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

Author

Listed:
  • Elodie Elkaim
  • Bénédicte Neven

    (CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Necker - Enfants Malades [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP), IMAGINE - U1163 - Imagine - Institut des maladies génétiques - UPD5 - Université Paris Descartes - Paris 5 - INSERM - Institut National de la Santé et de la Recherche Médicale, Service d'immuno-hématologie pédiatrique [CHU Necker] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Necker - Enfants Malades [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP))

  • Julie Bruneau

    (IMAGINE - U1163 - Imagine - Institut des maladies génétiques - UPD5 - Université Paris Descartes - Paris 5 - INSERM - Institut National de la Santé et de la Recherche Médicale, Département de Pathologie [CHU Necker] - UPD5 - Université Paris Descartes - Paris 5 - USPC - Université Sorbonne Paris Cité - Hôpital Necker - Enfants Malades [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP))

  • Kanako Mitsui-Sekinaka
  • Aurelie Stanislas
  • Lucie Heurtier
  • Carrie L. Lucas
  • Helen Matthews

    (Depat of Gastroenterology - St George's Hospital)

  • Marie-Celine Deau
  • Svetlana Sharapova
  • James Curtis
  • Janine Reichenbach

    (Inserm U980 - Génétique Humaine des Maladies Infectieuses - UPD5 - Université Paris Descartes - Paris 5 - INSERM - Institut National de la Santé et de la Recherche Médicale)

  • Catherine Glastre
  • David A. Parry
  • Gururaj Arumugakani
  • Elizabeth Mcdermott
  • Sara Sebnem Kilic
  • Motoi Yamashita
  • Despina Moshous

    (CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Necker - Enfants Malades [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP), IMAGINE - U1163 - Imagine - Institut des maladies génétiques - UPD5 - Université Paris Descartes - Paris 5 - INSERM - Institut National de la Santé et de la Recherche Médicale, Service d'immuno-hématologie pédiatrique [CHU Necker] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Necker - Enfants Malades [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP))

  • Hicham Lamrini
  • Burkhard Otremba
  • Andrew Gennery

    (Department of Pediatrics - Newcastle General Hospital)

  • Tanya Coulter
  • Isabella Quinti
  • Jean-Louis Stephan

    (CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne])

  • Vassilios Lougaris
  • Nicholas Brodszki
  • Vincent Barlogis

    (Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM] - AMU - Aix Marseille Université - APHM - Assistance Publique - Hôpitaux de Marseille - TIMONE - Hôpital de la Timone [CHU - APHM])

  • Takaki Asano
  • Lionel Galicier

    (Service d'immunologie clinique - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - UPD7 - Université Paris Diderot - Paris 7 - Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP), CHU Saint-Antoine [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - SU - Sorbonne Université, UPD7 - Université Paris Diderot - Paris 7)

  • David Boutboul

    (Service d'Immunopathologie [Hôpital Saint-Louis, Paris] - UPD7 - Université Paris Diderot - Paris 7 - AP-HP - Hopital Saint-Louis [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP))

  • Shigeaki Nonoyama
  • Andrew Cant
  • Kohsuke Imai
  • Capucine Picard

    (CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Necker - Enfants Malades [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP), IMAGINE - U1163 - Imagine - Institut des maladies génétiques - UPD5 - Université Paris Descartes - Paris 5 - INSERM - Institut National de la Santé et de la Recherche Médicale, Service d'immuno-hématologie pédiatrique [CHU Necker] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Necker - Enfants Malades [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP))

  • Sergey Nejentsev
  • Thierry Jo Molina

    (AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP))

  • Michael Lenardo

    (Laboratory of Immunology - National Institutes of Allergy and Infectious Diseases - NIH - National Institutes of Health [Bethesda, MD, USA])

  • Sinisa Savic
  • Marina Cavazzana

    (IMAGINE - U1163 - Imagine - Institut des maladies génétiques - UPD5 - Université Paris Descartes - Paris 5 - INSERM - Institut National de la Santé et de la Recherche Médicale)

  • Alain Fischer

    (CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Necker - Enfants Malades [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP), IMAGINE - U1163 - Imagine - Institut des maladies génétiques - UPD5 - Université Paris Descartes - Paris 5 - INSERM - Institut National de la Santé et de la Recherche Médicale, Service d'immuno-hématologie pédiatrique [CHU Necker] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Necker - Enfants Malades [AP-HP] - AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP), Collège de France - Chaire Médecine expérimentale (A. Fischer) - CdF (institution) - Collège de France)

  • Anne Durandy

    (IMAGINE - U1163 - Imagine - Institut des maladies génétiques - UPD5 - Université Paris Descartes - Paris 5 - INSERM - Institut National de la Santé et de la Recherche Médicale)

  • Sven Kracker

    (IMAGINE - U1163 - Imagine - Institut des maladies génétiques - UPD5 - Université Paris Descartes - Paris 5 - INSERM - Institut National de la Santé et de la Recherche Médicale)

Abstract

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) 2 ă (p110 delta-activating mutations causing senescent T cells, ă lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently ă described primary immunodeficiency, results from autosomal dominant ă mutations in PIK3R1, the gene encoding the regulatory subunit (p85 ă alpha, p55 alpha, and p50 alpha) of class IA phosphoinositide 3-kinases. ă Objectives: We sought to review the clinical, immunologic, and ă histopathologic phenotypes of APDS2 in a genetically defined ă international patient cohort. ă Methods: The medical and biological records of 36 patients with ă genetically diagnosed APDS2 were collected and reviewed. ă Results: Mutations within splice acceptor and donor sites of exon 11 of ă the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract ă infections (100%), pneumonitis (71%), and chronic lymphoproliferation ă (89%, including adenopathy [75%], splenomegaly [43%], and upper ă respiratory tract lymphoid hyperplasia [48%]) were the most common ă features. Growth retardation was frequently noticed (45%). Other ă complications were mild neurodevelopmental delay (31%); malignant ă diseases (28%), most of them being B-cell lymphomas; autoimmunity ă (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased ă serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell ă lymphopenia (88%) associated with an increased frequency of ă transitional B cells (93%), and decreased numbers of naive CD4 and ă naive CD8 cells but increased numbers of CD8 effector/memory T cells ă were predominant immunologic features. The majority of patients (89%) ă received immunoglobulin replacement; 3 patients were treated with ă rituximab, and 6 were treated with rapamycin initiated after diagnosis ă of APDS2. Five patients died from APDS2-related complications. ă Conclusion: APDS2 is a combined immunodeficiency with a variable ă clinical phenotype. Complications are frequent, such as severe bacterial ă and viral infections, lymphoproliferation, and lymphoma similar to ă APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, ă likely in the near future, selective phosphoinositide 3-kinase delta ă inhibitors are possible treatment options.

Suggested Citation

  • Elodie Elkaim & Bénédicte Neven & Julie Bruneau & Kanako Mitsui-Sekinaka & Aurelie Stanislas & Lucie Heurtier & Carrie L. Lucas & Helen Matthews & Marie-Celine Deau & Svetlana Sharapova & James Curtis, 2016. "Clinical and immunologic phenotype associated with activated ă phosphoinositide 3-kinase delta syndrome 2: A cohort study," Post-Print hal-01482361, HAL.
    • Handle: RePEc:hal:journl:hal-01482361
    DOI: 10.1016/j.jaci.2016.03.022
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