Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase ? syndrome 2: A cohort study - 01/07/16

Doi : 10.1016/j.jaci.2016.03.022

Elodie Elkaim, MD ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Benedicte Neven, MD, PhD ^a,^b,^c,^{^{∗
These authors contributed equally to this work.}}, Julie Bruneau, MD, PhD ^c,^d, Kanako Mitsui-Sekinaka, MD ^e, Aurelie Stanislas, MSc ^f, Lucie Heurtier, MSc ^b,^c, Carrie L. Lucas, PhD ^g, Helen Matthews, BSc ^g, Marie-Céline Deau, MSc ^b,^c, Svetlana Sharapova, PhD ^h, James Curtis, BSc ⁱ, Janine Reichenbach, MD ^j, Catherine Glastre, MD ^k, David A. Parry, PhD ^l, Gururaj Arumugakani, FRCPath, PhD ^m, Elizabeth McDermott, MD ⁿ, Sara Sebnem Kilic, MD ^o, Motoi Yamashita, MD ^p, Despina Moshous, MD, PhD ^a,^b,^c, Hicham Lamrini, MSc ^b,^c, Burkhard Otremba, MD ^q, Andrew Gennery, MD ^r, Tanya Coulter, MRCPI ^s,^t, Isabella Quinti, MD ^u, Jean-Louis Stephan, MD ^v, Vassilios Lougaris, MD ^w, Nicholas Brodszki, MD ^x, Vincent Barlogis, MD ^y, Takaki Asano, MD ^z, Lionel Galicier, MD ^aa, David Boutboul, MD, PhD ^aa, Shigeaki Nonoyama, MD, PhD ^e, Andrew Cant, MD, PhD ^r, Kohsuke Imai, MD ^e,^bb, Capucine Picard, MD, PhD ^b,^c,^cc, Sergey Nejentsev, PhD ⁱ, Thierry Jo Molina, MD, PhD ^c,^d, Michael Lenardo, MD ^g, Sinisa Savic, FRCPath, PhD ^l,^dd, Marina Cavazzana, MD, PhD ^b,^c,^f,^{‡
These authors contributed equally to this work.}, Alain Fischer, MD, PhD ^a,^b,^c,^ee,^{‡
These authors contributed equally to this work.}, Anne Durandy, MD, PhD ^b,^c,^{‡
These authors contributed equally to this work.}, Sven Kracker, PhD ^b,^c,^⁎
^a Department of Pediatric Immunology, Hematology and Rheumatology, AP-HP, Necker Children's Hospital, Paris, France
^b INSERM UMR1163, Paris, France
^c Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France
^d Department of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France
^e Department of Pediatrics, National Defense Medical College, Saitama, Japan
^f Départment de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
^g Laboratory of Immunology, Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, NIAID, NIH, Bethesda, Md
^h Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
ⁱ Department of Medicine, University of Cambridge, Cambridge, United Kingdom
^j 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
^k Service de Pédiatrie, Centre Hospitalier Annecy Genevois, Metz-Tessy, France
^l Centre for Genomic & Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
^m Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom
ⁿ Nottingham University Hospitals, Nottingham, United Kingdom
^o Pediatric Immunology Division, Uludag University Medical Faculty, Department of Pediatrics, Bursa, Turkey
^p Department of Pediatrics and Developmental Biology, School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
^bb Department of Pediatrics, Tokyo Medical and Dental University, Tokyo, Japan
^q Oncological Practice Oldenburg/Delmenhorst, Oldenburg, Germany
^r Institute of Cellular Medicine, Paediatric Immunology Department, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
^s Department of Immunology, School of Medicine, Trinity College Dublin, St James's Hospital, Dublin, Ireland
^t Department of Pediatric Immunology and Infectious Diseases, Our Lady's Children's Hospital Crumlin, Dublin, Ireland
^u Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
^v Department of Pediatric, Hôpital Nord, Saint-Etienne, France
^w Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di Brescia, Brescia, Italy
^x Children's Hospital, Skåne University Hospital, Lund, Sweden
^y Service d'Hématologie Pédiatrique, Marseille, France
^z Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan
^aa Clinical Immunology Department, Hôpital Saint Louis, Assistance Publique Hôpitaux de Paris, Université Paris Diderot, Paris, France
^cc Study Center for Primary Immunodeficiencies, Assistance Publique Hôpitaux de Paris, Necker Hospital, Paris, France
^dd 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
^ee Collège de France, Paris, France

^∗Corresponding author: Sven Kracker, PhD, INSERM U1163, Imagine Institute, 24 Boulevard du Montparnasse, F-75015 Paris, France.INSERM U1163Imagine Institute24 Boulevard du MontparnasseF-75015 ParisFrance

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.

