molecular profile and outcome in a multicenter cohort of patients with XLA from India. METHODS Data on XLA from all regional centers supported by the Foundation for Primary Immunodeficiency Diseases (FPID), USA and other institutions providing care to patients with PIDs were collated. Diagnosis of XLA was based on European Society for Immunodeficiencies (ESID) criteria. RESULTS We received clinical details of 195 patients with a provisional diagnosis of XLA from 12 centers. At final analysis, 145 patients were included (137 'definite XLA' and eight 'probable/possible XLA'). Median age at onset of symptoms was 12.0 (6.0, 36.0) months and median age at diagnosis was 60.0 (31.5, 108) months. Pneumonia was the commonest clinical manifestation (82.6%) followed by otitis media (50%) and diarrhea (42%). Arthritis was seen in 26% patients while 23% patients developed meningitis. Bronchiectasis was seen in 10% and encephalitis (likely viral) in 4.8% patients. Pseudomonas aeruginosa was the commonest bacterial pathogen identified followed by Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae. Molecular analysis revealed 86 variants in 105 unrelated cases. Missense variants in BTK gene were the most common (36%) followed by frameshift (22%) and nonsense variants (21%). Most pathogenic gene variants (53%) were clustered in the distal part of gene encompassing exons 14-19 encoding for the tyrosine kinase domain. Follow-up details were available for 108 patients. Of these, 12% had died till the time of this analysis. The 5-year and 10-year survival was 89.9% and 86.9% respectively. Median duration of follow-up was 61 months and total duration of follow-up was 6083.2 patient-months. All patients received intravenous immunoglobulin (IVIg) replacement therapy. However, in many patients IVIg could not be given at recommended doses or intervals due to difficulties in accessing this therapy because of financial reasons and lack of universal health insurance in India. Hematopoietic stem cell transplant was carried out in four (2.8%) patients. CONCLUSION There was a significant delay in the diagnosis and facilities for molecular diagnosis were not available at many centers. Optimal immunoglobulin replacement is still a challenge.
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Affiliation(s)
- Amit Rawat
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ankur Kumar Jindal
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Deepti Suri
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pandiarajan Vignesh
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anju Gupta
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Biman Saikia
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ranjana W. Minz
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Aaqib Zaffar Banday
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rahul Tyagi
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Kanika Arora
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vibhu Joshi
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sanjib Mondal
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jitendra Kumar Shandilya
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Madhubala Sharma
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Mukesh Desai
- Department of Immunology, B. J. Wadia Hospital, Mumbai, India
| | - Prasad Taur
- Department of Immunology, B. J. Wadia Hospital, Mumbai, India
| | | | - Vijaya Gowri
- Department of Immunology, B. J. Wadia Hospital, Mumbai, India
| | - Sneha Sawant-Desai
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohematology, K.E.M Hospital, Mumbai, India
| | - Maya Gupta
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohematology, K.E.M Hospital, Mumbai, India
| | - Aparna Dhondi Dalvi
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohematology, K.E.M Hospital, Mumbai, India
| | - Manisha Madkaikar
- Department of Pediatric Immunology and Leukocyte Biology, ICMR-National Institute of Immunohematology, K.E.M Hospital, Mumbai, India
| | - Amita Aggarwal
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Revathi Raj
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Chennai, India
| | - Ramya Uppuluri
- Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Chennai, India
| | - Sagar Bhattad
- Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, Aster CMI Hospital, Bengaluru, India
| | | | - Harsha Prasad Lashkari
- Department of Paediatrics, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India
| | - Liza Rajasekhar
- Department of Clinical Immunology and Rheumatology, Nizam's Institute of Medical Sciences, Hyderabad, India
| | - Deenadayalan Munirathnam
- Department of Pediatric Hematology Oncology and Bone Marrow Transplant, Kanchi Kamakoti Childs Trust Hospital, Chennai, India
| | - Manas Kalra
- Department of Pediatric Hematology, Oncology and BMT, Sir Ganga Ram Hospital, New Delhi, India
| | | | - Ruchi Saka
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rajni Sharma
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ravinder Garg
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Kohsuke Imai
- Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Shigeaki Nonoyama
- Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan
| | - Osamu Ohara
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan
| | - Pamela P. Lee
- Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Koon Wing Chan
- Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Yu-Lung Lau
- Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
| | - Surjit Singh
- Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Cinicola B, Uva A, Leonardi L, Moratto D, Giliani S, Carsetti R, Ferrari S, Zicari AM, Duse M. Case Report: A Case of X-Linked Agammaglobulinemia With High Serum IgE Levels and Allergic Rhinitis. Front Immunol 2020; 11:582376. [PMID: 33224144 PMCID: PMC7674281 DOI: 10.3389/fimmu.2020.582376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 10/06/2020] [Indexed: 11/13/2022] Open
Abstract
X-linked Agammaglobulinemia (XLA) is a rare genetic disorder of B-lymphocyte differentiation, characterized by the absence or paucity of circulating B cells, markedly reduced levels of all serum immunoglobulin isotypes and lack of specific antibody production. Bruton Tyrosine Kinase (BTK) gene encodes a cytoplasmic tyrosine kinase involved in the B cell maturation and its mutation, blocking B cell differentiation at the pre-B cell stage, and is responsible for XLA. All domains may be affected by the mutation, and the many genotypes are associated with a wide range of clinical presentations. Little is known about genotype-phenotype correlation in this disorder, and factors influencing the phenotype of XLA are not clearly understood. In this report we present a unique case of a young patient affected by XLA. The disease was genetically diagnosed at birth due to a family history of XLA, but during follow up, it was characterized by a CD19+ B cell percentage consistently greater than 2%. He never suffered severe infections, but at two years of age, he developed persistent rhinitis. Thus, total serum IgE levels were measured and detected over the normal range, and specific allergic investigations showed sensitization to dust mites. Further immunological tests (BTK expression, functional “in vitro” B cell proliferation upon CpG stimulation, B cell subset analysis) explained these findings as possible manifestations of a mild XLA phenotype. XLA patients rarely present with allergic manifestations, which could warrant further investigation. High serum IgE levels could be a sign of a mild phenotype, but their role and the mechanisms underlying their production in XLA need to be clarified.
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Affiliation(s)
- Bianca Cinicola
- Department of Pediatrics, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Andrea Uva
- Department of Pediatrics, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Lucia Leonardi
- Department of Pediatrics, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Daniele Moratto
- Cytogenetic and Medical Genetics Unit, "A. Nocivelli" Institute for Molecular Medicine Spedali Civili Hospital, Brescia, Italy.,Flow Cytometry Unit, Clinical Chemistry Laboratory, Spedali Civili Hospital, Brescia, Italy
| | - Silvia Giliani
- Cytogenetic and Medical Genetics Unit, "A. Nocivelli" Institute for Molecular Medicine Spedali Civili Hospital, Brescia, Italy.,Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Rita Carsetti
- B Cell Physiopathology Unit, Immunology Research Area, Bambino Gesù Children Hospital, Rome, Italy
| | - Simona Ferrari
- Medical Genetics Unit, S.Orsola-Malpighi University Hospital, Bologna, Italy
| | - Anna Maria Zicari
- Department of Pediatrics, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
| | - Marzia Duse
- Department of Pediatrics, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy
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14
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Hu XM, Yuan K, Chen H, Chen C, Fang YL, Zhu JF, Liang L, Wang CL. Novel deletion mutation in Bruton’s tyrosine kinase results in X-linked agammaglobulinemia: A case report. World J Clin Cases 2020; 8:3859-3866. [PMID: 32953865 PMCID: PMC7479573 DOI: 10.12998/wjcc.v8.i17.3859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/08/2020] [Accepted: 07/18/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND X-linked agammaglobulinemia is a primary immunodeficiency disease caused by gene mutations of Bruton’s tyrosine kinase (BTK). We found a new mutation point and summarized the correlation analysis and performed a literature review.
