International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity (original) (raw)

Abstract

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

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Introduction

In 1970, Drs. Fudenberg, Good, Hitzig, Kunkel, Roitt, Rosen, Rowe, Seligmann, and Soothill met under the auspices of the World Health Organization to classify the emerging “primary immune deficiencies.” This august group focused on understanding whether immunodeficiencies could be categorized as B cell disorders or T cell disorders [1, 2]. Their initial report identified 16 distinct immunodeficiencies and included the prophetic comment that “the variable immunodeficiency group probably lumps together a series of syndromes…. Included in this group are cases previously classified as ‘congenital’, non-sex linked or sporadic hypogammaglobulinemia, primary ‘dysgammglobulinemia’ of both childhood and adult life, and ‘acquired’ primary hypogammaglobulinemia. It is hoped that careful analysis of such patients…. will result in delineation of several homogeneous syndromes…”. Indeed, the emergence of monogenic causes of hypogammaglobulinemia (Table 3) and disorders with variable immunoglobulin abnormalities associated with immune dysregulation (Table 4) have been the groups of immunodeficiencies most transformed by the advent of new technologies. Another group dramatically impacted by resetting of the clinical radar and new techniques has been the set of disorders associated with a limited spectrum of infectious susceptibility. The graphs in Fig. 1 define the transformation of the field over the interval during which next-generation sequencing came to prominence. The tremendous progress, energy, and enthusiasm in the field currently have led to a greater need than ever for a current cataloging of the disorders.

Fig. 1

Each publication of the World Health Organization and IUIS Primary Immunodeficiencies Committee was reviewed for the number of conditions listed and displayed graphically [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. The rapid increase in the twenty-first century relates to improved awareness and increasing use of sequencing. Assuming 20,000 coding genes in the human genome, inborn errors of immunity are implicated through mutations in 1.7% of these genes. There are now 330 specific disorders, 320 monogenic defects, 312 distinct genes (nine genes with both LOF and GOF and C4 deficiency requiring defects in both C4A and C4B). a The categorization of the inborn errors of immunity according the schema in the current manuscript. b The categorization of the inborn errors of immunity according to their inheritance

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The new disorders (since 2015 [3]) represent an impressive spectrum of phenotypes. There are 354 distinct disorders with 344 different gene defects listed. The emerging dominance of next-generation sequencing has driven the rapid increase in the number of recognized disorders which has led to two major consequences. Often new inborn errors of immunity are initially described in a single kindred or a small number of kindreds. This may lead to incorrect assumptions about prevalence and phenotype. In fact, for most disorders, we have little idea of the prevalence within even the recognized population with the described phenotype. The second consequence of the rapid rise of next-generation sequencing is a striking expansion of the phenotypic spectrum associated with many diseases. Where once the phenotype of a given disorder was clear, the spectrum of manifestations often extends impressively once the ascertainment is not linked to a preconceived idea [20]. As a community, we recognize the importance of publishing cases and small series and to report specific mutations with clinical findings because publications are used to define likelihood of causality during bioinformatic analysis of next-generation sequencing results.

