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Activated Phosphoinositide 3-Kinase Δ Syndrome: Update From the Esid Registry and Comparison With Other Autoimmune-Lymphoproliferative Inborn Errors of Immunity Publisher Pubmed



Maccari ME1, 2 ; Wolkewitz M3 ; Schwab C4 ; Lorenzini T1, 10 ; Leiding JW11 ; Aladjdi N12 ; Abolhassani H13, 14 ; Abouchahla W15 ; Aiuti A18, 19 ; Azarnoush S20 ; Baris S38, 39 ; Barlogis V42 ; Barzaghi F18 ; Baumann U44 Show All Authors
Authors
  1. Maccari ME1, 2
  2. Wolkewitz M3
  3. Schwab C4
  4. Lorenzini T1, 10
  5. Leiding JW11
  6. Aladjdi N12
  7. Abolhassani H13, 14
  8. Abouchahla W15
  9. Aiuti A18, 19
  10. Azarnoush S20
  11. Baris S38, 39
  12. Barlogis V42
  13. Barzaghi F18
  14. Baumann U44
  15. Bloomfield M48, 49
  16. Bohynikova N50
  17. Bodet D51
  18. Boutboul D21
  19. Bucciol G52, 53
  20. Buckland MS54, 55
  21. Burns SO56, 59
  22. Cancrini C60, 61
  23. Cathebras P62
  24. Cavazzana M22, 28, 37
  25. Cheminant M22, 29
  26. Chinello M65
  27. Ciznar P66
  28. Coulter TI67
  29. Daveni M68, 69
  30. Ekwall O70, 71
  31. Eric Z73
  32. Eren E74
  33. Fasth A70, 72
  34. Frange P23, 30
  35. Fournier B31
  36. Garciaprat M75
  37. Gardembas M76
  38. Geier C5
  39. Ghosh S78
  40. Goda V79
  41. Hammarstrom L13
  42. Hauck F80
  43. Heeg M1
  44. Heropolitanskapliszka E50
  45. Hilfanova A82
  46. Jolles S83
  47. Karakocaydiner E38, 39, 40
  48. Kindle GR1, 6
  49. Kiykim A41
  50. Klemann C45, 84
  51. Koletsi P85
  52. Koltan S86
  53. Kondratenko I87
  54. Korholz J89
  55. Kruger R90, 91
  56. Jeziorski E92, 93
  57. Levy R31
  58. Le Guenno G94
  59. Lefevre G16, 17
  60. Lougaris V10
  61. Marzollo A96
  62. Mahlaoui N31, 36
  63. Malphettes M21
  64. Meinhardt A97
  65. Merlin E95
  66. Meyts I52, 53
  67. Milota T48, 49
  68. Moreira F59
  69. Moshous D25, 31, 36
  70. Mukhina A88
  71. Neth O98
  72. Neubert J78
  73. Neven B24, 31
  74. Nieters A1, 6
  75. Novejosserand R99
  76. Oksenhendler E21
  77. Ozen A38, 39, 40
  78. Olbrich P98
  79. Perlat A100
  80. Pac M50
  81. Schmid JP101, 102
  82. Pacillo L60, 61
  83. Parramartinez A75
  84. Paschenko O87
  85. Pellier I77
  86. Sefer AP38, 39
  87. Plebani A10
  88. Plantaz D104
  89. Prader S101, 102
  90. Raffray L105, 106
  91. Ritterbusch H1
  92. Riviere JG75
  93. Rivalta B60, 61
  94. Rusch S1
  95. Sakovich I107
  96. Savic S108, 109
  97. Scheible R1, 81
  98. Schleinitz N43
  99. Schuetz C89
  100. Schulz A110
  101. Sediva A48, 49
  102. Semeraro M33, 34
  103. Sharapova SO107
  104. Shcherbina A88
  105. Slatter MA111, 112
  106. Sogkas G46, 47
  107. Solerpalacin P75
  108. Speckmann C1, 2
  109. Stephan JL63, 64
  110. Suarez F22, 29
  111. Tommasini A113, 114
  112. Truck J101, 102
  113. Uhlmann A1, 7
  114. Van Aerde KJ115
  115. Van Montfrans J116
  116. Von Bernuth H90, 91
  117. Warnatz K1, 5, 103
  118. Williams T74
  119. Worth AJJ58
  120. Ip W57, 58
  121. Picard C26, 31, 32, 36
  122. Catherinot E117
  123. Nademi Z111, 112
  124. Grimbacher B1, 5, 8, 9, 47
  125. Forbes Satter LR118, 119
  126. Kracker S27
  127. Chandra A120, 121
  128. Condliffe AM122
  129. Ehl S1
Show Affiliations
Authors Affiliations
  1. 1. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  2. 2. Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  3. 3. Institute of Medical Biometry and Statistics, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  4. 4. Department of Pediatrics and Adolescent Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  5. 5. Department of Rheumatology and Clinical Immunology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  6. 6. Centre for Biobanking FREEZE, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  7. 7. Clinical Trials Unit, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  8. 8. DZIF—German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany
