Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review

Clin Rev Allergy Immunol. 2020 Dec;59(3):323-333. doi: 10.1007/s12016-019-08738-9.


Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively. Patients with APDS present a spectrum of clinical manifestations, particularly recurrent respiratory infections and lymphoproliferation. We searched PubMed, Web of Science, and Scopus databases for APDS patients and screened for eligibility criteria. A total of 243 APDS patients were identified from 55 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. Overall, 179 APDS1 and 64 APDS2 patients were identified. The most common clinical manifestations were respiratory tract infections (pneumonia (43.6%), otitis media (28.8%), and sinusitis (25.9%)), lymphoproliferation (70.4%), autoimmunity (28%), enteropathy (26.7%), failure to thrive (20.6%), and malignancy (12.8%). The predominant immunologic phenotype was hyper-IgM syndrome (48.1%). Immunologic profiling showed decreased B cells in 74.8% and CD4+ T cells in 64.8% of APDS patients. The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations. The majority of APDS patients were placed on long-term immunoglobulin replacement therapy. Immunosuppressive agents such as rituximab, tacrolimus, rapamycin, and leniolisib were also administered for autoimmunity and inflammatory complications. In addition, hematopoietic stem cell transplantation (HSCT) was used in 12.8% of patients. APDS has heterogynous clinical manifestations. It should be suspected in patients with history of recurrent respiratory infections, lymphoproliferation, and raised IgM levels. Moreover, HSCT should be considered in patients with severe and complicated clinical manifestations with no or insufficient response to the conventional therapies.

Keywords: APDS; Activated phosphoinositide 3-kinase δ syndrome; Hyper-IgM syndrome; Phosphoinositide-3-kinase δ.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adolescent
  • Adult
  • Autoimmunity
  • Biomarkers
  • Child
  • Class I Phosphatidylinositol 3-Kinases / genetics*
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Disease Susceptibility*
  • Female
  • Gain of Function Mutation
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Phenotype*
  • Primary Immunodeficiency Diseases / diagnosis*
  • Primary Immunodeficiency Diseases / epidemiology
  • Primary Immunodeficiency Diseases / etiology*
  • Young Adult


  • Biomarkers
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human

Supplementary concepts

  • Activated PI3K-delta Syndrome