title: Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study.
abstract: 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.
  
  
  
  We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort.
  
  
  
  The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pediatric Immunology, Hematology and Rheumatology, AP-HP, Necker Children's Hospital, Paris, France; INSERM UMR1163, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Elkaim
authors.affiliation: 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.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Neven
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Bruneau
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Mitsui-Sekinaka
authors.affiliation: Départment de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Stanislas
authors.affiliation: INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Heurtier
authors.affiliation: Laboratory of Immunology, Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, NIAID, NIH, Bethesda, Md.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Lucas
authors.affiliation: Laboratory of Immunology, Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, NIAID, NIH, Bethesda, Md.
authors.forename: Helen
authors.initials: H
authors.lastname: Matthews
authors.affiliation: INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Marie-Céline
authors.initials: MC
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authors.affiliation: Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus.
authors.forename: Svetlana
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authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: James
authors.initials: J
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authors.affiliation: 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.
authors.forename: Janine
authors.initials: J
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authors.affiliation: Service de Pédiatrie, Centre Hospitalier Annecy Genevois, Metz-Tessy, France.
authors.forename: Catherine
authors.initials: C
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authors.affiliation: Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.affiliation: Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Gururaj
authors.initials: G
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authors.affiliation: Nottingham University Hospitals, Nottingham, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
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authors.affiliation: Pediatric Immunology Division, Uludag University Medical Faculty, Department of Pediatrics, Bursa, Turkey.
authors.forename: Sara Sebnem
authors.initials: SS
authors.lastname: Kilic
authors.affiliation: Department of Pediatrics and Developmental Biology, School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: 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.
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.affiliation: INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Hicham
authors.initials: H
authors.lastname: Lamrini
authors.affiliation: Oncological Practice Oldenburg/Delmenhorst, Oldenburg, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Otremba
authors.affiliation: Institute of Cellular Medicine, Paediatric Immunology Department, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gennery
authors.affiliation: 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.
authors.forename: Tanya
authors.initials: T
authors.lastname: Coulter
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Quinti
authors.affiliation: Department of Pediatric, Hôpital Nord, Saint-Etienne, France.
authors.forename: Jean-Louis
authors.initials: JL
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authors.affiliation: Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.
authors.forename: Vassilios
authors.initials: V
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authors.forename: Vincent
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authors.lastname: Barlogis
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
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authors.forename: Lionel
authors.initials: L
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authors.affiliation: Clinical Immunology Department, Hôpital Saint Louis, Assistance Publique Hôpitaux de Paris, Université Paris Diderot, Paris, France.
authors.forename: David
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authors.lastname: Boutboul
authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan.
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authors.affiliation: Institute of Cellular Medicine, Paediatric Immunology Department, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: Andrew
authors.initials: A
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authors.affiliation: Department of Pediatrics, National Defense Medical College, Saitama, Japan; Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.affiliation: 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.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sergey
authors.initials: S
authors.lastname: Nejentsev
authors.affiliation: 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.
authors.forename: Thierry Jo
authors.initials: TJ
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authors.affiliation: Laboratory of Immunology, Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, NIAID, NIH, Bethesda, Md.
authors.forename: Michael
authors.initials: M
authors.lastname: Lenardo
authors.affiliation: 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.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Savic
authors.affiliation: 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.
authors.forename: Marina
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authors.lastname: Cavazzana
authors.affiliation: 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.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.affiliation: INSERM UMR1163, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France. Electronic address: sven.kracker@inserm.fr.
authors.forename: Sven
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mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis* / Q000209:etiology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D022821:RNA Splice Sites; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D022821:RNA Splice Sites; D058534:Class I Phosphatidylinositol 3-Kinases
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