CASE SUMMARY The proband was a 5-year-old boy. He was admitted to our hospital due to a recurrent cough and a fever that had persisted for a month. He had a history of multiple respiratory infections and sinusitis. There was no immunodeficiency or recurrent infection history among his family members. Agammaglobulinemia was characterized as follows: Immunoglobulin (Ig) A, 90.0 mg/dL (90-450 mg/dL); IgG, 20.0 mg/dL (800-1800 mg/dL); and IgM, 18.0 mg/dL (60-280 mg/dL). Notably, the assessment of IgG subtypes revealed the following very low levels: Subtype 1, 0.26 g/L (3.62-12.28 g/L); subtype 2, 0.10 g/L (0.57-2.9 g/L); subtype 3, 0.009 g/L (0.129-0.789 g/L); and subtype 4, 0.003 g/L (0.013-1.446 g/L). Cellular immunological test results were as follows: CD3, 74.6% (50%-84.0%); CD4, 47.3% (27.0%-51.0%); and CD8, 24.9% (15.0%-44.0%). A de novo hemizygous deletion in BTK was detected: c.902_c.904delAAG/p.E301del. Transcript levels of the mutant BTK were similar to those of the wild-type gene, though overexpression resulted in markedly reduced levels of mutant BTK (9.49% ± 1.58%), relative to the wild-type BTK (75.8% ± 2.98%, P < 0.01).
CONCLUSION This case of X-linked agammaglobulinemia was attributed to a de novo hemizygous deletion mutation in BTK (c.902_c.904delAAG/p.E301del). The mutation resulted in markedly reduced BTK protein stability in vitro.
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Affiliation(s)
- Xiao-Mei Hu
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Ke Yuan
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Hong Chen
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Chun Chen
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Yan-Lan Fang
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Fang Zhu
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Li Liang
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Chun-Lin Wang
- Department of Pediatrics, The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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15
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Gao S, Hu S, Duan H, Wang L, Kong X. Clinical characteristics and prenatal diagnosis for 22 families in Henan Province of China with X-linked agammaglobulinemia (XLA) related to Bruton's tyrosine kinase (BTK) gene mutations. BMC MEDICAL GENETICS 2020; 21:131. [PMID: 32552675 PMCID: PMC7302398 DOI: 10.1186/s12881-020-01063-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 06/04/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND X-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease for which recurrent severe infection is the major clinical symptom. BTK is the main causative gene, with X chromosome recessive inheritance. However, the mutations reported to date do not fully explain the disorder. METHODS We detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by flow cytometry and rate scatter immunoturbidimetry, and investigated the BTK mutation profile in 22 XLA patients using Sanger sequencing and real-time PCR . RESULTS We evaluated the clinical symptoms of 22 XLA patients and investigated genetic mutations present, identifying six novel mutations in the BTK gene: 2 missense mutations (c.23G > T and c.112 T > C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631 + 2 T > C). Prenatal diagnoses were performed in six families (F10, F11, F15, F18, F20 and F21), with the following results: the male fetus in Family 10 (F10) did not carry the c.922_923delGA mutation; the male fetus in Family 15 (F15) did not carry the c.1631 + 1G > T splicing mutation; the female fetus in Family 20 (F20) did not carry the c.1931 T > C mutation; the female fetus in Family 21 (F21) did not carry the large deletion mutation. Hence, these four fetuses are not likely to develop XLA. Male fetuses with c.1060delA and c.1684C > T mutations were identified in Family 11 and Family 18, respectively. The pregnant woman in F18 chose to terminate the pregnancy, whereas the pregnant woman in F11 chose to continue the pregnancy. CONCLUSION We confirmed the diagnosis of 22 XLA patients from 22 unrelated families and detected six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat infections in XLA children, saving their lives.
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Affiliation(s)
- Shanshan Gao
- The Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China), No. 1, Jianshe East Rd, Erqi District, Zhengzhou, Henan Province, China
| | - Shuang Hu
- The Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China), No. 1, Jianshe East Rd, Erqi District, Zhengzhou, Henan Province, China
| | - Huikun Duan
- The Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China), No. 1, Jianshe East Rd, Erqi District, Zhengzhou, Henan Province, China
| | - Li Wang
- The Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China), No. 1, Jianshe East Rd, Erqi District, Zhengzhou, Henan Province, China
| | - Xiangdong Kong
- The Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China), No. 1, Jianshe East Rd, Erqi District, Zhengzhou, Henan Province, China.
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16
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Maglione PJ. Chronic Lung Disease in Primary Antibody Deficiency: Diagnosis and Management. Immunol Allergy Clin North Am 2020; 40:437-459. [PMID: 32654691 DOI: 10.1016/j.iac.2020.03.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Chronic lung disease is a complication of primary antibody deficiency (PAD) associated with significant morbidity and mortality. Manifestations of lung disease in PAD are numerous. Thoughtful application of diagnostic approaches is imperative to accurately identify the form of disease. Much of the treatment used is adapted from immunocompetent populations. Recent genomic and translational medicine advances have led to specific treatments. As chronic lung disease has continued to affect patients with PAD, we hope that continued advancements in our understanding of pulmonary pathology will ultimately lead to effective methods that alleviate impact on quality of life and survival.
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Affiliation(s)
- Paul J Maglione
- Pulmonary Center, Boston University School of Medicine, 72 East Concord Street, R304, Boston, MA 02118, USA.
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17
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Rivière JG, Franco-Jarava C, Martínez-Gallo M, Aguiló-Cucurull A, Blasco-Pérez L, Paramonov I, Antolín M, Martín-Nalda A, Soler-Palacín P, Colobran R. Uncovering Low-Level Maternal Gonosomal Mosaicism in X-Linked Agammaglobulinemia: Implications for Genetic Counseling. Front Immunol 2020; 11:46. [PMID: 32117230 PMCID: PMC7028698 DOI: 10.3389/fimmu.2020.00046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 01/09/2020] [Indexed: 11/20/2022] Open
Abstract
X-linked agammaglobulinemia (XLA) is a clinically and genetically well-defined immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent bacterial infections, profound hypogammaglobulinemia, and few or no circulating B cells. XLA is caused by mutations in the BTK gene, which encodes Bruton's tyrosine kinase (BTK). Because of its X-linked recessive inheritance pattern, XLA virtually only affects males, and the mother is the carrier of the mutation in 80–85% of the males with this condition. In the remaining 15–20% of the cases, the affected male is considered to have a de novo mutation. Here, we present the case of a child with a diagnosis of XLA caused by a missense mutation in the BTK gene (c.494G>A/p.C165Y). Apparently, his mother was wild type for this gene, which implied that the mutation was de novo, but careful analysis of Sanger electropherograms and the use of high-coverage massive parallel sequencing revealed low-level maternal gonosomal mosaicism. The mutation was detected in various samples from the mother (blood, urine, buccal swab, and vaginal swab) at a low frequency of 2–5%, and the status of the patient's mutation changed from de novo to inherited. This study underscores the importance of accurately establishing the parents' status on detection of an apparently de novo mutation in a patient, as inadvertent low-level mosaicism may lead to misinterpretation of the risk of recurrence, vital for genetic counseling.