In 1999, the Committee on Primary Immunodeficiencies came under the auspices of the International Union of Immunological Societies (IUIS). The current committee met on February 23–24, 2017, in London to update the classification of human primary immunodeficiencies. Inclusion in this “master list” requires a body of literature supporting causality of a gene defect and a penetrance indicating clinical relevance [21]. Committee members vote on inclusion of each new disorder and this publications lists those included as of the February 2017 meeting. The landscape is changing so rapidly, and the number of primary immunodeficiencies growing so fast, that two major changes have been implemented. The published list will continue to serve as a reference; however, this list will now be available as a csv file on the IUIS website to enable sorting according to gene, disease name, or clinical/laboratory feature. This file will also include the associated ICD10 codes in order to promote harmonization of utilization. The second major change is to the nomenclature. The term primary immunodeficiency has an important legacy—the abbreviations PID or PIDD are often used by patient organizations and are recognized around the world. However, this terminology does limit the conceptualization of disorders to those in which susceptibility to infection is the main manifestation. The improving recognition of immune dysregulation diseases, including the growing field of autoinflammatory disorders and interferonopathies, has mandated that a more encompassing terminology be used. This manuscript, therefore, utilizes “inborn errors of immunity” as the descriptor for the work and the categorization. In addition to embracing technology to remain updated, the companion publication “Update of the Phenotypical IUIS Classification for Primary Immunodeficiencies” will provide a phenotype-oriented approach to the IUIS categorization of disorders. Moreover, a new free application can be found as “PID phenotypical diagnosis” or “PID classification” from iTunes and Android app stores [[22](/article/10.1007/s10875-017-0464-9#ref-CR22 "Boufiha A, Phenotypical classification of PIDD. 2017. https://play.google.com/store/apps/details?id=com.horiyasoft.pidclassification

              ."), [23](/article/10.1007/s10875-017-0464-9#ref-CR23 "Bousfiha A, Phenotypical classification of PIDD, iTunes. 2017. 
                https://itunes.apple.com/us/app/pid-phenotypical-diagnosis/id1160729399?mt=8
                
              .")\]. Information that is readily accessible is the new standard, and the IUIS Expert Committee on Primary Immunodeficiencies believes that improved access to information will positively impact patient care around the world.

The tables divide disease categories according to common phenotypes for ease of review and searching. Table 1 lists combined immunodeficiencies, Table 2 lists combined immunodeficiencies with syndromic features, Table 3 lists predominantly antibody deficiencies, Table 4 lists diseases of immune dysregulation, Table 5 lists defects of phagocyte number or function, Table 6 lists defects in intrinsic and innate immunity, Table 7 lists autoinflammatory diseases, Table 8 lists complement deficiencies, and Table 9 lists phenocopies of inborn errors of immunity. The division into phenotypes for the purpose of this list does not imply that the presentation is homogeneous. Each disorder is listed only once for the sake of simplicity although distinct modes of inheritance can be listed separately. There are nine genes for which both loss-of-function and gain-of-function variants have been identified: CFB, C3, CARD11, STAT1, STAT3, WAS, JAK1, IFIH1, and ZAP70. For these, the loss-of-function and gain-of-function aspects are listed. Within each table, there are additional sub-tables that segregate into coherent phenotypic sets. At the end of each table, the new disorders, added for this publication, are listed for easy reference. Other features important for navigation of the list include the use of OMIM links [[24](/article/10.1007/s10875-017-0464-9#ref-CR24 "OMIM Online Mendelian Inheritance in Man. https://www.ncbi.nlm.nih.gov/omim

              .")\]. For additional information on a gene, the links can be accessed from within the online publication. For the second time, we also include non-inborn errors of immunity in Table [9](/article/10.1007/s10875-017-0464-9#Tab9), representing phenocopies of inborn errors which might be important to consider diagnostically.

Table 1 Immunodeficiencies affecting cellular and humoral immunity

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Table 2 Combined immunodeficiencies with associated or syndromic features

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Table 3 Predominantly antibody deficiencies

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Table 4 Diseases of immune dysregulation

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Table 5 Congenital defects of phagocyte number or function

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Table 6 Defects in intrinsic and innate immunity

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Table 7 Autoinflammatory disorders

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Table 8 Complement deficiencies

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Table 9 Phenocopies of inborn errors of immunity

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The goal of the IUIS Expert Committee on Primary Immunodeficiencies is to increase awareness, facilitate recognition, promote optimal treatment, and support research in the field of immune deficiency disorders. Thus, the “IUIS PID Committee Report on Inborn Errors of Immunity” and “Update of the Phenotypical IUIS Classification for Primary Immunodeficiencies” publications are important resources for clinicians and researchers. In addition, these tables form the basis of lists used for sequencing panels and are used to monitor health utilization which will influence health services funding by federal or state governments and/or insurance companies in various global settings. The addition of ICD10 codes for the online version will promote a harmonization between the diagnostic tables and coding items that will facilitate bioinformatics research going forward.

