Abstract
Phosphoinositide-3-kinase δ (PI3Kδ) is found in immune cells and is part of the PI3K/AKT/mTOR/S6K signalling pathway essential to cell survival, growth and differentiation. Hyperactivation of PI3Kδ enzyme results in Activated PI3-kinase delta syndrome (APDS). This childhood onset, autosomal dominant, combined immunodeficiency, is caused by heterozygous gain of function (GOF) mutations in PIK3CD (encodes PI3Kδ catalytic subunit p110δ), mutations in PIK3R1 (encodes PI3Kδ regulatory subunit p85α) or LOF mutations in PTEN (terminates PI3Kδ signalling) leading to APDS1, APDS2 and APDS-Like (APDS-L), respectively. APDS was initially described in 2013 and over 285 cases have now been reported. Prompt diagnosis of APDS is beneficial as targeted pharmacological therapies such as sirolimus and potentially PI3Kδ inhibitors can be administered. In this review, we provide an update on the clinical and laboratory features of this primary immunodeficiency. We discuss the common manifestations such as sinopulmonary infections, bronchiectasis, lymphoproliferation, susceptibility to herpesvirus, malignancy, as well as more rare non-immune features such as short stature and neurodevelopmental abnormalities. Laboratory characteristics, such as antibody deficiency and B cell and T cell, phenotypes are also summarised.
Highlights
In this review, we discuss the clinical and immunological features of Activated PI3-Kinase Delta Syndromes - Activated PI3-Kinase Delta Syndrome 1 (APDS1) and Activated PI3-Kinase Delta Syndromes 2 (APDS2) and the APDS-Like (APDS-L) condition phosphatase and tensin homologue (PTEN) deficiency.PI3-kinase δ is a class 1 phosphoinositide-3-kinase consisting of the catalytic subunit p110δ and, most commonly, the regulatory subunit p85α, association with other regulatory subunits is possible (1). p110δ is expressed primarily in haematopoietic cells and cells of the nervous system, whereas p85α expression is more ubiquitous (1, 2)
APDS1 is caused by autosomal dominant, gain of function (GOF) mutations in the p110δ catalytic subunit
Germline biallelic loss of function (LOF) mutations leading to underactivation of PI3Kδ present with infections, colitis, panhypogammaglobulinemia and lymphopenia (1)
Summary
B cell lymphomas are the most common malignancy and are often associated with EBV infection. Clinical manifestations of APDS typically progress from recurrent infections and lymphoproliferation in early childhood, to autoimmunity in mid-childhood, and malignancy in late childhood-adulthood. Hyper IgM is the most common immunoglobulin pattern, but a range of antibody defects can occur; hypogammaglobulinaemia, agammaglobulinaemia, IgG subclass deficiency, specific antibody deficiency (poor response to pneumococcal polysaccharide vaccination), and normal immunoglobulin levels. A diagnosis of APDS should not be ruled out based on immunoglobulin levels alone. Treatment is tailored according to the clinical phenotype and includes prophylactic antibiotics, immunoglobulin replacement therapy, immunosuppression (steroids, rituximab, sirolimus) and HSCT. Recognition and disease diagnosis are important in trying to prevent long term complications such as bronchiectasis, hearing loss, and malignancy They have an increased frequency of autoimmune thyroiditis and solid organ tumours, in contrast to cytopenias and B cell lymphomas
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