AA Bousfiha

Amos Etzioni

Aziz Bousfiha

C Troedson

Capucine Picard

Charlotte Cunningham‐Rundles

Christoph Klein

Eric Oksenhendler

Fatima Ailal

GW Sewell

H. Bobby Gaspar

Hans D. Ochs

HD Ochs

Jean‐Laurent Casanova

Jennifer M. Puck

Jose Luis Franco

Kathleen E. Sullivan

Leïla Jeddane

Mary Ellen Conley

Mimi L. K. Tang

MJ Ciancanelli

S Federici

Shigeaki Nonoyama

Steven M. Holland

Talal Chatila

V Modell

Waleed Al-Herz

Abstract
          There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes are ascribed to Primary Immunodeficiency Diseases (PID), making PIDs a rapidly expanding field of medicine. The International Union of Immunological Societies (IUIS) PID expert committee (EC) has published every other year a classification of these disorders into tables, defined by shared pathogenesis and/or clinical consequences. In 2013, the IUIS committee also proposed a more user-friendly, phenotypic classification, based on the selection of key phenotypes at the bedside. We herein propose the revised figures, based on the accompanying 2015 IUIS PID EC classification.</jats:p

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ORIGINAL RESEARCHThe 2015 IUIS Phenotypic Classification for PrimaryImmunodeficienciesAziz Bousfiha1 & Leïla Jeddane1 & Waleed Al-Herz2,3 & Fatima Ailal1 &Jean‐Laurent Casanova4,5,6,7,8 & Talal Chatila9 & Mary Ellen Conley4 &Charlotte Cunningham‐Rundles10 & Amos Etzioni11 & Jose Luis Franco12 &H. Bobby Gaspar13 & Steven M. Holland14 & Christoph Klein15 &Shigeaki Nonoyama16 & Hans D. Ochs17 & Eric Oksenhendler18,19 &Capucine Picard5,20 & Jennifer M. Puck21 & Kathleen E. Sullivan22 & Mimi L. K. Tang23,24,25Received: 11 August 2015 /Accepted: 16 September 2015 /Published online: 7 October 2015# Springer Science+Business Media New York 2015Abstract There are now nearly 300 single-gene inborn errorsof immunity underlying phenotypes as diverse as infection,malignancy, allergy, auto-immunity, and auto-inflammation.For each of these five categories, a growing variety ofphenotypes are ascribed to Primary ImmunodeficiencyDiseases (PID), making PIDs a rapidly expanding field ofmedicine. The International Union of Immunological Socie-ties (IUIS) PID expert committee (EC) has published every* Aziz Bousfihaprofbousfiha@gmail.com1 Clinical Immunology Unit, A. Harouchi Hospital, Ibn RoshdMedical School, King Hassan II University, Casablanca, Morocco2 Department of Pediatrics, Faculty of Medicine Kuwait University,Jabriya, Kuwait3 Allergy and Clinical Immunology Unit, Department of Pediatrics,Al-Sabah Hospital, Kuwait City, Kuwait4 St. Giles Laboratory of Human Genetics of Infectious Diseases,Rockefeller Branch, The Rockefeller University, New York, NY,USA5 Howard Hughes Medical Institute, New York, NY, USA6 Laboratory of Human Genetics of Infectious Diseases, NeckerBranch, INSERM UMR1163, Necker Hospital for Sick Children,Paris, France7 Imagine Institute, University Paris Descartes, Paris, France8 Pediatric Hematology & Immunology Unit, Necker Hospital for SickChildren, Paris, France9 Division of Immunology, Children’s Hospital Boston, Boston, MA,USA10 Department of Medicine and Pediatrics, Mount Sinai School ofMedicine, New York, NY, USA11 Meyer Children’s Hospital‐Technion, Haifa, Israel12 Group of Primary Immunodeficiencies, University of Antioquia,Medellin, Colombia13 UCL Institute of Child Health, London, UK14 Laboratory of Clinical Infectious Diseases, National Institute ofAllergy and Infectious Diseases, Bethesda, MD, USA15 Dr von Hauner Children’s Hospital, Ludwig‐Maximilians UniversityMunich, Munich, Germany16 Department of Pediatrics, National Defense Medical College,Saitama, Japan17 