  9. 9. CIBSS—Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany
  10. 10. Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia and ASST–Spedali Civili of Brescia, Brescia, Italy
  11. 11. Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Md
  12. 12. Pediatric Haemato-Immunology, Clinical Investigation Center (CIC) 1401, Institut National de la Sante et de la Recherche Medicale (INSERM) Centre d'Investigation Clinique Pluridisciplinaire (CICP), Bordeaux University Hospital and Centre de Reference National des Cytopenies Auto-immunoes de l'Enfant (CEREVANCE), Bordeaux, France
  13. 13. Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
  14. 14. Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  15. 15. Department of Pediatric Hematology, Jeanne de Flandre Hospital, Centre Hospitalier Universitaire (CHU), Lille, France
  16. 16. CHU Lille, Institut d'Immunologie and University of Lille, Lille, France
  17. 17. Inserm U995, LIRIC—Lille Inflammation Research International Center, Lille, France
  18. 18. San Raffaele Telethon Institute for Gene Therapy (Sr-Tiget), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy
  19. 19. Universita Vita-Salute San Raffaele, Milan, Italy
  20. 20. Pediatric Hematology and Immunology Unit, Robert Debre Hospital, Paris, France
  21. 21. Clinical Immunology Department, Hopital Saint-Louis, Paris, France
  22. 22. Imagine Institute, INSERM U1163, Institut Imagine, Universite Paris Cite, Paris, France
  23. 23. Unite de Recherche Propre 7328, Federation pour l'Etude et evaluation des Therapeutiques intra-UterineS (FETUS), Institut Imagine, Universite Paris Cite, Paris, France
  24. 24. Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Institut Imagine, Universite Paris Cite, Paris, France
  25. 25. Laboratories of Dynamique du Genome et Systeme Immunitaire, Institut Imagine, Universite Paris Cite, Paris, France
  26. 26. Lymphocyte Activation and Susceptibility to EBV Infection, Institut Imagine, Universite Paris Cite, Paris, France
  27. 27. Human Lymphohematopoiesis, INSERM Unite Mixte de Recherche (UMR) 1163, Institut Imagine, Universite Paris Cite, Paris, France
  28. 28. Biotherapy Department, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris (AP-HP) Centre, Paris, France
  29. 29. Service d'Hematologie Adulte, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris (AP-HP) Centre, Paris, France
  30. 30. Laboratory of Clinical Microbiology, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris (AP-HP) Centre, Paris, France
  31. 31. Pediatric Immunology-Hematology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris (AP-HP) Centre, Paris, France
  32. 32. Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris (AP-HP) Centre, Paris, France
  33. 33. Clinical Investigation Center (CIC) 1419, Necker-Enfants Malades Hospital, AP-HP, Groupe Hospitalier Paris Centre, Paris, France
  34. 34. EA7323 Pediatric and Perinatal Drug Evaluation and Pharmacology Research Unit, Universite Paris Cite, Paris, France
  35. 35. Universite Paris Cite, Paris, France
  36. 36. Necker Enfants Malades University Hospital, AP-HP, French National Reference Center for Primary Immune Deficiencies (CEREDIH), Paris Universite Cite, Paris, France
  37. 37. Biotherapy Clinical Investigation Center Groupe Hospitalier Centre, AP-HP, INSERM, Paris, France
  38. 38. Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey
  39. 39. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
  40. 40. Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
  41. 41. Pediatric Allergy and Immunology, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey
  42. 42. Pediatric Hematology, Immunology and Oncology, Aix-Marseille Universite, Marseille, France
