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

doi:10.1016/j.jaci.2016.03.022

. 2016 Jul;138(1):210-218.e9.

doi: 10.1016/j.jaci.2016.03.022. Epub 2016 Apr 21.

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

Elodie Elkaim¹, Benedicte Neven², Julie Bruneau³, Kanako Mitsui-Sekinaka⁴, Aurelie Stanislas⁵, Lucie Heurtier⁶, Carrie L Lucas⁷, Helen Matthews⁷, Marie-Céline Deau⁶, Svetlana Sharapova⁸, James Curtis⁹, Janine Reichenbach¹⁰, Catherine Glastre¹¹, David A Parry¹², Gururaj Arumugakani¹³, Elizabeth McDermott¹⁴, Sara Sebnem Kilic¹⁵, Motoi Yamashita¹⁶, Despina Moshous², Hicham Lamrini⁶, Burkhard Otremba¹⁷, Andrew Gennery¹⁸, Tanya Coulter¹⁹, Isabella Quinti²⁰, Jean-Louis Stephan²¹, Vassilios Lougaris²², Nicholas Brodszki²³, Vincent Barlogis²⁴, Takaki Asano²⁵, Lionel Galicier²⁶, David Boutboul²⁶, Shigeaki Nonoyama⁴, Andrew Cant¹⁸, Kohsuke Imai²⁷, Capucine Picard²⁸, Sergey Nejentsev⁹, Thierry Jo Molina³, Michael Lenardo⁷, Sinisa Savic²⁹, Marina Cavazzana³⁰, Alain Fischer³¹, Anne Durandy⁶, Sven Kracker³²

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

Free article

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

Elodie Elkaim et al. J Allergy Clin Immunol. 2016 Jul.

Free article

. 2016 Jul;138(1):210-218.e9.

doi: 10.1016/j.jaci.2016.03.022. Epub 2016 Apr 21.

Authors

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.

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

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

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