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Acknowledgements

The authors wish to thank Dawn Westerfer for the expert secretarial support and Ulrika Smrekova for the administrative support.

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Authors and Affiliations

1. Center for the Study of Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
   Capucine Picard
2. Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, Paris Descartes University, Paris, France
   Capucine Picard
3. UCL Great Ormond Street Institute of Child Health, London, UK
   H. Bobby Gaspar
4. Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
   Waleed Al-Herz
5. Laboratoire d’Immunologie Clinique, d’Inflammation et d’Allergy LICIA Clinical Immunology Unit, Casablanca Children’s Hospital, Ibn Rochd Medical School, King Hassan II University, Casablanca, Morocco
   Aziz Bousfiha
6. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
   Jean-Laurent Casanova
7. Howard Hughes Medical Institute, New York, NY, USA
   Jean-Laurent Casanova
8. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, University Paris Descartes, Paris, France
   Jean-Laurent Casanova
9. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children APHP, Paris, France
   Jean-Laurent Casanova
10. Division of Immunology, Children’s Hospital Boston, Boston, MA, USA
    Talal Chatila
11. Laboratory of Neuroinflammation and Neurogenetics, Necker Branch, INSERM UMR1163, Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France
    Yanick J. Crow
12. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
    Yanick J. Crow
13. Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, NewYork, NY, USA
    Charlotte Cunningham-Rundles
14. Ruth’s Children’s Hospital-Technion, Haifa, Israel
    Amos Etzioni
15. Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia
    Jose Luis Franco
16. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
    Steven M. Holland
17. Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
    Christoph Klein
18. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
    Tomohiro Morio
19. Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, WA, USA
    Hans D. Ochs & Troy R. Torgerson
20. Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, University Paris Diderot, Sorbonne Paris Cité, Paris, France
    Eric Oksenhendler
21. Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’s Hospital, San Francisco, CA, USA
    Jennifer Puck
22. Murdoch Children’s Research Institute, Melbourne, VIC, Australia
    Mimi L. K. Tang
23. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
    Mimi L. K. Tang
24. Department of Allergy and Immunology, Royal Children’s Hospital, Melbourne, Australia
    Mimi L. K. Tang
25. Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
    Stuart G. Tangye
26. St Vincent’s Clinical School, University of NSW, Sydney, Australia
    Stuart G. Tangye
27. Division of Allergy Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, ARC 1216-I 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA
    Kathleen E. Sullivan

Authors

1. Capucine Picard
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2. H. Bobby Gaspar
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3. Waleed Al-Herz
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4. Aziz Bousfiha
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5. Jean-Laurent Casanova
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6. Talal Chatila
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7. Yanick J. Crow
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8. Charlotte Cunningham-Rundles
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9. Amos Etzioni
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10. Jose Luis Franco
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11. Steven M. Holland
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12. Christoph Klein
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13. Tomohiro Morio
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14. Hans D. Ochs
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15. Eric Oksenhendler
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16. Jennifer Puck
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17. Mimi L. K. Tang
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18. Stuart G. Tangye
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19. Troy R. Torgerson
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20. Kathleen E. Sullivan
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Correspondence toKathleen E. Sullivan.

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Picard, C., Bobby Gaspar, H., Al-Herz, W. et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity.J Clin Immunol 38, 96–128 (2018). https://doi.org/10.1007/s10875-017-0464-9

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• Received: 19 July 2017
• Accepted: 31 October 2017
• Published: 11 December 2017
• Issue Date: January 2018
• DOI: https://doi.org/10.1007/s10875-017-0464-9

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