Genetic Etiologies and Outcomes in Malignancy and Mortality in Activated Phosphoinositide 3-Kinase Delta Syndrome: A Systematic Review.

Introduction: This analysis evaluated literature on patients with activated phosphoinositide 3-kinase delta syndrome (APDS) to better understand the genetic etiologies and occurrence of mortality in this population.

Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach, including all articles published in English prior to March 13, 2023, in PubMed and Embase. Patients included in the study had reported either (1) APDS diagnosis or (2) ≥ 1 clinical sign consistent with APDS and a first-degree relative with genetically confirmed APDS. Reported age at last observation was also a required outcome. Publications not meeting these criteria were excluded. Data were summarized using descriptive statistics.

Results: The search identified 108 publications describing 351 unique patients with 39 distinct disease-causing variants. Among these, 41 (12%) deaths were reported, with a mean age at last follow-up of 19.6 (range, 1-64) years. A cause of death was reported for 80% (33/41) of deaths; lymphoma (24%, 10/41) and infections (22%, 9/41) were the most common causes. Types of infections causing death were severe uncontrollable infections (n = 3), sepsis (n = 2), viral infection (varicella zoster pneumonitis [n = 1], cytomegalovirus and adenovirus [n = 1], and Epstein-Barr virus [n = 1]), and infection (n = 1). Mean age at death for lymphoma was 24.9 (range, 1-41) years, and all nine patients who died from infections died before the age of 15 years. The mean age at first APDS symptom was 2.0 (range, < 1-22) years, and mean age at APDS diagnosis was 13.4 (range, 0-56) years; the mean time between symptoms and diagnosis was 10.6 (range, 0-44) years. Limitations of the study were primarily related to the data source.

Conclusion: Patients with APDS suffer early mortality, largely from lymphoma and infection, with large time gaps between symptoms and diagnosis. These findings highlight the need for improved diagnostics, earlier genetic testing for APDS, increased awareness of familial testing, and targeted therapies.