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

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, Janine Reichenbach, Catherine Glastre, David A. Parry, Gururaj Arumugakani, Elizabeth Mcdermott, Sara Sebnem Kilic, Motoi Yamashita, Despina Moshous (), Hicham Lamrini, 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 and Sven Kracker ()
Additional contact information
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)
Helen Matthews: Depat of Gastroenterology - St George's Hospital
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
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)
Andrew Gennery: Department of Pediatrics - Newcastle General Hospital
Jean-Louis Stephan: CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
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]
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)
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)
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]
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

Post-Print from HAL

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.

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Date: 2016-07
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Published in Journal of Allergy and Clinical Immunology, 2016, 138 (1), pp.210+. ⟨10.1016/j.jaci.2016.03.022⟩

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Persistent link: https://EconPapers.repec.org/RePEc:hal:journl:hal-01482361

DOI: 10.1016/j.jaci.2016.03.022

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