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Affiliation(s)
- Jacques G Rivière
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Jeffrey Model Foundation Excellence Center, Barcelona, Spain
| | - Clara Franco-Jarava
- Jeffrey Model Foundation Excellence Center, Barcelona, Spain.,Immunology Division, Department of Cell Biology, Physiology and Immunology, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain
| | - Mónica Martínez-Gallo
- Jeffrey Model Foundation Excellence Center, Barcelona, Spain.,Immunology Division, Department of Cell Biology, Physiology and Immunology, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain
| | - Aina Aguiló-Cucurull
- Jeffrey Model Foundation Excellence Center, Barcelona, Spain.,Immunology Division, Department of Cell Biology, Physiology and Immunology, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain
| | - Laura Blasco-Pérez
- Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Ida Paramonov
- Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - María Antolín
- Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Andrea Martín-Nalda
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Jeffrey Model Foundation Excellence Center, Barcelona, Spain
| | - Pere Soler-Palacín
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Jeffrey Model Foundation Excellence Center, Barcelona, Spain
| | - Roger Colobran
- Jeffrey Model Foundation Excellence Center, Barcelona, Spain.,Immunology Division, Department of Cell Biology, Physiology and Immunology, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain.,Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain
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18
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Kasahara Y, Imamura M, Shin C, Shimizu H, Utsumi J, Hosokai R, Iwabuchi H, Takachi T, Kakita A, Kanegane H, Saitoh A, Imai C. Fatal Progressive Meningoencephalitis Diagnosed in Two Members of a Family With X-Linked Agammaglobulinemia. Front Pediatr 2020; 8:579. [PMID: 33042921 PMCID: PMC7530192 DOI: 10.3389/fped.2020.00579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 08/06/2020] [Indexed: 01/03/2023] Open
Abstract
Chronic enteroviral meningoencephalitis is a well-known complication in patients with X-linked agammaglobulinemia (XLA). However, progressive neurodegenerative disorders or chronic neuroinflammatory diseases with no causative microorganisms have been recognized as rare central nervous system (CNS) complications in XLA. We herein report a family in which two of three members with XLA had developed progressive meningoencephalitis with an unknown etiology. A 15-month-old male infant presented with left-sided ptosis. Initially, the family denied any family history of inherited diseases, but later disclosed a family history of agammaglobulinemia previously diagnosed in two family members. In the early 1980s, one of the elder brothers of the index patient's mother who had been treated with intramuscular immunoglobulin [or later intravenous immunoglobulin (IVIG)] for agammaglobulinemia deceased at 10 years of age after showing progressive neurological deterioration during the last several years of his life. The index patient was diagnosed with XLA caused by Bruton tyrosine kinase deficiency (654delG; Val219Leufs*9), and chronic meningoencephalitis with an unknown infectious etiology. Magnetic resonance imaging of the brain demonstrated inflammatory changes in the basal ganglia, hypothalamus, midbrain, and pons, with multiple nodular lesions with ring enhancement, which showed impressive amelioration after the initiation of IVIG replacement therapy. Pleocytosis, which was characterized by an increase in CD4-positive and CD8-positive T cells expressing an activation marker and an elevation in inflammatory cytokines in the cerebrospinal fluid, was identified. No microorganism was identified as a cause of CNS complications. He thereafter developed brain infarction at 19 months of age and fatal status epilepticus at 5 years of age, despite regular IVIG with high trough levels and regular intraventricular immunoglobulin administration. The etiology of this rare CNS complication in XLA is currently unknown. Previous studies have suggested a possible association of IVIG, which was clearly denied in our index case because of the demonstration of his neurological disorder at presentation. In the future, extensive and unbiased molecular methods to detect causative microorganisms, as well as to investigate the possible role of autoimmunity are needed to clarify the etiology of CNS complications.
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Affiliation(s)
- Yasushi Kasahara
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masaru Imamura
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Chansu Shin
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hiroshi Shimizu
- Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Jirou Utsumi
- Department of Pediatrics, Niigata Cancer Center Hospital, Niigata, Japan
| | - Ryosuke Hosokai
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Haruko Iwabuchi
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takayuki Takachi
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Akiyoshi Kakita
- Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan
| | - Hirokazu Kanegane
- Department of Pediatrics, Graduate School of Medicine, University of Toyama, Toyama, Japan.,Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Akihiko Saitoh
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Chihaya Imai
- Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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19
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Krüger R, Baumann U, Borte S, Kölsch U, Lorenz MR, Keller B, Harder I, Warnatz K, Ehl S, Schwarz K, Wahn V, Bernuth H. Impaired polysaccharide responsiveness without agammaglobulinaemia in three patients with hypomorphic mutations in
Bruton Tyrosine Kinase
—No detection by newborn screening for primary immunodeficiencies. Scand J Immunol 2019; 91:e12811. [DOI: 10.1111/sji.12811] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 07/10/2019] [Accepted: 07/31/2019] [Indexed: 01/12/2023]
Affiliation(s)
- Renate Krüger
- Department of Pediatric Pneumology, Immunology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt‐Universität zu Berlin and Berlin Institute of Health Berlin Germany
| | - Ulrich Baumann
- Department of Pediatric Pulmonology Hannover Medical School Hannover Germany
| | - Stephan Borte
- ImmunoDeficiencyCenter Leipzig (IDCL), Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies Municipal Hospital St. Georg Leipzig Germany
| | - Uwe Kölsch
- Department of Immunology Labor Berlin - Charité Vivantes GmbH Berlin Germany
| | - Myriam Ricarda Lorenz
- Institute for Transfusion Medicine, German Red Cross Blood Service Baden‐Wuerttemberg–Hessen University Ulm and Institute for Clinical Transfusion Medicine and Immunogenetics Ulm Ulm Germany
| | - Baerbel Keller
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center‐University of Freiburg University of Freiburg Freiburg Germany
- Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center‐University of Freiburg University of Freiburg Freiburg Germany
| | - Ina Harder
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center‐University of Freiburg University of Freiburg Freiburg Germany
- Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center‐University of Freiburg University of Freiburg Freiburg Germany
| | - Klaus Warnatz
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, Medical Center‐University of Freiburg University of Freiburg Freiburg Germany
- Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center‐University of Freiburg University of Freiburg Freiburg Germany
| | - Stephan Ehl
- Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center‐University of Freiburg University of Freiburg Freiburg Germany
| | - Klaus Schwarz
- Institute for Transfusion Medicine, German Red Cross Blood Service Baden‐Wuerttemberg–Hessen University Ulm and Institute for Clinical Transfusion Medicine and Immunogenetics Ulm Ulm Germany
| | - Volker Wahn
- Department of Pediatric Pneumology, Immunology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt‐Universität zu Berlin and Berlin Institute of Health Berlin Germany
| | - Horst Bernuth
- Department of Pediatric Pneumology, Immunology and Intensive Care, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin Humboldt‐Universität zu Berlin and Berlin Institute of Health Berlin Germany
- Department of Immunology Labor Berlin - Charité Vivantes GmbH Berlin Germany
- Berlin Center for Regenerative Therapies (BCRT) Charité‐Universitätsmedizin Berlin Germany
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20
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Yazdani R, Abolhassani H, Kiaee F, Habibi S, Azizi G, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, Gharagozlou M, Movahedi M, Hamidieh AA, Behniafard N, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Shirkani A, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari A, Mansouri M, Mesdaghi M, Babaie D, Ahanchian H, Khoshkhui M, Soheili H, Eslamian MH, Cheraghi T, Dabbaghzadeh A, Tavassoli M, Kalmarzi RN, Mortazavi SH, Kashef S, Esmaeilzadeh H, Tafaroji J, Khalili A, Zandieh F, Sadeghi-Shabestari M, Darougar S, Behmanesh F, Akbari H, Zandkarimi M, Abolnezhadian F, Fayezi A, Moghtaderi M, Ahmadiafshar A, Shakerian B, Sajedi V, Taghvaei B, Safari M, Heidarzadeh M, Ghalebaghi B, Fathi SM, Darabi B, Bazregari S, Bazargan N, Fallahpour M, Khayatzadeh A, Javahertrash N, Bashardoust B, Zamani M, Mohsenzadeh A, Ebrahimi S, Sharafian S, Vosughimotlagh A, Tafakoridelbari M, Rahim M, Ashournia P, Razaghian A, Rezaei A, Samavat A, Mamishi S, Khazaei HA, Mohammadi J, Negahdari B, Parvaneh N, Rezaei N, Lougaris V, Giliani S, Plebani A, Ochs HD, Hammarström L, Aghamohammadi A. Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2019; 7:864-878.e9. [DOI: 10.1016/j.jaip.2018.09.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 09/03/2018] [Accepted: 09/04/2018] [Indexed: 12/15/2022]
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21
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Damaging BTK Variant Demonstrated by Carrier, Allele-Specific BTK Expression in B Cells and Monocytes. J Clin Immunol 2019; 39:23-25. [PMID: 30627929 DOI: 10.1007/s10875-019-0591-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 01/03/2019] [Indexed: 10/27/2022]
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22
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Esenboga S, Cagdas D, Ozgur TT, Gur Cetinkaya P, Turkdemir LM, Sanal O, VanDerBurg M, Tezcan I. Clinical and genetic features of the patients with X-Linked agammaglobulinemia from Turkey: Single-centre experience. Scand J Immunol 2018; 87. [PMID: 29424453 DOI: 10.1111/sji.12647] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 02/01/2018] [Indexed: 12/11/2022]
Abstract
X-linked agammaglobulinemia is a primary immunodeficiency disorder resulting from BTK gene mutations. There are many studies in the literature suggesting contradictory ideas about phenotype-genotype correlation. The aim of this study was to identify the mutations and clinical findings of patients with XLA in Turkey, to determine long-term complications related to the disease and to analyse the phenotype-genotype correlation. Thirty-two patients with XLA diagnosed between 1985 and 2016 in Pediatric Immunology Department of Hacettepe University Ihsan Dogramaci Children's Hospital were investigated. A clinical survey including clinical features of the patients was completed, and thirty-two patients from 26 different families were included in the study. Getting early diagnosis and regular assessment with imaging techniques seem to be the most important issues for improving the health status of the patients with XLA. Early molecular analysis gives chance for definitive diagnosis and genetic counselling, but not for predicting the clinical severity and prognosis.
