Activated phosphoinositide 3-kinase delta syndrome: Pathogenesis, clinical manifestations, and treatment

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an autosomal dominant inborn errors of immunity resulting from gain of function mutations in the PIK3CD gene or loss of function mutations in the PIK3R1 gene. These mutations lead to hyperactivation of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) signaling pathways, causing complex deficiencies in cellular and humoral immunity. APDS patients exhibit diverse clinical manifestations including recurrent respiratory infections, nonneoplastic lymphoproliferation, an increasing risk of malignancy, and autoimmune diseases. Neurodevelopmental abnormalities, short stature, failure to thrive, and psychological disorders are also observed. Management strategies for APDS involve antibiotic prophylaxis and immunoglobulin replacement therapy, immunosuppressive therapies, and hematopoietic stem cell transplantation for severe cases. Targeted therapies, such as the mTOR inhibitor sirolimus and the elective Phosphoinositide 3-kinase delta inhibitor leniolisib, have emerged as promising options, demonstrating both safety and effectiveness. Continuous monitoring and further research are essential to optimize treatment strategies and understand the long-term implications of these interventions. This review aims to summarize the pathogenesis, clinical manifestations, and treatment of APDS.