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Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study
TI. Coulter, A. Chandra, CM. Bacon, J. Babar, J. Curtis, N. Screaton, JR. Goodlad, G. Farmer, CL. Steele, TR. Leahy, R. Doffinger, H. Baxendale, J. Bernatoniene, JD. Edgar, HJ. Longhurst, S. Ehl, C. Speckmann, B. Grimbacher, A. Sediva, T. Milota,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
- MeSH
- analýza přežití MeSH
- antibiotická profylaxe MeSH
- dítě MeSH
- dospělí MeSH
- fosfatidylinositol-3-kinasy třídy I antagonisté a inhibitory genetika MeSH
- herpetické infekce genetika mortalita terapie MeSH
- infekce dýchací soustavy genetika mortalita terapie MeSH
- inhibitory enzymů terapeutické užití MeSH
- intravenózní imunoglobuliny terapeutické užití MeSH
- kohortové studie MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfoproliferativní nemoci genetika mortalita terapie MeSH
- mezinárodní spolupráce MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace genetika MeSH
- myši MeSH
- předškolní dítě MeSH
- průzkumy a dotazníky MeSH
- recidiva MeSH
- syndromy imunologické nedostatečnosti genetika mortalita terapie MeSH
- transplantace hematopoetických kmenových buněk MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
Barts Health NHS Trust London United Kingdom
Center for Chronic Immunodeficiency University Hospital Freiburg Freiburg Germany
Centre de Référence Déficits Immunitaires Héréditaires AP HP Paris France
Collège de France Paris France
Department of Clinical Biochemistry and Immunology Addenbrooke's Hospital Cambridge United Kingdom
Department of Clinical Immunology and Allergy St James's University Hospital Leeds United Kingdom
Department of Immunology Epsom and St Helier University Hospitals NHS Trust Surrey United Kingdom
Department of Immunology Great Ormond Street Hospital NHS Foundation Trust London United Kingdom
Department of Medicine University of Cambridge Cambridge United Kingdom
Department of Pathology Queen Elizabeth University Hospital Glasgow United Kingdom
Department of Pathology Western General Hospital Edinburgh United Kingdom
Department of Pediatrics and Adolescent Medicine University Medical Center Freiburg Germany
Department of Radiology Cambridge University Hospitals NHS Foundation Trust Cambridge United Kingdom
Department of Royal Hospital for Children Glasgow United Kingdom
Howard Hughes Medical Institute Chevy Chase Md
Institute of Immunology University Hospital Motol Prague Czech Republic
Lymphocyte Signalling and Development Babraham Institute Cambridge United Kingdom
National Institute for Health Research Cambridge Biomedical Research Centre Cambridge United Kingdom
Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne United Kingdom
Papworth Hospital NHS trust Papworth Everard Cambridge United Kingdom
Raigmore Hospital Inverness United Kingdom
Regional Immunology Service The Royal Hospitals Belfast United Kingdom
Royal Aberdeen Childrens' Hospital Aberdeen United Kingdom
UCL Cancer Institute University College London London United Kingdom
Unité d'Onco hémato immunologie Pédiatrique CHU Angers Angers France
Université Paris Descartes Sorbonne Paris Cité Institut Imagine Paris France
University College London Institute of Immunity and Transplantation London United Kingdom
Citace poskytuje Crossref.org
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- $a Coulter, Tanya I $u Department of Immunology, School of Medicine, Trinity College, Dublin, and St James's Hospital, Dublin, Ireland; Department of Paediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
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- $a Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study / $c TI. Coulter, A. Chandra, CM. Bacon, J. Babar, J. Curtis, N. Screaton, JR. Goodlad, G. Farmer, CL. Steele, TR. Leahy, R. Doffinger, H. Baxendale, J. Bernatoniene, JD. Edgar, HJ. Longhurst, S. Ehl, C. Speckmann, B. Grimbacher, A. Sediva, T. Milota, SN. Faust, AP. Williams, G. Hayman, ZY. Kucuk, R. Hague, P. French, R. Brooker, P. Forsyth, R. Herriot, C. Cancrini, P. Palma, P. Ariganello, N. Conlon, C. Feighery, PJ. Gavin, A. Jones, K. Imai, MA. Ibrahim, G. Markelj, M. Abinun, F. Rieux-Laucat, S. Latour, I. Pellier, A. Fischer, F. Touzot, JL. Casanova, A. Durandy, SO. Burns, S. Savic, DS. Kumararatne, D. Moshous, S. Kracker, B. Vanhaesebroeck, K. Okkenhaug, C. Picard, S. Nejentsev, AM. Condliffe, AJ. Cant,
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- $a BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.
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- $a Chandra, Anita $u Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom; Lymphocyte Signalling & Development, Babraham Institute, Cambridge, United Kingdom; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
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- 700 1_
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- 700 1_
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- 700 1_
- $a Williams, Anthony P $u Faculty of Medicine and Institute of Life Sciences, University of Southampton, Southampton, United Kingdom.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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