Department of Pediatrics, University of Washington and SeattleChildren’s Research Institute, Seattle, WA, USA18 Department of Clinical Immunology, Hôpital Saint-Louis,Assistance Publique‐Hôpitaux de Paris, Paris, France19 Université Paris Diderot, Sorbonne Paris Cité, Paris, France20 Centre d’étude des déficits immunitaires (CEDI), Hôpital Necker‐Enfants Malades, AP-HP, Paris, France21 Department of Pediatrics, University of California San Francisco andUCSF Benioff Children’s Hospital, San Francisco, CA, USA22 Division of Allergy Immunology, Department of Pediatrics, TheChildren’s Hospital of Philadelphia, Philadelphia, PA, USA23 Murdoch Childrens Research Institute, Melbourne, VIC, Australia24 Department of Paediatrics, University of Melbourne,Melbourne, VIC, Australia25 Department of Allergy and Immunology, Royal Children’s Hospital,Melbourne, VIC, AustraliaJ Clin Immunol (2015) 35:727–738DOI 10.1007/s10875-015-0198-5other year a classification of these disorders into tables, de-fined by shared pathogenesis and/or clinical consequences. In2013, the IUIS committee also proposed a more user-friendly,phenotypic classification, based on the selection of key phe-notypes at the bedside. We herein propose the revised figures,based on the accompanying 2015 IUIS PID EC classification.Keywords Primary immunodeficiencies . classification .IUIS PID expert committeeAbbreviationsαFP Alpha- fetoproteinAb AntibodyAD Autosomal dominant inheritanceADA Adenosine deaminaseAdp AdenopathyALPS Autoimmune lymphoproliferative syndromeAML Acute myeloid leukemiaAnti PPS Anti- pneumococcus antibodyAR Autosomal recessive inheritanceBCG Bacilli Calmette-GuerinBL B lymphocyteCAMPS CARD14 mediated psoriasisCANDLE Chronic atypical neutrophilic dermatosis withlipodystrophy and elevated temperaturesyndromeCAPS Cryopyrin-associated periodic syndromesCBC Complete blood countCD Cluster of differentiationCDG-IIb Congenital disorder of glycosylation, type IIbCGD Chronic granulomatous diseaseCID Combined immunodeficiencyCINCA Chronic infantile neurologic cutaneous and ar-ticular syndromeCMC Chronic mucocutaneous candidiasisCMF Flow cytometry availableCMV CytomegalovirusCMML Chronic myelomonocytic leukemiaCNS Central nervous systemCSF Cerebrospinal fluidCT Computed tomographyCTL Cytotoxic T-lymphocyteDA Duration of attacksDef DeficiencyDHR DiHydroRhodamineDip DiphtheriaDITRA Deficiency of interleukin 36 receptor antagonistEBV Epstein-Barr virusEDA Anhidrotic ectodermal dysplasiaEDA-ID Anhidrotic ectodermal dysplasia withimmunodeficiencyEO EosinophilsFA Frequency of attacksFCAS Familial cold autoinflammatory syndromeFILS Facial dysmorphism, immunodeficiency, livedo,and short statureFISH Fluorescence in situ hybridizationGI GastrointestinalGOF Gain-of-functionHHV8 Human herpes virus type 8Hib Haemophilus influenzae serotype bHIDS Hyper IgD syndromeHIES Hyper IgE syndromeHIGM Hyper Ig M syndromeHLA Human leukocyte antigenHLH Hemophagocytic lymphohistiocytosisHPV Human papilloma virusHSM HepatosplenomegalyHSV Herpes simplex virusHUS Hemolytic uremic syndromeHx Medical historyIBD Inflammatory bowel diseaseIFNγ Interferon gammaIg ImmunoglobulinIL InterleukinIUGR Intrauterine growth retardLAD Leukocyte adhesion deficiencyLOF Loss-of-functionMC Molluscum contagiosumMKD Mevalonate kinase deficiencyMSMD Mendelian susceptibility to mycobacterialdiseaseMWS Muckle-wells syndromeN Normal, not lowNK Natural killerNKT Natural killer T cellNN NeonatalNOMID Neonatal onset multisystem inflammatorydiseaseNP NeutropeniaPAPA Pyogenic sterile arthritis, pyodermagangrenosum, acne syndromePMN NeutrophilsSCID Severe combined immuno deficiencySd SyndromeSLE Systemic lupus erythematosusSPM