Thyroid Carcinoma in a Child with Activated Phosphoinositide 3-Kinase δ Syndrome: Somatic Effect of a Germline Mutation

Excerpt

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently characterized primary immunodeficiency caused by heterozygous gain-of-function mutations in the PIK3CD or PIK3R1 genes [1‐4]. PIK3CD encodes the protein product p110δ, a catalytic subunit that constitutively associates with a p85α regulatory subunit, encoded by PIK3R1, to form a heterodimeric lipid kinase, phosphoinositide 3-kinase δ (PI3K). PI3Kδ is selectively expressed in the immune system and contributes to important signaling pathways for the development and function of lymphocytes and myeloid cells [4, 5]. Activating mutations of PI3Kδ induce hyperactivation of AKT and mTOR and suppression of FOXO transcription factors. This interferes with class switch recombination and somatic hypermutation in the B cells and induces hyperactivation of the T compartment, which in turn results in IgG and/or IgA hypogammaglobulinemia with normal to increased IgM levels, lymphoproliferation and T cell senescence with low naïve T cells, and low CD4+ and increased CD8+ T cells [1, 5]. …