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Affiliation(s)
- S Esenboga
- Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - D Cagdas
- Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - T T Ozgur
- Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - P Gur Cetinkaya
- Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - L M Turkdemir
- Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - O Sanal
- Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - M VanDerBurg
- Erasmus Medical Center, Laboratory Medical Immunology, Division of Immunology, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - I Tezcan
- Department of Pediatrics, Division of Immunology, Hacettepe University Faculty of Medicine, Ankara, Turkey
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23
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Walter JE, Farmer JR, Foldvari Z, Torgerson TR, Cooper MA. Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2017; 4:1089-1100. [PMID: 27836058 DOI: 10.1016/j.jaip.2016.08.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Revised: 08/01/2016] [Accepted: 08/19/2016] [Indexed: 01/27/2023]
Abstract
A broad spectrum of autoimmunity is now well described in patients with primary immunodeficiencies (PIDs). Management of autoimmune disease in the background of PID is particularly challenging given the seemingly discordant goals of immune support and immune suppression. Our growing ability to define the molecular underpinnings of immune dysregulation has facilitated novel targeted therapeutics. This review focuses on mechanism-based treatment strategies for the most common autoimmune and inflammatory complications of PID including autoimmune cytopenias, rheumatologic disease, and gastrointestinal disease. We aim to provide guidance regarding the rational use of these agents in the complex PID patient population.
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Affiliation(s)
- Jolan E Walter
- Department of Pediatrics & Medicine, University of South Florida at Johns Hopkins All Children's Hospital, St Petersburg, Fla; Division of Pediatric Allergy & Immunology, Massachusetts General Hospital for Children, Boston, Mass; Division of Immunology, Boston Children's Hospital, Boston, Mass.
| | - Jocelyn R Farmer
- Department of Allergy & Immunology, Massachusetts General Hospital, Boston, Mass
| | - Zsofia Foldvari
- Department of Cancer Immunology, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K. G. Jebsen Centers for Cancer Immunotherapy and for Inflammation Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Troy R Torgerson
- Department of Pediatrics, University of Washington School of Medicine, Seattle, Wash
| | - Megan A Cooper
- Department of Pediatrics, Division of Rheumatology, Washington University School of Medicine, St Louis, Mo
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24
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Petersheim D, Massaad MJ, Lee S, Scarselli A, Cancrini C, Moriya K, Sasahara Y, Lankester AC, Dorsey M, Di Giovanni D, Bezrodnik L, Ohnishi H, Nishikomori R, Tanita K, Kanegane H, Morio T, Gelfand EW, Jain A, Secord E, Picard C, Casanova JL, Albert MH, Torgerson TR, Geha RS. Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. J Allergy Clin Immunol 2017. [PMID: 28629746 DOI: 10.1016/j.jaci.2017.05.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis. OBJECTIVE We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. METHODS A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts. RESULTS Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin β receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID.
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Affiliation(s)
- Daniel Petersheim
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | - Michel J Massaad
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | - Saetbyul Lee
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | - Alessia Scarselli
- Division of Immunology and Infectious Diseases, Department of Pediatrics, Bambino Gesù Children's Hospital, Rome, and University of Rome Tor Vergata, Rome, Italy
| | - Caterina Cancrini
- Division of Immunology and Infectious Diseases, Department of Pediatrics, Bambino Gesù Children's Hospital, Rome, and University of Rome Tor Vergata, Rome, Italy
| | | | - Yoji Sasahara
- Department of Pediatrics, Tohoku University, Tohoku, Japan
| | - Arjan C Lankester
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Morna Dorsey
- Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California, San Francisco, Calif
| | - Daniela Di Giovanni
- Immunology Service, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - Liliana Bezrodnik
- Immunology Service, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | | | | | - Kay Tanita
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hirokazu Kanegane
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomohiro Morio
- Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
| | - Erwin W Gelfand
- Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, Colo
| | - Ashish Jain
- Merck Research Laboratories Boston, Boston, Mass
| | - Elizabeth Secord
- Division of Allergy, Asthma, and Immunology, Children's Hospital of Michigan, Detroit, Mich
| | - Capucine Picard
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital, Paris Descartes University, Paris, France
| | - Jean-Laurent Casanova
- Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital, Paris Descartes University, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY
| | - Michael H Albert
- Department of Pediatric Hematology and Oncology, Dr von Hauner University Children's Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Troy R Torgerson
- Department of Pediatrics, University of Washington School of Medicine, Seattle, Wash
| | - Raif S Geha
- Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
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25
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Barmettler S, Otani IM, Minhas J, Abraham RS, Chang Y, Dorsey MJ, Ballas ZK, Bonilla FA, Ochs HD, Walter JE. Gastrointestinal Manifestations in X-linked Agammaglobulinemia. J Clin Immunol 2017; 37:287-294. [PMID: 28236219 PMCID: PMC5414010 DOI: 10.1007/s10875-017-0374-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 02/08/2017] [Indexed: 12/17/2022]
Abstract
PURPOSE X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in X-linked agammaglobulinemia (XLA), the spectrum of gastrointestinal manifestations has not previously been fully explored. METHODS We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the United States Immunodeficiency Network, a national registry of primary immunodeficiencies. RESULTS In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide ranging, and management strategies were diverse and mainly experimental. CONCLUSIONS Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.
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Affiliation(s)
| | - Iris M Otani
- Massachusetts General Hospital, Boston, MA, USA
- University of San Francisco, San Francisco, CA, USA
| | - Jasmit Minhas
- Lahey Hospital & Medical Center, Burlington, MA, USA
| | | | - Yenhui Chang
- University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA
| | | | | | | | - Hans D Ochs
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA
| | - Jolan E Walter
- Massachusetts General Hospital, Boston, MA, USA
- University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA
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26
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Schussler E, Beasley MB, Maglione PJ. Lung Disease in Primary Antibody Deficiencies. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2016; 4:1039-1052. [PMID: 27836055 PMCID: PMC5129846 DOI: 10.1016/j.jaip.2016.08.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 08/03/2016] [Accepted: 08/22/2016] [Indexed: 01/08/2023]
Abstract
Primary antibody deficiencies (PADs) are the most common form of primary immunodeficiency and predispose to severe and recurrent pulmonary infections, which can result in chronic lung disease including bronchiectasis. Chronic lung disease is among the most common complications of PAD and a significant source of morbidity and mortality for these patients. However, the development of lung disease in PAD may not be solely the result of recurrent bacterial infection or a consequence of bronchiectasis. Recent characterization of monogenic immune dysregulation disorders and more extensive study of common variable immunodeficiency have demonstrated that interstitial lung disease (ILD) in PAD can result from generalized immune dysregulation and frequently occurs in the absence of pneumonia history or bronchiectasis. This distinction between bronchiectasis and ILD has important consequences in the evaluation and management of lung disease in PAD. For example, treatment of ILD in PAD typically uses immunomodulatory approaches in addition to immunoglobulin replacement and antibiotic prophylaxis, which are the stalwarts of bronchiectasis management in these patients. Although all antibody-deficient patients are at risk of developing bronchiectasis, ILD occurs in some forms of PAD much more commonly than in others, suggesting that distinct but poorly understood immunological factors underlie the development of this complication. Importantly, ILD can have earlier onset and may worsen survival more than bronchiectasis. Further efforts to understand the pathogenesis of lung disease in PAD will provide vital information for the most effective methods of diagnosis, surveillance, and treatment of these patients.
