Activated PI3K Delta Syndrome: A Case Presentation and Literature Review

Activated PI3K delta syndrome (APDS) is a rare primary immunodeficiency caused by gain-of-function (GOF) mutations in <i>PIK3CD</i> or <i>PIK3R1</i>, leading to immune dysregulation. It typically presents with recurrent respiratory infections, lymphoproliferation, autoimmunity, and increased risk of malignancy. Although gastrointestinal involvement has been described, it is less frequent and often underrecognized. To our knowledge, this is the first genetically confirmed case of APDS in Mexico, highlighting an atypical presentation with significant gastrointestinal symptoms. This case underscores the challenges in diagnosing APDS in settings with limited access to genetic testing and emphasizes the importance of early recognition in patients with complex infectious and inflammatory histories. A four-year-old male presented with chronic diarrhea, failure to thrive, and recurrent respiratory infections since infancy. Clinical evaluation revealed hepatosplenomegaly, generalized lymphadenopathy, severe malnutrition, and infections with <i>Pseudomonas aeruginosa</i>, <i>Clostridium difficile,</i> and parainfluenza virus. Endoscopic findings included malakoplakia and <i>Helicobacter pylori</i> gastritis. A multigene panel identified a heterozygous pathogenic variant in <i>PIK3CD</i> (c.3061G>A, p.Glu1021Lys), confirming APDS1. Additionally, a risk variant in <i>NOD2</i> was detected, which may have contributed to the gastrointestinal phenotype. The patient was managed with immunoglobulin replacement, antimicrobial prophylaxis, and multidisciplinary care, leading to clinical improvement. This case illustrates the variable presentation of APDS and highlights the importance of including primary immunodeficiencies in the differential diagnosis of children with recurrent infections and gastrointestinal manifestations. Early genetic confirmation facilitates tailored management and improves outcomes. Future research should explore genotype-phenotype correlations, especially in patients with multiple genetic variants, and assess the long-term benefits of targeted therapies such as PI3Kδ inhibitors.