SplenomegalyStaph Staphylococcus sp.728 J Clin Immunol (2015) 35:727–738subcl SubclassTCR T-cell receptorTet TetanusT T lymphocyteTNF Tumor necrosis factorTRAPS TNF receptor-associated periodic syndromeVZV Varicella zoster virusWBC White blood cellsXL X-linkedIntroductionHuman Primary Immunodeficiency Diseases (PID) compriseat least 300 genetically-defined single-gene inborn errors ofimmunity [1]. Long considered as rare diseases, recent studiestend to show that they are more common than generallythought, if only by their rapidly increasing number [2]. Theymay be even more common, if we consider the emergingmonogenic determinants leading to common infectious dis-eases, such as severe influenza [3]; autoimmune diseases, suchas systemic lupus erythematosus [4], and auto-inflammatorydiseases, such as Crohn’s disease [5]. The International Unionof Immunological Societies (IUIS) PID expert committee hasFig. 1 Immunodeficiencies affecting cellular and humoral immunity.ADA Adenosine Deaminase, Adp adenopathy, AR Autosomal Recessiveinheritance, CBC Complete Blood Count, CD Cluster of Differentiation,CID Combined Immunodeficiency, EBV Epstein-Barr Virus, EOEosinophils, HHV8 Human Herpes virus type 8, HIGM Hyper IgMsyndrome, HLA Human Leukocyte Antigen, HSM Hepatosplenomegaly,HPV Human papilloma virus, IBD Inflammatory bowel disease, IgImmunoglobulin, MCMolluscum contagiosum, N Normal, not low, NKNatural Killer, NN Neonatal, NP Neutropenia, SCID Severe CombinedImmunoDeficiency, Staph Staphylococcus sp., TCR T-Cell Receptor,XL X-LinkedJ Clin Immunol (2015) 35:727–738 729Fig. 2 CID with associated or syndromic features. These syndromes aregenerally associated with T-cell immunodeficiency. αFP alpha-fetoprotein, AD Autosomal Dominant inheritance, AR AutosomalRecessive inheritance, CMF Flow cytometry available, EDA Anhidroticectodermal dysplasia, EDA-ID Anhidrotic Ectodermal Dysplasia withImmunodeficiency, FILS Facial dysmorphism, immunodeficiency,livedo, and short stature, FISH Fluorescence in situ Hybridization, HSMHepatosplenomegaly, HSV Herpes simplex virus, Ig Immunoglobulin,VZV Varicella Zoster virus, WAS Wiskott-Aldrich syndrome, XLX-Linked inheritance730 J Clin Immunol (2015) 35:727–738Fig. 3 Predominantly Antibody deficiencies. Ab Antibody, Adpadenopathy, Anti PPS Anti- pneumococcus Antibody, AR AutosomalRecessive inheritance, CD Cluster of Differentiation, CDG-IIbCongenital disorder of glycosylation, type IIb, CMV Cytomegalovirus,CT Computed Tomography, EBV Epstein-Barr Virus, Dip Diphtheria, GIGastrointestinal, Hib Haemophilus influenzae serotype b, Hx medicalhistory, Ig Immunoglobulin, SPM Splenomegaly, subcl subclass, TetTetanus, XL X-Linked inheritanceJ Clin Immunol (2015) 35:727–738 731Fig. 4 Diseases of Immune Dysregulation. AD Autosomal Dominantinheritance, ALPS Autoimmune lymphoproliferative syndrome, ARAutosomal Recessive inheritance, CD Cluster of Differentiation, CMFFlow cytometry available, CSF Cerebrospinal fluid, CTL Cytotoxic T-Lymphocyte, EBV Epstein-Barr Virus, GOF Gain-of-function, HLHHemophagocytic lymphohistiocytosis, HSM Hepatosplenomegaly, IBDInflammatory bowel disease, IFNγ Interferon gamma, IgImmunoglobulin, IL interleukin, Inflam Inflammation,NKNatural Killer,NKT Natural Killer T cell, T T lymphocyte, XL X-Linked inheritance732 J Clin Immunol (2015) 35:727–738Fig. 5 Congenital defects of phagocyte number, function, or both. ForDHR assay, the results can distinct XL-CGD from AR-CGD, andgp40phox defect from others AR forms. AD Autosomal Dominantinheritance, AML Acute Myeloid Leukemia, AR Autosomal Recessiveinheritance, BCG Bacilli Calmette-Guérin, CBC Complete Blood Count,CD Cluster of Differentiation, CGD