Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Abstract

BackgroundActivated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).ObjectiveWe sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.MethodsWe applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.ResultsRecurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.ConclusionAPDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Mutations in the adaptor-binding domain and associated linker region of p110δ cause Activated PI3K-δ Syndrome 1 (APDS1)

“…3,11,10 Since the diagnosis of APDS1, P1 and P3 were treated with rapamycin and are under consideration for HSCT. Inhibitors specific for p110δ are currently in clinical trials (EudraCT Numbers: 2015-002900-10; 2015-005541-30; 2014-003876-22; 2015-004876-31) and could offer a new treatment option for APDS patients with possibly higher efficiency and less unwanted side effects.…”

“…It highlights that mutations occurring in different parts of the gene can lead to the very same consequences, and should thus be screened in patients with a phenotype resembling APDS. Jean-Marc Plaza, 4 Mélanie Parisot, 5 Benoit Dumont, 6 Delphine Turpin, 7 Etienne Merlin, 8 Despina Moshous, 1,2,9 Nathalie Aladjidi, 10 Bénédicte Neven, 1,2,9 Capucine Picard, 1,2,3 Marina Cavazzana, 1,2,11 Alain Fischer, 1,2,9,12 Anne Durandy, 1,2 Jean-Louis Stephan 6 and Sven Kracker …”

Novel PIK3CD mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans

“…It is caused by heterozygous, gain-of-function mutation in the PIK3CD (1, 2) or PIK3R1 (3, 4) genes encoding the p110δ catalytic or p85α regulatory subunit of the phosphoinositide 3-kinase complex PI3Kδ. Augmented PI3Kδ signaling causes terminal differentiation and senescence of T cells, increased transitional B cells, and immunoglobulin derangements (5, 6). …”

“…The regulatory p85 subunit makes inhibitory contacts with the C2, helical, and kinase domains of p110δ, and it is these three domains that are affected by previously described APDS1 mutations. Specifically, heterozygous PIK3CD mutations causing amino acid changes N334K and C416R in the C2 domain, E525K and E525A in the helical domain, and E1021K in the kinase domain have been reported (5, 6). Additionally, the p110 ABD makes a putative intramolecular inhibitory contact with the kinase domain (7).…”

Molecules in medicine mini-review: isoforms of PI3K in biology and disease

“…[46]). This disease is an autosomallydominant primary immune deficiency, which often (but not always) predisposes to respiratory infections and airway damage, and can lead to early death from infection-related causes and possibly lymphoma.…”