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Affiliation(s)
- Edith Schussler
- Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Mary B Beasley
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Paul J Maglione
- Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
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27
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Intracranial abscess as a complication of X-linked agammaglobulinemia. Childs Nerv Syst 2016; 32:2049-2051. [PMID: 27550432 DOI: 10.1007/s00381-016-3219-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 08/08/2016] [Indexed: 11/26/2022]
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28
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Xu Y, Qing Q, Liu X, Chen S, Chen Z, Niu X, Tan Y, He W, Liu X, Li Y, Chen R, Chen L. Bruton's agammaglobulinemia in an adult male due to a novel mutation: a case report. J Thorac Dis 2016; 8:E1207-E1212. [PMID: 27867589 DOI: 10.21037/jtd.2016.10.12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
X-linked agammaglobulinemia (XLA) is caused by mutation in the gene coding for Bruton's tyrosine kinase (BTK), which impairs peripheral B cell maturation and hypogammaglobulinemia. In this report, we present a case of XLA in a 22-year-old adult male. Genetic testing revealed a novel mutation located at the conserved region (c.383T>C). The patient had a history of recurrent respiratory tract infection which eventually progressed to chronic type II respiratory failure. Several pathogenic bacteria were isolated on culture of respiratory secretions obtained on bronchoscopy. The patient improved on treatment with antibiotics.
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Affiliation(s)
- Yuanda Xu
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Qi Qing
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Xuesong Liu
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Sibei Chen
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Ziyi Chen
- Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xuefeng Niu
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Yaxia Tan
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Weiqun He
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Xiaoqing Liu
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Yimin Li
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Rongchang Chen
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China
| | - Ling Chen
- State Key Lab of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated to Guangzhou Medical University, Guangzhou 510120, China; ; Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
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29
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Singh S, Rawat A, Suri D, Gupta A, Garg R, Saikia B, Minz RW, Sehgal S, Chan KW, Lau YL, Kamae C, Honma K, Nakagawa N, Imai K, Nonoyama S, Oshima K, Mitsuiki N, Ohara O. X-linked agammaglobulinemia: Twenty years of single-center experience from North West India. Ann Allergy Asthma Immunol 2016; 117:405-411. [PMID: 27593100 DOI: 10.1016/j.anai.2016.07.044] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 07/27/2016] [Accepted: 07/30/2016] [Indexed: 12/29/2022]
Abstract
BACKGROUND X-linked agammaglobulinemia (XLA) is an X-linked genetic defect in maturation of B lymphocytes that results in the absence of B lymphocytes in the peripheral blood and profound hypogammaglobulinemia. It is caused by a mutation in the BTK gene located on the X chromosome. There are no large series describing XLA from the developing world. OBJECTIVE To analyze the clinical features, immunologic and genetic characteristics, and outcomes of 36 patients with XLA diagnosed and managed for a period of 2 decades. METHODS Diagnosis of XLA was made on the basis of presence of BTK gene mutation or marked reduction of B lymphocytes in peripheral blood with a family history of an affected male relative. The diagnosis was confirmed by genetic mutation studies in 28 patients with 25 unique mutations in the BTK gene. RESULTS There was a significant delay in diagnosis in most of the patients. The mean (SD) delay in the diagnosis was 4.2 (3.5) years. Point mutations were the most common mutations detected, accounting for 68% of all mutations. Deletions and insertions were also seen in a few cases. Four of the mutations are novel mutations that have not been previously reported. Seven of the 36 patients (19%) were dead at the time of analysis in the present cohort. The mean survival was 137 months (95% confidence interval, 13-163 months). CONCLUSION The present study is perhaps the largest series of patients with XLA from any developing country so far.
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Affiliation(s)
- Surjit Singh
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Amit Rawat
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | - Deepti Suri
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anju Gupta
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ravinder Garg
- Pediatric Allergy and Immunology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Biman Saikia
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ranjana Walker Minz
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shobha Sehgal
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Koon-Wing Chan
- Department of Pediatrics and Adolescent Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Yu Lung Lau
- Department of Pediatrics and Adolescent Medicine, Queen Mary Hospital, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Chikako Kamae
- Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Kenichi Honma
- Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Noriko Nakagawa
- Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Kohsuke Imai
- Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Shigeaki Nonoyama
- Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Koichi Oshima
- Kazusa DNA Research Institute, Kisarazu, Chiba, Japan
| | | | - Osamu Ohara
- Kazusa DNA Research Institute, Kisarazu, Chiba, Japan
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Chen XF, Wang WF, Zhang YD, Zhao W, Wu J, Chen TX. Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015). Medicine (Baltimore) 2016; 95:e4544. [PMID: 27512878 PMCID: PMC4985333 DOI: 10.1097/md.0000000000004544] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency. XLA patients typically present with very low numbers of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Most XLA patients carry mutations in Bruton tyrosine kinase (BTK) gene.The genetic background and clinical features of 174 Chinese patients with XLA were investigated. The relationship between specific BTK gene mutations and severity of clinical manifestations was also examined. Mutations were graded from mild to severe based on structural and functional prediction through bioinformatics analysis.One hundred twenty-seven mutations were identified in 142 patients from 124 families, including 45 novel mutations and 82 recurrent mutations that were distributed over the entire BTK gene sequence. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset.This report constitutes the largest group of patients with BTK mutations in China. A genotype-phenotype correlation was observed in this study. Early diagnosis of congenital agammaglobulinemia should be based on clinical symptoms, family history, and molecular analysis of the BTK gene.
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Affiliation(s)
- Xia-Fang Chen
- Department of Allergy and Immunology, Shanghai Children's Medical Center
- Division of Immunology, Institute of Pediatric Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Wei-Fan Wang
- Department of Allergy and Immunology, Shanghai Children's Medical Center
| | - Yi-Dan Zhang
- Department of Internal Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Wei Zhao
- Division of Allergy and Immunology, Department of Pediatrics, Virginia Commonwealth University, Richmond, VA
| | - Jing Wu
- Department of Allergy and Immunology, Shanghai Children's Medical Center
- Division of Immunology, Institute of Pediatric Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Tong-Xin Chen
- Department of Allergy and Immunology, Shanghai Children's Medical Center
- Division of Immunology, Institute of Pediatric Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai
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Bhattad S, Vignesh P, Rawat A, Suri D, Gupta A, Vyas S, Singh S. Spondylodiscitis in a Boy with X-linked Agammaglobulinemia: an Unusual Occurrence. J Clin Immunol 2016; 36:360-362. [PMID: 26961362 DOI: 10.1007/s10875-016-0261-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 03/01/2016] [Indexed: 10/22/2022]
Affiliation(s)
- Sagar Bhattad
- Paediatric Allergy & Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education & Research (PGIMER), Sector 12, Chandigarh, 160012, India
| | - Pandiarajan Vignesh
- Paediatric Allergy & Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education & Research (PGIMER), Sector 12, Chandigarh, 160012, India
| | - Amit Rawat
- Paediatric Allergy & Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education & Research (PGIMER), Sector 12, Chandigarh, 160012, India.
| | - Deepti Suri
- Paediatric Allergy & Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education & Research (PGIMER), Sector 12, Chandigarh, 160012, India
| | - Anju Gupta
- Paediatric Allergy & Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education & Research (PGIMER), Sector 12, Chandigarh, 160012, India
| | - Sameer Vyas
- Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Surjit Singh
- Paediatric Allergy & Immunology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education & Research (PGIMER), Sector 12, Chandigarh, 160012, India
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Flow Cytometry, a Versatile Tool for Diagnosis and Monitoring of Primary Immunodeficiencies. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2016; 23:254-71. [PMID: 26912782 DOI: 10.1128/cvi.00001-16] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Genetic defects of the immune system are referred to as primary immunodeficiencies (PIDs). These immunodeficiencies are clinically and immunologically heterogeneous and, therefore, pose a challenge not only for the clinician but also for the diagnostic immunologist. There are several methodological tools available for evaluation and monitoring of patients with PIDs, and of these tools, flow cytometry has gained prominence, both for phenotyping and functional assays. Flow cytometry allows real-time analysis of cellular composition, cell signaling, and other relevant immunological pathways, providing an accessible tool for rapid diagnostic and prognostic assessment. This minireview provides an overview of the use of flow cytometry in disease-specific diagnosis of PIDs, in addition to other broader applications, which include immune phenotyping and cellular functional measurements.