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

Abbreviations used : APDS, CHL, CMV, DLBCL, ENT, HIGM, HSCT, PASLI, PI3K

Plan

Methods

Results

Patients' characteristics

Genetics of heterozygous splice site mutations in PIK3R1

Clinical presentation

Immunologic features

Nonimmunologic features

Treatment

Discussion

A.F., A.D., and S.K. are supported by the European Union's 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE contract 249816). A.F., A.D., M.C., and S.K. are supported by a government grant managed by the French Agence Nationale de la Recherche as part of the “Investments for the Future” program (ANR-10-IAHU-01). S.K. is a researcher at the Centre National de la Recherche Scientifique-CNRS (France). A.F., A.D., M.C., and S.K. are supported by the Institut National de la Santé et de la Recherche Médicale. S.K. is also supported by the Fondation pour la Recherche Médicale (grant no. ING20130526624), la Ligue Contre le Cancer (Comité de Paris), the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), and the Agence Nationale de la Recherche (ANR-15-CE15-0020 [ANR-PIKimun]). J.R. is supported by the Gebert Rüf Stiftung program “Rare Diseases—New Approaches” (grant no. GRS-046/10), EU-FP7 CELL-PID HEALTH-2010-261387 and EU-FP7 NET4CGD, as well as the Zurich Centre for Integrative Human Physiology (ZIHP), the Gottfried und Julia Bangerter-Rhyner-Stiftung, and the Rossi Stiftung. S. Nejentsev is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (095198/Z/10/Z) and is also supported by the European Research Council Starting grant 260477, the EU FP7 collaborative grant 261441 (PEVNET project), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. S. Nonoyama is partially supported by grants from MEXT/JSPS, Ministry of Health Labor and Welfare, Ministry of Defense, and the Practical Research for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, AMED. S.S. is supported by grants from National Institute for Health Research–Leeds Musculoskeletal Biomedical Research Unit (and Leeds Teaching Hospitals Charitable Foundation). T.C. is supported by National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland. M.L., C.L.L., and H.M. are supported by the Intramural Research Program of the National Institutes of Health/National Institute of Allergy and Infectious Diseases. C.L.L. was also supported by the Postdoctoral Research Associate (PRAT) Fellowship, National Institute of General Medical Sciences(NIGMS)/NIH.

Disclosure of potential conflict of interest: M.-C. Deau has received research support from FRM. T. Coulter has received research support from the National Children's Research Centre, D8, Dublin, and has received travel support from Baxter Healthcare, Ireland. I. Quinti is on the Baxalta Board; has received research support from PPTA; has received lecture fees from Baxalta, Kedrion, and CSL Behring; and has received travel support from Baxalta, Kedrion, and CSL Behring. L. Galicier has received payment for developing educational presentations from Raison et Sante, Amgen, Janssen, and GlaxoSmithKline and has received travel support from Janssen. A. Cant has received consultancy fees from LFB Biomedicaments. K. Imai has received research support from CSL Behring KK, Sony, the Japan Ministry of Defense, and the Japan Ministry of Health, Labour and Welfare; has received consultancy fees from CSL Behring KK; and has received lecture fees from Japan Blood Products Organization and CSL Behring KK. S. Nejentsev has received research support from MRC and GlaxoSmithKline. T. J. Molina has received consultancy fees from Merck and Novartis and travel support from Gilead and Mundipharma. S. Kracker has received research support from the ERC advanced grant PID-Immune contract 249816, Foundation pour la Recherche Medicale (ING20130526624), la Ligue Contre le Cancer (Comité de Paris), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), French Agence Nationale de la Recherche as part of the “Investments for the Future” program (ANR-10-IAHU-01), French Agence Nationale de la Recherche (ANR-15-CE15-0020), Fondation ARC pour la recherche sur le cancer and has received travel support from Novartis Institutes for Biomedical Research. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 138 - N° 1

P. 210 - juillet 2016 Retour au numéro

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Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase ? syndrome 2: A cohort study - 01/07/16

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