Chronic Granulomatous Disease,CMML Chronic MyeloMonocytic Leukemia, DHR DiHydroRhodamine,IUGR Intrauterine growth retard, LAD Leukocyte Adhesion Deficiency,NP Neutropenia, PNN Neutrophils, SCN Severe congenital neutropenia,WBCWhite Blood Cells, XL X-Linked inheritanceJ Clin Immunol (2015) 35:727–738 733Fig. 6 Defects in Intrinsec and Innate Immunity. AD AutosomalDominant inheritance, AR Autosomal Recessive inheritance, BCGBacilli Calmette-Guérin, BL B lymphocyte, CMC Chronicmucocutaneous candidiasis, HSV Herpes simplex virus, IFNγ Interferongamma, Ig Immunoglobulin, IL interleukin, LOF Loss-of-function,MSMD Mendelian Susceptibility to Mycobacterial Disease, PMNNeutrophils, XL X-Linked inheritance734 J Clin Immunol (2015) 35:727–738Fig. 7 Autoinflammatory Disorders. AD Autosomal Dominantinheritance, AR Autosomal Recessive inheritance, CAMPS CARD14mediated psoriasis, CANDLE Chronic atypical neutrophilic dermatosiswith lipodystrophy and elevated temperature syndrome, CAPSCryopyrin-Associated Periodic syndromes, CINCA Chronic InfantileNeurologic Cutaneous and Articular syndrome, DA Duration ofAttacks, DITRA deficiency of interleukin 36 Receptor antagonist, FAFrequency of Attacks, HIDS Hyper IgD syndrome, Ig Immunoglobulin,IL interleukin,MKDMevalonate Kinase deficiency,MWSMuckle-Wellssyndrome, NOMID Neonatal Onset Multisystem InflammatoryDisease, PAPA Pyogenic sterile Arthritis, Pyoderma gangrenosum, Acnesyndrome, SPM Splenomegaly, TNF Tumor Necrosis Factor, TRAPSTNF Receptor-Associated Periodic SyndromeJ Clin Immunol (2015) 35:727–738 735Fig. 8 Complement deficiencies. AD Autosomal Dominant inheritance, GOF Gain-of-function, LOF Loss-of-function, LAD Leukocyte AdhesionDeficiency, SLE Systemic Lupus Erythematosus736 J Clin Immunol (2015) 35:727–738Fig. 9 Phenocopies of primaryimmunodeficiencies. AbAntibody, ALPS Autoimmunelymphoproliferative syndrome,CMC Chronic mucocutaneouscandidiasis, CID CombinedImmunodeficiency, HUSHemolytic uremic syndrome,IFNγ Interferon gamma, ILInterleukin, MSMDMendelianSusceptibility to MycobacteriaDisease, VZV Varicella ZostervirusJ Clin Immunol (2015) 35:727–738 737proposed a PID classification [1], which facilitates clinicalresearch and comparative studies world-wide; it is updatedevery other year to include new disorders or disease-causinggenes. This classification is organized in tables, each of whichgroups PIDs that share a given pathogenesis. As this classifi-cation may be cumbersome for use by the clinician at thebedside, the IUIS PID expert committee recently proposed aphenotypic complement to its classification [6]. As the num-ber of PIDs is quickly increasing, and at an even faster pacesince the advent of next-generation sequencing, the phenotyp-ic classification from 2013 became outdated and requires re-vision at the same pace as the classical IUIS classification. Ouroriginal phenotypic classification proved successful, whichplaced it in the 96th percentile for citation rank in Springerjournals [7]. Given the success of our user-friendly classifica-tion of PIDs, providing a tree-based decision-making processbased on the observation of clinical and biological pheno-types, we present here an update of these figures, based onthe accompanying 2015 PID classification.MethodologyWe included all diseases included in the 2015 update of theIUIS PID classification [1], keeping the nine major categoriesunchanged. In addition, we considered other articles propos-ing a PID classification published recently [8, 9]. An algo-rithm was assigned to each of the nine main groups of theclassification and the same color was used for each group ofsimilar conditions. Disease names are presented in