PIK3CD – Activated Phosphoinositide 3-Kinase Delta Syndrome

Activated phosphoinositide 3-kinase delta syndrome (APDS1) is a primary immunodeficiency 14 caused by heterozygous gain-of-function variants in PIK3CD, encoding the leukocyte-restricted p110δ catalytic subunit of class IA PI3Ks. APDS1 follows an autosomal dominant inheritance pattern and manifests with recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and increased lymphoma risk. Diagnostic confirmation relies on genetic testing and functional assays demonstrating hyperactivation of PI3K-AKT signaling.

A systematic review identified 351 unique APDS1 patients harboring 39 distinct pathogenic PIK3CD variants, including recurrent hotspot mutations such as c.3061G>A (p.Glu1021Lys) observed in multiple unrelated probands (PMID:39636570). Most variants cluster within the helical and kinase domains, underscoring critical regulatory regions. Additional cohort studies reported familial aggregation in affected siblings and multigenerational lineages, supporting dominant segregation (PMID:26437962).

Clinically, APDS1 patients present in infancy or early childhood with recurrent respiratory tract infections (HP:0005425), lymphadenopathy, hepatosplenomegaly, and variable autoimmunity including cytopenias and vasculitis. Viral infections such as EBV and CMV are common, and up to 12% develop lymphoma, with Hodgkin lymphoma reported in case series (PMID:31033788). Immunologic profiling reveals elevated IgM, reduced class-switched memory B cells, CD4 lymphopenia, and skewed T cell differentiation.

Mechanistic studies demonstrate that APDS1 mutations disrupt inhibitory interactions within p110δ, leading to 2- to >300-fold basal kinase activation, augmented PIP3 production, and downstream AKT/mTOR/S6 hyperphosphorylation in patient lymphocytes (PMID:28167755). Murine knock-in models recapitulate human immunologic and neurodevelopmental phenotypes, validating disease causality. Functional assays using flow cytometry for phospho-Akt/S6 reliably distinguish APDS1 from other immunodeficiencies and correlate with genotype (PMID:39620215).

Targeted therapy with selective PI3Kδ inhibitors (idelalisib, leniolisib) effectively normalizes signaling, ameliorates lymphoproliferation, and resolves refractory vasculitis. Hematopoietic stem cell transplantation offers curative potential in severe or treatment-refractory cases. Early genetic diagnosis and intervention are critical given substantial diagnostic delays (mean 10.6 years) and elevated morbidity and mortality from infections and malignancy.

Key Take-home: Heterozygous PIK3CD gain-of-function mutations cause autosomal dominant APDS1, a definitive gene-disease association with robust genetic and experimental evidence; timely molecular diagnosis and PI3Kδ-targeted therapies markedly improve patient outcomes.

References

• Advances in therapy • 2025 • Genetic Etiologies and Outcomes in Malignancy and Mortality in Activated Phosphoinositide 3-Kinase Delta Syndrome: A Systematic Review. PMID:39636570
• Proceedings of the National Academy of Sciences of the United States of America • 2017 • Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1. PMID:28167755
• Frontiers in immunology • 2018 • Activated PI3 Kinase Delta Syndrome: From Genetics to Therapy. PMID:29535736
• Journal of pediatric hematology/oncology • 2020 • A Rare Case of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) Presenting With Hemophagocytosis Complicated With Hodgkin Lymphoma. PMID:31033788
• Clinical and experimental immunology • 2016 • Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency. PMID:26437962

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