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Clinical and mutational features of X-linked agammaglobulinemia in Mexico. Clin Immunol 2016; 165:38-44. [PMID: 26960951 DOI: 10.1016/j.clim.2016.02.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 11/14/2015] [Accepted: 02/29/2016] [Indexed: 11/20/2022]
Abstract
X-linked agammaglobulinemia (XLA) is caused by BTK mutations, patients typically show <2% of peripheral B cells and reduced levels of all immunoglobulins; they suffer from recurrent infections of bacterial origin; however, viral infections, autoimmune-like diseases, and an increased risk of developing gastric cancer are also reported. In this work, we report the BTK mutations and clinical features of 12 patients diagnosed with XLA. Furthermore, a clinical revision is also presented for an additional cohort of previously reported patients with XLA. Four novel mutations were identified, one of these located in the previously reported mutation refractory SH3 domain. Clinical data support previous reports accounting for frequent respiratory, gastrointestinal tract infections and other symptoms such as the occurrence of reactive arthritis in 19.2% of the patients. An equal proportion of patients developed septic arthritis; missense mutations and mutations in SH1, SH2 and PH domains predominated in patients who developed arthritis.
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Aadam Z, Kechout N, Barakat A, Chan KW, Ben-Ali M, Ben-Mustapha I, Zidi F, Ailal F, Attal N, Doudou F, Abbadi MC, Kaddache C, Smati L, Touri N, Chemli J, Gargah T, Brini I, Bakhchane A, Charoute H, Jeddane L, El Atiqi S, El Hafidi N, Hida M, Saile R, Alj HS, Boukari R, Bejaoui M, Najib J, Barbouche MR, Lau YL, Mellouli F, Bousfiha AA. X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations. J Clin Immunol 2016; 36:187-94. [PMID: 26931785 DOI: 10.1007/s10875-016-0251-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 02/21/2016] [Indexed: 11/26/2022]
Abstract
PURPOSE X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. METHODS Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2% peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing. RESULTS We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5% vs. 85%). No strong evidence for genotype-phenotype correlation was observed. CONCLUSIONS This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.
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Affiliation(s)
- Zahra Aadam
- Laboratory of Biology and Health URAC34-Metabolic and Immunologic pathology Research Team, Faculty of Science of BenM'sik, King Hassan II University, Casablanca, Morocco
- Institut Pasteur, Human Molecular Genetic Laboratory, Casablanca, Morocco
| | - Nadia Kechout
- Department of Immunology, Institut Pasteur d'Algérie, Faculty of Medicine, Algiers, Algeria
| | - Abdelhamid Barakat
- Institut Pasteur, Human Molecular Genetic Laboratory, Casablanca, Morocco.
| | - Koon-Wing Chan
- Departments of Pediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Meriem Ben-Ali
- Laboratory of Transmission, Control and Immunobiology of Infections (LR11IPT02), Institut Pasteur de Tunis, and University Tunis El Manar, Tunis, Tunisia
| | - Imen Ben-Mustapha
- Laboratory of Transmission, Control and Immunobiology of Infections (LR11IPT02), Institut Pasteur de Tunis, and University Tunis El Manar, Tunis, Tunisia
| | - Fethi Zidi
- Department of Pediatrics, Regional Hospital of Tozeur, Tozeur, Tunisia
| | - Fatima Ailal
- Clinical Immunology Unit, Ibn Rochd Hospital, King Hassan II University-AinChok, Casablanca, Morocco
| | - Nabila Attal
- Department of Immunology, Institut Pasteur d'Algérie, Faculty of Medicine, Algiers, Algeria
| | - Fatouma Doudou
- Department of Immunology, Institut Pasteur d'Algérie, Faculty of Medicine, Algiers, Algeria
| | - Mohamed-Cherif Abbadi
- Department of Immunology, Institut Pasteur d'Algérie, Faculty of Medicine, Algiers, Algeria
| | | | - Leila Smati
- Department of Pediatrics, EPH Bologhine, Faculty of Medicine, Algiers, Algeria
| | - Nabila Touri
- Department of Pediatrics, CHU Blida, Blida, Algeria
| | - Jalel Chemli
- Department of Pediatrics, Sahloul Hospital, Sousse, Tunisia
| | - Tahar Gargah
- Department of Pediatrics, Charles Nicolle Hospital, Tunis, Tunisia
| | - Ines Brini
- Department of Pediatrics B, Children's Hospital of Tunis, Tunis, Tunisia
| | - Amina Bakhchane
- Institut Pasteur, Human Molecular Genetic Laboratory, Casablanca, Morocco
| | - Hicham Charoute
- Institut Pasteur, Human Molecular Genetic Laboratory, Casablanca, Morocco
| | - Leila Jeddane
- Clinical Immunology Unit, Ibn Rochd Hospital, King Hassan II University-AinChok, Casablanca, Morocco
| | - Sara El Atiqi
- Clinical Immunology Unit, Ibn Rochd Hospital, King Hassan II University-AinChok, Casablanca, Morocco
| | - Naïma El Hafidi
- Department of Pediatric Infectious Diseases, Avicenne University Hospital, Rabat, Morocco
| | - Mustapha Hida
- Department of Pediatrics, Hassan II University Hospital, Fez, Morocco
| | - Rachid Saile
- Laboratory of Biology and Health URAC34-Metabolic and Immunologic pathology Research Team, Faculty of Science of BenM'sik, King Hassan II University, Casablanca, Morocco
| | - Hanane Salih Alj
- Laboratory of Biology and Health URAC34-Metabolic and Immunologic pathology Research Team, Faculty of Science of BenM'sik, King Hassan II University, Casablanca, Morocco
| | - Rachida Boukari
- Department of Pediatrics, CHU Mustapaha Bacha, Faculty of Medicine, Algiers, Algeria
| | - Mohamed Bejaoui
- National Bone Marrow Transplantation Center, Jebel Lakhdar, Tunis, Tunisia
| | - Jilali Najib
- Clinical Immunology Unit, Ibn Rochd Hospital, King Hassan II University-AinChok, Casablanca, Morocco
| | - Mohamed-Ridha Barbouche
- Laboratory of Transmission, Control and Immunobiology of Infections (LR11IPT02), Institut Pasteur de Tunis, and University Tunis El Manar, Tunis, Tunisia
| | - Yu-Lung Lau
- Departments of Pediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Fethi Mellouli
- National Bone Marrow Transplantation Center, Jebel Lakhdar, Tunis, Tunisia
| | - Ahmed Aziz Bousfiha
- Clinical Immunology Unit, Ibn Rochd Hospital, King Hassan II University-AinChok, Casablanca, Morocco
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Abolhassani H, Vitali M, Lougaris V, Giliani S, Parvaneh N, Parvaneh L, Mirminachi B, Cheraghi T, Khazaei H, Mahdaviani SA, Kiaei F, Tavakolinia N, Mohammadi J, Negahdari B, Rezaei N, Hammarstrom L, Plebani A, Aghamohammadi A. Cohort of Iranian Patients with Congenital Agammaglobulinemia: Mutation Analysis and Novel Gene Defects. Expert Rev Clin Immunol 2016; 12:479-86. [DOI: 10.1586/1744666x.2016.1139451] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Preece K, Lear G. X-linked Agammaglobulinemia With Normal Immunoglobulin and Near-Normal Vaccine Seroconversion. Pediatrics 2015; 136:e1621-4. [PMID: 26527549 DOI: 10.1542/peds.2014-3907] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/30/2015] [Indexed: 11/24/2022] Open
Abstract
We present a 22-month-old boy with X-linked agammaglobulinemia masked by normal immunoglobulin levels and vaccine seroconversion. Diagnosis was made after strong clinical suspicion of immune deficiency led to identification of markedly reduced B-cell numbers and confirmation with identification of a novel Bruton tyrosine kinase gene mutation. He was commenced on replacement immunoglobulin therapy with excellent clinical improvement. This case highlights the variability of phenotypic presentation and apparent disunity between routine immunologic investigations and severe disease in X-linked agammaglobulinemia, necessitating clinical acumen to make the diagnosis.
