Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study

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Background: Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. Objectives: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort. Methods: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed. Results: Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications. Conclusion: APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.


  • Elodie Elkaim
  • Benedicte Neven
  • Julie Bruneau
  • Kanako Mitsui-Sekinaka
  • Aurelie Stanislas
  • Lucie Heurtier
  • Carrie L. Lucas
  • Helen Matthews
  • Marie Céline Deau
  • Svetlana Sharapova
  • James Curtis
  • Janine Reichenbach
  • Catherine Glastre
  • David A. Parry
  • Gururaj Arumugakani
  • Elizabeth McDermott
  • Sara Sebnem Kilic
  • Motoi Yamashita
  • Despina Moshous
  • Hicham Lamrini
  • Och 23 andra
  • Burkhard Otremba
  • Andrew Gennery
  • Tanya Coulter
  • Isabella Quinti
  • Jean Louis Stephan
  • Vassilios Lougaris
  • Nicholas Brodszki
  • Vincent Barlogis
  • Takaki Asano
  • Lionel Galicier
  • David Boutboul
  • Shigeaki Nonoyama
  • Andrew Cant
  • Kohsuke Imai
  • Capucine Picard
  • Sergey Nejentsev
  • Thierry Jo Molina
  • Michael Lenardo
  • Sinisa Savic
  • Marina Cavazzana
  • Alain Fischer
  • Anne Durandy
  • Sven Kracker
Externa organisationer
  • National Institute for Health and Medical Research, France
  • Paris Descartes University
  • Hopital Necker Enfants Malades
  • National Defense Medical College
  • National Institute of Allergy and Infectious Diseases
  • Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
  • University of Cambridge
  • Kinderspital Zurich
  • Centre Hospitalier Annecy Genevois
  • University of Edinburgh
  • St James's University Hospital
  • Queen's Medical Centre, Nottingham
  • Uludağ University
  • Tokyo Medical and Dental University
  • Oncological Practice Oldenburg/Delmenhorst
  • Great North Children's Hospital
  • Our Lady's Children's Hospital, Crumlin
  • Sapienza University of Rome
  • Hopital Nord CHU de Sainte-Etienne
  • University of Brescia
  • Skåne University Hospital
  • Hiroshima University
  • Paris Diderot University
  • College de France

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Immunologi inom det medicinska området
  • Pediatrik


Sidor (från-till)210-218.e9
TidskriftJournal of Allergy and Clinical Immunology
Utgåva nummer1
Tidigt onlinedatum2016 apr 21
StatusPublished - 2016
Peer review utfördJa
Externt publiceradJa