  43. 43. Departement de Medecine Interne, Timone Hospital, Assistance Publique-Hopitaux de Marseille, Aix-Marseille Universite, Marseille, France
  44. 44. Pediatric Pulmonology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany
  45. 45. Departments of Human Genetics, Hannover Medical School, Hannover, Germany
  46. 46. Rheumatology and Immunology, Hannover Medical School, Hannover, Germany
  47. 47. Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
  48. 48. Department of Immunology, Motol University Hospital, Prague, Czech Republic
  49. 49. Second Faculty of Medicine, Charles University, Prague, Czech Republic
  50. 50. Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland
  51. 51. Department of Pediatric Hematology and Oncology, University Hospital of Caen, Caen, France
  52. 52. Departments of Pediatrics, University Hospitals Leuven, Leuven, Belgium
  53. 53. Microbiology, Immunology, and Transplantation, University Hospitals Leuven, Leuven, Belgium
  54. 54. Barts Health National Health Service Trust, London, United Kingdom
  55. 55. Molecular and Cellular Immunology Section, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, London, United Kingdom
  56. 56. Institute of Immunity and Transplantation, London, United Kingdom
  57. 57. Great Ormond Street Institute of Child Health, London, United Kingdom
  58. 58. Great Ormond Street Hospital for Children, University College London, London, United Kingdom
  59. 59. Department of Immunology, Royal Free London National Health Service Foundation Trust, London, United Kingdom
  60. 60. Department of System Medicine, Pediatric Chair, University of Tor Vergata, Rome, Italy
  61. 61. Research and Clinical Unit of Primary Immunodeficiencies, IRCCS Bambin Gesu Children Hospital, Rome, Italy
  62. 62. Internal Medicine, University Hospital, Saint-Etienne, France
  63. 63. Department of Pediatrics, North Hospital, University Hospital of Saint Etienne, Saint-Etienne, France
  64. 64. University Jean Monnet, Saint-Etienne, France
  65. 65. Pediatric Hematology Oncology, Department of Mother and Child, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
  66. 66. Pediatric Department, Comenius University Medical Faculty, Bratislava, Slovakia
  67. 67. Belfast Health and Social Care Trust, Ireland, United Kingdom
  68. 68. Department of Hematology, Nancy University Hospital, Universite de Lorraine, Nancy, France
  69. 69. UMR 7365, Centre National de la Recherche Scientifique, Ingenierie Moleculaire et Physiopathologie Articulaire, Universite de Lorraine, Nancy, France
  70. 70. Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  71. 71. Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  72. 72. Department of Medicine, Queen Silvia Children's Hospital, Gothenburg, Sweden
  73. 73. University Clinical Centre of the Republic of Srpska, Republic of Srpska, Bosnia and Herzegovina
  74. 74. University Hospital Southampton, Southampton, United Kingdom
  75. 75. Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital, Barcelona, Spain
  76. 76. Hematology Department, CHU, Angers, France
  77. 77. Pediatric Unit, Angers University Hospital, Angers, France
  78. 78. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University–University Hospital Dusseldorf, Dusseldorf, Germany
  79. 79. Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
  80. 80. Division of Pediatric Immunology and Rheumatology, Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universitat Munchen, Munich, Germany
  81. 81. Institute for AI and Informatics in Medicine, University Hospital Rechts der Isar, Technical University Munich, Munich, Germany
  82. 82. Department of Pediatrics, Immunology, Infectious and Rare Diseases, European Medical School, International European University, Kyiv, Ukraine
  83. 83. Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom