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Affiliation(s)
- Kahn Preece
- Paediatric Immunology Department, Starship Children's Health, Auckland, New Zealand; and
| | - Graeme Lear
- Department of Paediatrics, Tairawhiti District Health, Gisborne, New Zealand
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37
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Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW, Bernstein DI, Blessing-Moore J, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol 2015; 136:1186-205.e1-78. [PMID: 26371839 DOI: 10.1016/j.jaci.2015.04.049] [Citation(s) in RCA: 434] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 04/18/2015] [Accepted: 04/23/2015] [Indexed: 02/07/2023]
Abstract
The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the "Practice parameter for the diagnosis and management of primary immunodeficiency." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.
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A novel BTK gene mutation creates a de-novo splice site in an X-linked agammaglobulinemia patient. Gene 2015; 560:245-8. [PMID: 25680287 DOI: 10.1016/j.gene.2015.02.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/30/2015] [Accepted: 02/08/2015] [Indexed: 11/21/2022]
Abstract
Bruton's tyrosine kinase (BTK), encoded by the BTK gene, is a cytoplasmic protein critical in B cell development. Mutations in the BTK gene cause X-linked agammaglobulinemia (XLA), a primary immunodeficiency with characteristically low or absent B cells and antibodies. This report describes a five year-old boy who presented with otitis externa, arthritis, reduced immunoglobulins and no B cells. Flow cytometry showed undetectable monocyte BTK expression. Sequencing revealed a novel mutation at exon 13 of the BTK gene which created a de novo splice site with a proximal 5 nucleotide loss resulting in a truncated BTK protein. The patient still suffered from ear infection despite intravenous immunoglobulin replacement therapy. In this study, mosaicism was seen only in the mother's genomic DNA. These results suggest that a combination of flow cytometry and BTK gene analysis is important for XLA diagnosis and carrier screening.
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39
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Clinical characteristics and outcomes of primary antibody deficiency: A 20-year follow-up study. J Formos Med Assoc 2014; 113:340-8. [DOI: 10.1016/j.jfma.2012.07.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 07/05/2012] [Accepted: 07/10/2012] [Indexed: 10/28/2022] Open
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López-Herrera G, Vargas-Hernández A, González-Serrano ME, Berrón-Ruiz L, Rodríguez-Alba JC, Espinosa-Rosales F, Santos-Argumedo L. Bruton's tyrosine kinase--an integral protein of B cell development that also has an essential role in the innate immune system. J Leukoc Biol 2013; 95:243-50. [PMID: 24249742 DOI: 10.1189/jlb.0513307] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Btk is the protein affected in XLA, a disease identified as a B cell differentiation defect. Btk is crucial for B cell differentiation and activation, but its role in other cells is not fully understood. This review focuses on the function of Btk in monocytes, neutrophils, and platelets and the receptors and signaling cascades in such cells with which Btk is associated.
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Affiliation(s)
- Gabriela López-Herrera
- 1.Col. Insurgentes Cuicuilco, Torre de Investigación 9o. piso, Mexico, D.F., Mexico 04530.
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Distribution, clinical features and molecular analysis of primary immunodeficiency diseases in Chinese children: a single-center study from 2005 to 2011. Pediatr Infect Dis J 2013; 32:1127-34. [PMID: 23673420 DOI: 10.1097/inf.0b013e31829aa9e9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
METHODS Two hundred three children with genetically proven primary immunodeficiency diseases (PIDs) from 197 unrelated families were enrolled from January 2005 to December 2011. RESULTS On the basis of criteria developed by the International Union of Immunological Societies, 79 patients were diagnosed as "other well-defined immunodeficiency syndromes" (38.9%), 62 (30.6%) with "predominant antibody deficiencies," 26 (12.8%) with "congenital defects of phagocyte," 25 (12.3%) with "T- and B-cell immunodeficiency" and 11 (5.4%) with "diseases of immune dysregulation." The median time to the diagnosis was 27.9 months and the patients had a wide range of clinical presentations. In addition, a total of 23 pathogenic genes were identified and 213 mutations were detected, including 42 novel mutations. CONCLUSIONS With the increase in the awareness of PIDs and diagnostic competence, more PID patients will be diagnosed and we will be able to more accurately identify the frequency and the distribution of PIDs in the most populous country in the world.
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Qin X, Jiang LP, Tang XM, Wang M, Liu EM, Zhao XD. Clinical features and mutation analysis of X-linked agammaglobulinemia in 20 Chinese patients. World J Pediatr 2013; 9:273-7. [PMID: 23335184 DOI: 10.1007/s12519-013-0400-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Accepted: 05/17/2012] [Indexed: 01/21/2023]
Abstract
BACKGROUND X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene mutation. XLA patients have an extremely small amount of peripheral B cells and profound deficiency in all immunoglobulin isotypes. We analyzed the clinical, immunologic, and molecular characteristics of children with XLA in an attempt to improve the diagnosis and treatment of XLA in China. METHODS Twenty children with XLA-compatible phenotypes from 18 unrelated families were enrolled in this study. The BTK gene was amplified and sequenced, followed by mutation analysis in these children and their female relatives. RESULTS Eighteen different mutations of the BTK gene were identified in the 20 patients. Eleven mutations had been reported previously including eight missense mutations (c.994C>T, c.1987C>A, c.1885G>T, c.502T>C, c.1085C>T, c.1816C>T, c.214C>T, c.1912G>A) and three nonsense mutations (c.1267T>A, c.1793C>G, c.1618C>T). Seven novel mutations of the BTK gene were also presented and included five missense mutations (c.134T>A, c.1646T>A, c.1829C>G, c.711G>T, c.1235G>A), one splice-site mutation (c.523+1G>A) and one insertion mutation (c.1024-1025in sTTGCTAAAGCAACTGCTAAAGCAAG). Eight out of 18 mutations of the BTK gene were located in the TK domain, 4 in the PH domain, 4 in the SH2 domain and 2 in the TH domain. Genetic study for carrier status was carried out in 18 families with definite BTK gene mutations. Nine carriers with BTK gene mutations were identified. Six families without carriers were detected, and 3 patients were not tested in this study. CONCLUSION Our results support that molecular genetic testing represents an important tool for early confirmed diagnosis of congenital agammaglobulinemia and may allow accurate carrier detection and prenatal diagnosis.
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Affiliation(s)
- Xian Qin
- Division of Immunology, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
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Yao CM, Han XH, Zhang YD, Zhang H, Jin YY, Cao RM, Wang X, Liu QH, Zhao W, Chen TX. Clinical characteristics and genetic profiles of 44 patients with severe combined immunodeficiency (SCID): report from Shanghai, China (2004-2011). J Clin Immunol 2012; 33:526-39. [PMID: 23250629 DOI: 10.1007/s10875-012-9854-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Accepted: 12/09/2012] [Indexed: 01/18/2023]
Abstract
Severe combined immunodeficiency (SCID), a rare type of genetic associated immune disorder, is poorly characterized in mainland China. We retrospectively reviewed 44 patients with SCID who received treatment from 2004 to 2011 in Shanghai, China, and herein summarize their clinical manifestations and immunological and preliminary genetic features. The male-to-female ratio was 10:1. Twenty five patients presented with X-SCID symptoms. Only one patient was diagnosed before the onset of symptoms due to positive family history. The mean time of delay in the diagnosis of X-SCID was 2.69 months (range, 0.5-8.67). Thirty-seven of the 44 patients died by the end of 2011 with the mean age of death being 7.87 months (range, 1.33-31). Six patients received hematopoietic stem cell transplantation (HSCT); only one of them survived, who was transplanted twice. The time between onset and death was shorter in the HSCT-treated group compared with the untreated group (2.87 ± 1.28 and 3.34 ± 0.59 months, respectively), probably due to active infections during transplantation. Bacillus Calmette-Guérin (BCG) complications occurred in 14 of the 34 patients who received BCG vaccination. Transfusion-induced graft-versus-host disease occurred in 5 patients. Total 20 mutations in interleukin-2 receptor subunit gamma (IL2RG) were identified in 22 patients, including 11 novel mutations. Most patients were misdiagnosed before referred to our SCID Center. Therefore, establishing more diagnostic centers dedicated to the care of PID and accessible by primary immunodeficiency patients will facilitate early, correct diagnosis and better care of SCID in China.
