Immunodeficiency: primary or acquired
Common Variable Immunodeficiency (CVID) affects about 1 in 25,000 people and causes impaired B cell differentiation, hypogammaglobulinemia, poor vaccine response, recurrent infections, lung/GI disease, autoimmunity, and susceptibility to lymphoma. Activated PI3Kδ Syndrome (APDS) is one of the most common forms of monogenic CVID. It is caused by heterozygous, gain-of-function mutations in the leukocyte-restricted p110δ PI3K (PIK3CD) or its binding partner p85α (PIK3R1) and leads to hyperactivation of the PI3K pathway. This causes increased effector cell differentiation, lymphoproliferative burst, CD8 T cell senescence, decreased memory T cell function and decreased control of EBV/CMV. Patients have recurrent bacterial and persistent viral infections, lymphoproliferative/autoimmune disease, and pathologic inflammation. We describe an APDS patient with a new mutation in the helical domain of p110δ. Activating mutations in the homologous residue of the ubiquitously expressed PIK3CA are described in cancer. The patient is a 14-year-old female who has recurrent infections, autoimmune vasculitis, asthma, and allergies. She has the classic APDS phenotype involving loss of switched memory B cells, as well as eosinophilia and hyper-IgE, which have not been previously described in this disease. We show this mutation leads to hyperactivation of the PI3K pathway. E522K in PIK3CD is functionally relevant given the association of the mutation in PIK3CA with cancer and hyperactivation of the PI3K pathway. Future directions involve finding more patients with this mutation to see if the allergy phenotype is shared and measuring the in vitro kinase activity.