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. 2023 Oct;152(4):984-996.e10.
doi: 10.1016/j.jaci.2023.06.015. Epub 2023 Jun 28.

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Maria Elena Maccari  1 , Martin Wolkewitz  2 , Charlotte Schwab  3 , Tiziana Lorenzini  4 , Jennifer W Leiding  5 , Nathalie Aladjdi  6 , Hassan Abolhassani  7 , Wadih Abou-Chahla  8 , Alessandro Aiuti  9 , Saba Azarnoush  10 , Safa Baris  11 , Vincent Barlogis  12 , Federica Barzaghi  13 , Ulrich Baumann  14 , Marketa Bloomfield  15 , Nadezda Bohynikova  16 , Damien Bodet  17 , David Boutboul  18 , Giorgia Bucciol  19 , Matthew S Buckland  20 , Siobhan O Burns  21 , Caterina Cancrini  22 , Pascal Cathébras  23 , Marina Cavazzana  24 , Morgane Cheminant  25 , Matteo Chinello  26 , Peter Ciznar  27 , Tanya I Coulter  28 , Maud D'Aveni  29 , Olov Ekwall  30 , Zelimir Eric  31 , Efrem Eren  32 , Anders Fasth  33 , Pierre Frange  34 , Benjamin Fournier  35 , Marina Garcia-Prat  36 , Martine Gardembas  37 , Christoph Geier  38 , Sujal Ghosh  39 , Vera Goda  40 , Lennart Hammarström  41 , Fabian Hauck  42 , Maximilian Heeg  43 , Edyta Heropolitanska-Pliszka  16 , Anna Hilfanova  44 , Stephen Jolles  45 , Elif Karakoc-Aydiner  46 , Gerhard R Kindle  47 , Ayca Kiykim  48 , Christian Klemann  49 , Patra Koletsi  50 , Sylwia Koltan  51 , Irina Kondratenko  52 , Julia Körholz  53 , Renate Krüger  54 , Eric Jeziorski  55 , Romain Levy  35 , Guillaume Le Guenno  56 , Guillaume Lefevre  57 , Vassilios Lougaris  58 , Antonio Marzollo  59 , Nizar Mahlaoui  60 , Marion Malphettes  18 , Andrea Meinhardt  61 , Etienne Merlin  62 , Isabelle Meyts  19 , Tomas Milota  15 , Fernando Moreira  63 , Despina Moshous  64 , Anna Mukhina  65 , Olaf Neth  66 , Jennifer Neubert  39 , Benedicte Neven  67 , Alexandra Nieters  47 , Raphaele Nove-Josserand  68 , Eric Oksenhendler  18 , Ahmet Ozen  46 , Peter Olbrich  66 , Antoinette Perlat  69 , Malgorzata Pac  16 , Jana Pachlopnik Schmid  70 , Lucia Pacillo  22 , Alba Parra-Martinez  36 , Olga Paschenko  52 , Isabelle Pellier  71 , Asena Pinar Sefer  11 , Alessandro Plebani  58 , Dominique Plantaz  72 , Seraina Prader  70 , Loic Raffray  73 , Henrike Ritterbusch  43 , Jacques G Riviere  36 , Beatrice Rivalta  22 , Stephan Rusch  43 , Inga Sakovich  74 , Sinisa Savic  75 , Raphael Scheible  76 , Nicolas Schleinitz  77 , Catharina Schuetz  53 , Ansgar Schulz  78 , Anna Sediva  15 , Michaela Semeraro  79 , Svetlana O Sharapova  74 , Anna Shcherbina  65 , Mary A Slatter  80 , Georgios Sogkas  81 , Pere Soler-Palacin  36 , Carsten Speckmann  82 , Jean-Louis Stephan  83 , Felipe Suarez  25 , Alberto Tommasini  84 , Johannes Trück  70 , Annette Uhlmann  85 , Koen J van Aerde  86 , Joris van Montfrans  87 , Horst von Bernuth  54 , Klaus Warnatz  88 , Tony Williams  32 , Austen J J Worth  89 , Winnie Ip  90 , Capucine Picard  91 , Emilie Catherinot  92 , Zohreh Nademi  80 , Bodo Grimbacher  93 , Lisa R Forbes Satter  94 , Sven Kracker  95 , Anita Chandra  96 , Alison M Condliffe  97 , Stephan Ehl  43 ; European Society for Immunodeficiencies Registry Working Party
Collaborators, Affiliations
Free article

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Maria Elena Maccari et al. J Allergy Clin Immunol. 2023 Oct.
Free article

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.

Keywords: APDS; CTLA4; ESID; IEI; NFKB1; PI3K; PIK3CD; PIK3R1; STAT3; immunodeficiency.

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