Clinical spectrum and features of activated PI3-kinase delta syndrome: a large patient cohort study

Publication date: Available online 16 July 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Tanya I. Coulter, Anita Chandra, Chris M. Bacon, Judith Babar, James Curtis, Nick Screaton, John R. Goodlad, George Farmer, Cathal Laurence Steele, Timothy Ronan Leahy, Rainer Doffinger, Helen Baxendale, Jolanta Bernatoniene, J.D.M. Edgar, Hilary J. Longhurst, Stephan Ehl, Carsten Speckmann, Bodo Grimbacher, Anna Sediva, Tomas Milota, Saul N. Faust, Anthony P. Williams, Grant Hayman, Zeynep Yesim Kucuk, Rosie Hague, Paul French, Richard Brooker, Peter Forsyth, Richard Herriot, Caterina Cancrini, Paolo Palma, Paola Ariganello, Niall Conlon, Conleth Feighery, Patrick J. Gavin, Alison Jones, Kohsuke Imai, Mohammad A.A. Ibrahim, Gašper Markelj, Mario Abinun, Frédéric Rieux-Laucat, Sylvain Latour, Isabelle Pellier, Alain Fischer, Fabien Touzot, Jean-Laurent Casanova, Anne Durandy, Siobhan O. Burns, Sinisa Savic, D.S. Kumararatne, Despina Moshous, Sven Kracker, Bart Vanhaesebroeck, Klaus Okkenhaug, Capucine Picard, Sergey Nejentsev, Alison M. Condliffe, Andrew James Cant
BackgroundActivated PI3-Kinase Delta 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).ObjectiveTo review the clinical, immunological, histopathological and radiological features of APDS in a large genetically-defined international cohort.MethodsClinical questionnaire, and review of medical notes, radiology histopathology and laboratory investigations of 53 APDS patients.ResultsRecurrent sino-pulmonary infections (98%) and non-neoplastic 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 (CNS); consistent with this PI3Kδ is broadly expressed in the developing murine CNS. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Elevated IgM (78%), IgG deficiency (43%) and CD4 lymphopenia (84%) were significant immunological features. No immunological 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 five patients underwent haematopoietic stem cell transplant (HSCT). 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 HSCT for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Teaser

We describe complications, outcomes, management and laboratory and radiological features of APDS in the largest to date cohort of 53 patients, highlighting APDS as a clinically significant combined immune deficiency.


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