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

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

  • J Allergy Clin Immunol. 2016 Jul;138(1):210-218.e9. doi: 10.1016/j.jaci.2016.03.022.
Elodie Elkaim 1,  Benedicte Neven 2,  Julie Bruneau 3,  Kanako Mitsui-Sekinaka 4,  Aurelie Stanislas 5,  Lucie Heurtier 6,  Carrie L Lucas 7,  Helen Matthews 7,  Marie-Céline Deau 6,  Svetlana Sharapova 8,  James Curtis 9,  Janine Reichenbach 10,  Catherine Glastre 11,  David A Parry 12,  Gururaj Arumugakani 13,  Elizabeth McDermott 14,  Sara Sebnem Kilic 15,  Motoi Yamashita 16,  Despina Moshous 2,  Hicham Lamrini 6,  Burkhard Otremba 17,  Andrew Gennery 18,  Tanya Coulter 19,  Isabella Quinti 20,  Jean-Louis Stephan 21,  Vassilios Lougaris 22,  Nicholas Brodszki 23,  Vincent Barlogis 24,  Takaki Asano 25,  Lionel Galicier 26,  David Boutboul 26,  Shigeaki Nonoyama 4,  Andrew Cant 18,  Kohsuke Imai 27,  Capucine Picard 28,  Sergey Nejentsev 9,  Thierry Jo Molina 3,  Michael Lenardo 7,  Sinisa Savic 29,  Marina Cavazzana 30,  Alain Fischer 31,  Anne Durandy 6,  Sven Kracker 32
Affiliations

Affiliations

  • 1 Department of Pediatric Immunology, Hematology and Rheumatology, AP-HP, Necker Children's Hospital, Paris, France; INSERM UMR1163, Paris, France.
  • 2 Department of Pediatric Immunology, Hematology and Rheumatology, AP-HP, Necker Children's Hospital, Paris, France; INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
  • 3 Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Department of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France.
  • 4 Department of Pediatrics, National Defense Medical College, Saitama, Japan.
  • 5 Départment de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
  • 6 INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
  • 7 Laboratory of Immunology, Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, NIAID, NIH, Bethesda, Md.
  • 8 Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus.
  • 9 Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
  • 10 Division of Immunology, University Children's Hospital Zurich, Children's Research Center, Competence Center for Applied Biotechnology and Molecular Medicine and the Swiss Center for Regenerative Medicine, University Zurich, Zurich, Switzerland.
  • 11 Service de Pédiatrie, Centre Hospitalier Annecy Genevois, Metz-Tessy, France.
  • 12 Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
  • 13 Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom.
  • 14 Nottingham University Hospitals, Nottingham, United Kingdom.
  • 15 Pediatric Immunology Division, Uludag University Medical Faculty, Department of Pediatrics, Bursa, Turkey.
  • 16 Department of Pediatrics and Developmental Biology, School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
  • 17 Oncological Practice Oldenburg/Delmenhorst, Oldenburg, Germany.
  • 18 Institute of Cellular Medicine, Paediatric Immunology Department, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.
  • 19 Department of Immunology, School of Medicine, Trinity College Dublin, St James's Hospital, Dublin, Ireland; Department of Pediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
  • 20 Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
  • 21 Department of Pediatric, Hôpital Nord, Saint-Etienne, France.
  • 22 Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.
  • 23 Children's Hospital, Skåne University Hospital, Lund, Sweden.
  • 24 Service d'Hématologie Pédiatrique, Marseille, France.
  • 25 Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
  • 26 Clinical Immunology Department, Hôpital Saint Louis, Assistance Publique Hôpitaux de Paris, Université Paris Diderot, Paris, France.
  • 27 Department of Pediatrics, National Defense Medical College, Saitama, Japan; Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
  • 28 INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Study Center for Primary Immunodeficiencies, Assistance Publique Hôpitaux de Paris, Necker Hospital, Paris, France.
  • 29 Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; National Institute for Health Research-Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU) and Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), St James's University Hospital, Leeds, United Kingdom.
  • 30 INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Départment de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
  • 31 Department of Pediatric Immunology, Hematology and Rheumatology, AP-HP, Necker Children's Hospital, Paris, France; INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Collège de France, Paris, France.
  • 32 INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France. Electronic address: sven.kracker@inserm.fr.
PMID: 27221134 DOI: 10.1016/j.jaci.2016.03.022
Abstract

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.

Keywords

Primary immunodeficiency; activated phosphoinositide 3-kinase δ syndrome; adenopathy; and immunodeficiency; antibody deficiency; hyper-IgM; immunodeficiency; lymphadenopathy; p110δ; p110δ-activating mutations causing senescent T cells; p85α; phosphoinositide 3-kinase.

Figures