red andgenes in bold. In addition, we classed diseases or genes frommost common to less common, at the best of our knowledge[10, 11]. These algorithms were first established by a smallcommittee; then validated by one or two experts for eachfigure.ResultsAn update of our classification, validated by the IUIS PIDexpert committee, is presented in Figs. 1, 2, 3, 4, 5, 6, 7, 8and 9.DiscussionSince our 2013 study, 70 new diseases have been included inthe 2015 classification. Four disorders have been removed, asthe reports concerning associated immunodeficiency or genet-ic base were not confirmed. We also eliminated duplication ofa disease in more than one figure and profoundly revised somefigures, following the 2015 IUIS classification.ConclusionThe IUIS PID expert committee developed this phenotypicclassification in order to help clinicians at the bedside to diag-nose PIDs but also to promote collaboration with national andinternational research centers. Needless to say, the expert com-mittee encourages the development of other types of PID clas-sification. Indeed, given the success encountered by the twocurrent IUIS classifications, others classifications are likely tobe useful and complementary.References1. IUIS classification (to be precised) 2015.2. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N,Casanova JL, et al. Primary immunodeficiency diseases worldwide:more common than generally thought. J Clin Immunol. 2013;33(1):1–7.3. Ciancanelli MJ, Huang SX, Luthra P, Garner H, Itan Y, Volpi S,et al. Life-threatening influenza and impaired interferon amplifica-tion in human IRF7 deficiency. Science. 2015;348(6233):448–53.4. Troedson C, Wong M, Dalby-Payne J, Wilson M, Dexter M, RiceGI, et al. Systemic lupus erythematosus due to C1q deficiency withprogressive encephalopathy, intracranial calcification and acquiredmoyamoya cerebral vasculopathy. Lupus. 2013;22(6):639–43.5. Sewell GW, Rahman FZ, Levine AP, Jostins L, Smith PJ, WalkerAP, et al. Defective tumor necrosis factor release from Crohn’sdisease macrophages in response to Toll-like receptor activation:relationship to phenotype and genome-wide association suscepti-bility loci. Inflamm Bowel Dis. 2012;18(11):2120–7.6. Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME,Cunningham-Rundles C, et al. A phenotypic approach for IUISPID classification and diagnosis: guidelines for clinicians at thebedside. J Clin Immunol. 2013;33(6):1078–87.7. Springer Science. In: Citations Springer. 2015. http://citations.springer.com/item?doi=10.1007/s10875-013-9901-6.Accessed 20 Jul 2015.8. Ochs HD, Hagin D. Primary immunodeficiency disorders: generalclassification, new molecular insights, and practical approach todiagnosis and treatment. Ann Allergy Asthma Immunol.2014;112(6):489–95.9. Federici S, Martini A, Gattorno M. The central role of anti-IL1blockade in the treatment of monogenic and multi-factorialautoinflammatory diseases. Front Immunol. 2013;4:351.10. Modell V, Knaus M, Modell F, Roifman C, Orange J, NotarangeloLD. Global overview of primary immunodeficiencies: a report fromJeffrey Modell Centers worldwide focused on diagnosis, treatment,and discovery. Immunol Res. 2014;60(1):132–44.11. Online Mendelian Inheritance in Man (OMIM). An Online Catalogof Human Genes and Genetic Disorders. In: Online MendelianInheritance in Man. http://omim.org/ Accessed 20 Jul 2015.738 J Clin Immunol (2015) 35:727–738

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The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies

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The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies

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