A rare case report of activated PI3K delta syndrome (APDS): diagnostic pitfalls

Activated PI3Kδ Syndrome (APDS) is a rare inborn error of immunity characterized by recurrent infections, lymphoproliferation, and autoimmunity. It results from mutations in the phosphoinositide 3-kinase delta (PI3Kδ) signalling pathway, leading to either gain-of-function (APDS1) or loss-of-function (APDS2) phenotypes. Clinical presentation ranges from asymptomatic to severe, depending on the underlying genetic defect. Malignancy, particularly lymphoma, represents the most frequent and life-threatening complication. Due to overlapping features with other primary immunodeficiencies, APDS is often misdiagnosed as combined immunodeficiency. Early molecular testing, particularly genetic analysis, is therefore crucial for accurate diagnosis. Although management remains complex and heterogeneous, there is growing interest in targeted approaches, particularly PI3Kδ-specific therapy.

We describe a 12-year-old boy with recurrent respiratory and ear infections since infancy, accompanied by persistent lymphadenopathy, hepatosplenomegaly, and thrombocytopenia. Initial immunological evaluation suggested combined immunodeficiency, and prophylactic antibiotics were initiated, but genetic testing was deferred due to mild clinical features and parental reluctance. Following multiple years of enduring symptoms, genetic investigation identified a PIK3CD mutation leading in a missense alteration p.Glu1021Lys, confirming APDS 1. The patient was subsequently commenced on immunoglobulin replacement therapy and consulted for consideration of immunosuppressive and targeted pathway blocker therapy.

This case highlights the diagnostic challenges of APDS, arising from both overlapping clinical features with other immunodeficiencies and external factors such as cost and parental decision-making. Early genetic testing facilitates accurate diagnosis, and timely recognition of APDS enables appropriate management, including immunosuppressive, targeted therapies and, in selected cases, potentially curative hematopoietic stem cell transplantation.