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Affiliation(s)
- Chun-Mei Yao
- Department of Pediatrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 20092, China
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Dendritic and T cell response to influenza is normal in the patients with X-linked agammaglobulinemia. J Clin Immunol 2012; 32:421-9. [PMID: 22289994 PMCID: PMC3350625 DOI: 10.1007/s10875-011-9639-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2011] [Accepted: 12/20/2011] [Indexed: 12/22/2022]
Abstract
Introduction Influenza virus is a potential cause of severe disease in the immunocompromised. X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by the lack of immunoglobulin, B cells, and plasma cells, secondary to mutation in Bruton’s tyrosine kinase (Btk) gene. Btk is expressed in both B and dendritic cells (DC). However, little is known about the immune response of DC and T cells to influenza virus in XLA patients. Methods The in vitro maturation and antigen presenting function of monocyte-derived immature DC (imDC) from 12 XLA patients and 23 age-matched normal controls in response to influenza virus were examined. Influenza virus-specific CD4 and CD8 T cell responses in the patients and controls were further determined after administration of inactivated trivalent influenza vaccine. Results imDC from XLA patients had normal maturation based on major histocompatibility complex (MHC)-I, MHC-II, CD83 and CD86 expression, and interferon (IFN)-α and interleukin-12 production upon influenza virus stimulation. They also had a normal capacity to induce allogeneic T cell proliferation in response to influenza virus. TIV was well tolerated in XLA patients. Influenza virus-specific CD4+IFN-γ+ and CD8+ IFN-γ+ T cells and HLA-A2/M158–66-tetramer+ CTLs could be induced by TIV in XLA patients, and the levels and duration of maintaining these virus-specific cells in XLA patients are comparable to that in normal controls. Conclusion We demonstrated for the first time that XLA patients have fully competent DC and T cell immune responses to influenza virus. TIV is safe and could be an option for providing T cell-mediated protection against influenza virus infection in XLA patients.
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Lee PPW, Lau YL. Improving care, education, and research: the Asian primary immunodeficiency network. Ann N Y Acad Sci 2012; 1238:33-41. [PMID: 22129051 DOI: 10.1111/j.1749-6632.2011.06225.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The field of primary immunodeficiencies (PIDs) is marked by continuous discoveries in the mechanisms of disease, genetic etiologies, and treatments. A widening gap between cutting-edge scientific research and its translation to clinical practice is noticeable. To narrow this gap, collaborative networks must be made that bring together a critical mass of specialists to share the knowledge required for the next innovations. In this paper, we describe the current status of the Asian primary immunodeficiency network, which links 40 hospitals in China and Southeast Asia. Over the past 10 years, genetic studies performed on more than 500 patients have led to genetic confirmation of primary immunodeficiency in 272 patients, as well as generating cohort studies that have provided unique phenotypic observations. The network has a dynamic capacity to accommodate priorities and interests of collaborating units, from consultations and genetic testing to scientific research involving next-generation sequencing technologies.
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Affiliation(s)
- Pamela Pui-Wah Lee
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, China
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Al-Herz W, Moussa MAA. Survival and predictors of death among primary immunodeficient patients: a registry-based study. J Clin Immunol 2011; 32:467-73. [PMID: 22205205 DOI: 10.1007/s10875-011-9636-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Accepted: 12/13/2011] [Indexed: 11/30/2022]
Abstract
PURPOSES The aims of this study were to investigate survival among patients with primary immunodeficiency disorders (PID) in Kuwait and to determine whether certain variables were associated with increased risk of death. METHODS The data of 176 patients (98 males and 78 females) were extracted from the Kuwait National Primary Immunodeficiency Disorders Registry and the observation period was from January 2004 to July 2011. RESULTS The distribution of the reported patients was combined T- and B-cell immunodeficiencies (30.1%), predominantly antibody immunodeficiency (19.9%), other well-defined immunodeficiencies (25%), diseases of immune dysregulation (14.8%), congenital defects of phagocyte number, function or both (6.25%), and complement deficiencies (4.0%). In a total of 619.1 patient-years at risk, 48 patients died (mortality incidence rate 77.53 per 1,000 person-years). The overall survival in the studied cohort was 72.7% (72.4% for males and 73.1% for females). The most common cause of death was sepsis (46%) followed by pneumonia (29%). The probabilities that a patient survived 2, 4, and 6 years after onset of symptoms were 76%, 73%, and 69%, respectively. The variables that were found to be predictors for death are parental consanguinity, sepsis, adenovirus and CMV infections, failure to thrive, PID category, and onset age <6 months. CONCLUSIONS Patients with PID have decreased probabilities of survival that are variable between PID categories. Early diagnosis and aggressive therapeutic interventions specifically of patients with history of the variables associated with increased risk of death may help increase their chance of survival.
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Affiliation(s)
- Waleed Al-Herz
- Department of Pediatrics, Faculty of Medicine, Kuwait University, 24923 Safat, Zip code 13110, Kuwait, Kuwait.
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Zhang ZY, Zhao XD, Jiang LP, Liu EM, Wang M, Yu J, Liu P, Yang XQ. Clinical characteristics and molecular analysis of 21 Chinese children with congenital agammaglobulinemia. Scand J Immunol 2011; 72:454-9. [PMID: 21039741 DOI: 10.1111/j.1365-3083.2010.02457.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Congenital agammaglobulinemia is a humoral primary immunodeficiency and affected patients have extremely low levels of peripheral B cells and profound deficiency of all immunoglobulin isotypes. Mutations of the Bruton's tyrosine kinase (BTK) gene are responsible for most of the congenital agammaglobulinemia. In this study, the phenotypes of congenital agammaglobulinemia were investigated in 21 male children from 21 unrelated Chinese families. Sixteen different mutations of BTK gene were identified in 18 patients, and three patients did not have BTK gene mutations. Nine mutations had been reported previously including one gross deletion (c.722_2041del), one missense mutation (c.1764G>T), three non-sense mutations (c.194C>A, c.895C>T and c.1821G>A) and four invariant splice-site mutations (c.971+2T>C, c.1481+2T>A, c.1482-2A>G, c.1699-2A>G). Seven novel mutations were identified (c.373_441del, c. 504delG, c.537delC, c.851delA, c.1637G>A, c.1879T>C and c. 1482_1882 del). Ten of the eighteen mutations of BTK gene were located in the TK domain, four in the PH domain, three in the SH3 domain and one spanned the TH, SH3, SH2 and TK domain. Candidate genes of autosomal-recessive agammaglobulinemia, including IGHM, CD79a, CD79b and IGLL1, were screened in three patients without mutations in the BTK gene. A compound heterozygosity mutation in the IGHM gene (c.1956G>A, c.175_176insC) was identified in one patient. The results of our study further support that molecular genetic testing represents an important tool for early confirmed diagnosis of congenital agammaglobulinemia and may allow accurate carrier detection and prenatal diagnosis.
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Affiliation(s)
- Z-Y Zhang
- Division of Immunology, Children's Hospital, Chongqing Medical University, Chongqing, China
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Wang LL, Jin YY, Hao YQ, Wang JJ, Yao CM, Wang X, Cao RM, Zhang H, Chen Y, Chen TX. Distribution and Clinical Features of Primary Immunodeficiency Diseases in Chinese Children (2004–2009). J Clin Immunol 2011; 31:297-308. [DOI: 10.1007/s10875-010-9493-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2010] [Accepted: 12/02/2010] [Indexed: 12/18/2022]
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