Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
No Canadian affiliation. An affiliation-only frame — the usual design — would never have seen this work. It is one of the works that make the case for inverting the frame.
Machine scores (provisional)
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
- Teacher spread
- 0.272 · how far apart the two teachers sit on this one work
- Validation status
score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
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.
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The record
- Venue
- Journal of Allergy and Clinical Immunology
- Topic
- Immunodeficiency and Autoimmune Disorders
- Field
- Immunology and Microbiology
- Canadian institutions
- —
- Funders
- NIHR Sheffield Biomedical Research CentreNIHR Cambridge Biomedical Research CentreMedical Research CouncilNovartis Institutes for BioMedical ResearchUniversity College London Hospitals NHS Foundation TrustKing's College LondonCentre National de la Recherche ScientifiqueLigue Contre le CancerBundesministerium für Bildung und ForschungCSL BehringNational Institute for Health and Care ResearchUniversity of CambridgeBiotechnology and Biological Sciences Research CouncilUniversity College LondonWellcome TrustCancer Research UKImmunodeficiency CanadaFondation ARC pour la Recherche sur le CancerGrifolsAgence Nationale de la RechercheRegeneron PharmaceuticalsJapan Blood Products OrganizationDeutsches Zentrum für InfektionsforschungDeutsche ForschungsgemeinschaftDirectorate for Biological SciencesGlaxoSmithKlinePfizerBiogenEuropean CommissionSanofiBaxaltaGenentechBritish Lung Foundation
- Keywords
- CohortMedicinePhosphoinositide 3-kinaseInternal medicinePI3K/AKT/mTOR pathwaySignal transductionBiologyGenetics
- Has abstract in OpenAlex
- yes