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J Allergy Clin Immunol. 2017 Feb;139(2):597-606.e4. doi: 10.1016/j.jaci.2016.06.021. Epub 2016 Jul 16.

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

Author information

1
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.
2
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.
3
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Northern England Haemato-Oncology Diagnostic Service, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
4
Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
5
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
6
Department of Radiology, Papworth Hospital NHS Foundation Trust, Papworth Everard Hospital, Cambridge, United Kingdom.
7
Department of Pathology, Western General Hospital, Edinburgh, United Kingdom.
8
Raigmore Hospital, Inverness, United Kingdom.
9
Regional Immunology Service, The Royal Hospitals, Belfast, United Kingdom.
10
Department of Paediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
11
Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom; National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
12
Papworth Hospital NHS trust, Papworth Everard, Cambridge, United Kingdom.
13
Department of Infectious Disease and Immunology, University Hospitals Bristol NHS Foundation Trust, Bristol Royal Hospital for Children, Bristol, United Kingdom.
14
Barts Health NHS Trust, London, United Kingdom.
15
Center for Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany.
16
Center for Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany; Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany.
17
Institute of Immunology, University Hospital Motol, Prague, Czech Republic.
18
Faculty of Medicine and Institute of Life Sciences, University of Southampton, Southampton, United Kingdom; NIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
19
Faculty of Medicine and Institute of Life Sciences, University of Southampton, Southampton, United Kingdom.
20
Department of Immunology, Epsom & St Helier University Hospitals NHS Trust, Surrey, United Kingdom.
21
Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
22
Department of Royal Hospital for Children, Glasgow, United Kingdom.
23
Department of Pathology, Queen Elizabeth University Hospital, Glasgow, United Kingdom.
24
Royal Aberdeen Childrens' Hospital, Aberdeen, United Kingdom.
25
Department of Pediatrics, Ospedale Pediatrico Bambino Gesù and University of Rome "Tor Vergata", Rome, Italy.
26
Department of Immunology, School of Medicine, Trinity College, Dublin, and St James's Hospital, Dublin, Ireland.
27
Department of Immunology, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom.
28
Department of Community Pediatrics, Perinatal and Maternal Medicine Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
29
King's College London, King's Health Partners, King's College Hospital NHS Foundation Trust, School of Medicine, Division of Asthma, Allergy & Lung Biology, Department of Immunological Medicine, London, United Kingdom.
30
Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia.
31
Department of Paediatric Immunology, Newcastle upon Tyne hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom.
32
Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France.
33
Unité d'Onco-hémato-immunologie Pédiatrique, CHU Angers, Angers, France; Centre de Référence Déficits Immunitaires Héréditaires, AP-HP, Paris, France; Inserm UMR 892, Angers, France; CNRS UMR 6299, Angers, France.
34
Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France; Department of Pediatric Immunology, Hematology and Rheumatology, AP-HP, Necker Children's Hospital, Paris, France; Collège de France, Paris, France.
35
Départment de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France.
36
Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Department of Pediatric Immunology, Hematology and Rheumatology, AP-HP, Necker Children's Hospital, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Children's Hospital, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Howard Hughes Medical Institute, Chevy Chase, Md.
37
University College London Institute of Immunity and Transplantation, London, United Kingdom.
38
Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom.
39
Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, United Kingdom.
40
Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Department of Pediatric Immunology, Hematology and Rheumatology, AP-HP, Necker Children's Hospital, Paris, France.
41
UCL Cancer Institute, University College London, London, United Kingdom.
42
Lymphocyte Signalling & Development, Babraham Institute, Cambridge, United Kingdom.
43
Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France; Department of Pediatric Immunology, Hematology and Rheumatology, AP-HP, Necker Children's Hospital, Paris, France; Centre de Référence Déficits Immunitaires Héréditaires, AP-HP, Paris, France; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Children's Hospital, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY.
44
Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom. Electronic address: a.m.condliffe@sheffield.ac.uk.

Abstract

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.

KEYWORDS:

Activated phosphoinositide 3-kinase δ syndrome; PIK3CD gene; bronchiectasis; hematopoietic stem cell transplantation; immunodeficiency; p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency; phosphoinositide 3-kinase inhibitor; phosphoinositide 3-kinase δ

PMID:
27555459
PMCID:
PMC5292996
DOI:
10.1016/j.jaci.2016.06.021
[Indexed for MEDLINE]
Free PMC Article

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