  84. 84. Department of Pediatric Immunology, Rheumatology, & Infectiology, Hospital for Children and Adolescents, Leipzig University, Leipzig, Germany
  85. 85. Department of Pediatrics, Penteli Children's Hospital, Athens, Greece
  86. 86. Department of Paediatric Haematology and Oncology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland
  87. 87. Russian Clinical Childrens Hospital, Pirogov Russian National Research Medical University, Moscow, Russian Federation
  88. 88. Department of Immunology, Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
  89. 89. Department of Pediatrics, Universitatsklinikum Carl-Gustav-Carus, Technische Universitat Dresden, Dresden, Germany
  90. 90. Charite–Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin and Humboldt–Universitat zu Berlin, Berlin, Germany
  91. 91. Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Berlin Institute of Health, Berlin, Germany
  92. 92. General Pediatrics, CHU Montpellier, Montpellier, France
  93. 93. Pathogenesis and Control of Chronic Infections, INSERM, Universite de Montpellier, Montpellier, France
  94. 94. Department of Internal Medicine, Hopital d'Estaing, Clermont-Ferrand, France
  95. 95. Department of Pediatrics, CHU Clermont-Ferrand, Clermont-Ferrand, France
  96. 96. Pediatric Hematology, Oncology, and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy
  97. 97. Center for Pediatrics and Adolescent Medicine, Department of Pediatric Hematology and Oncology, Medical Center, University Hospital Giessen, Giessen, Germany
  98. 98. Paediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Red de Investigacion Translacional en Infectologia Pediatrica, Seville, Spain
  99. 99. Hospices Civils de Lyon, Lyon, France
  100. 100. Department of Internal Medicine, CHU Rennes, Rennes, France
  101. 101. Division of Immunology, University Children's Hospital Zurich, Zurich, Switzerland
  102. 102. Children's Research Center, Zurich, Switzerland
  103. 103. Department of Immunology, University Hospital Zurich, Zurich, Switzerland
  104. 104. Unit of Pediatric Immuno Hemato and Oncology, University Hospital Centre of Grenoble, Grenoble, France
  105. 105. Internal Medicine Department, Felix Guyon University Hospital, Saint Denis, La Reunion, France
  106. 106. Mixed Research Unit (UMR) “Infectious Processes in Tropical Island Environments�, La Reunion, France
  107. 107. Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology, Minsk, Belarus
  108. 108. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
  109. 109. Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom
  110. 110. Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
  111. 111. Great North Children' s Hospital, Newcastle upon Tyne, United Kingdom
  112. 112. Newcastle University, Newcastle upon Tyne, United Kingdom
  113. 113. Department of Medical Sciences, University of Trieste, Trieste, Italy
  114. 114. Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy
  115. 115. Amalia Children's Hospital, Radboudumc, Nijmegen, Netherlands
  116. 116. Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, Netherlands
  117. 117. Service de Pneumologie, Hopital Foch, Suresnes, France
  118. 118. Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Tex
  119. 119. William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex
  120. 120. Department of Clinical Immunology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom
  121. 121. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
  122. 122. Department of Infection, Immunity and Cardiovascular Diseases, University of Sheffield, Sheffield, United Kingdom

Source: Journal of Allergy and Clinical Immunology Published:2023


Abstract

Background: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients. © 2023 American Academy of Allergy, Asthma & Immunology
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