. 2018 Jan;38(1):129-143.

doi: 10.1007/s10875-017-0465-8. Epub 2017 Dec 11.

The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies

Aziz Bousfiha¹, Leïla Jeddane^{2

3}, Capucine Picard^{4

5}, Fatima Ailal², H Bobby Gaspar⁶, Waleed Al-Herz⁷, Talal Chatila⁸, Yanick J Crow^{9

10}, Charlotte Cunningham-Rundles¹¹, Amos Etzioni¹², Jose Luis Franco¹³, Steven M Holland¹⁴, Christoph Klein¹⁵, Tomohiro Morio¹⁶, Hans D Ochs¹⁷, Eric Oksenhendler¹⁸, Jennifer Puck¹⁹, Mimi L K Tang^{20

21

22}, Stuart G Tangye^{23

24}, Troy R Torgerson¹⁷, Jean-Laurent Casanova^{25

26

27

28}, Kathleen E Sullivan²⁹

Affiliations

¹ Laboratory of Clinical Immunology, Inflammation and Allergy LICIA, Faculty of Medicine and Pharmacy, King Hassan II University, Casablanca, Morocco. profbousfiha@gmail.com.
² Laboratory of Clinical Immunology, Inflammation and Allergy LICIA, Faculty of Medicine and Pharmacy, King Hassan II University, Casablanca, Morocco.
³ Laboratoire National de Référence, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco.
⁴ Center for the Study of Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris(APHP), Paris, France.
⁵ Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, Paris Descartes University, Paris, France.
⁶ UCL Great Ormond Street Institute of Child Health, London, UK.
⁷ Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
⁸ Division of Immunology, Children's Hospital Boston, Boston, MA, USA.
⁹ Laboratory of Neuroinflammation and Neurogenetics, Necker Branch, INSERM UMR1163, Sorbonne-Paris-Cité, Institut Imagine, Paris Descartes University, Paris, France.
¹⁰ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
¹¹ Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, NewYork, NY, USA.
¹² Ruth's Children's Hospital-Technion, Haifa, Israel.
¹³ Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia.
¹⁴ Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
¹⁵ Dr von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
¹⁶ Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
¹⁷ Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
¹⁸ Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
¹⁹ Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, CA, USA.
²⁰ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²¹ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
²² Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia.
²³ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
²⁴ St Vincent's Clinical School, University of NSW, Sydney, Australia.
²⁵ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
²⁶ Howard Hughes Medical Institute, New York, NY, USA.
²⁷ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, University Paris Descartes, Paris, France.
²⁸ Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children APHP, Paris, France.
²⁹ Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

PMID: 29226301
PMCID: PMC5742599
DOI: 10.1007/s10875-017-0465-8

The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies

Aziz Bousfiha et al. J Clin Immunol. 2018 Jan.

. 2018 Jan;38(1):129-143.

doi: 10.1007/s10875-017-0465-8. Epub 2017 Dec 11.

Authors

Affiliations

¹ Laboratory of Clinical Immunology, Inflammation and Allergy LICIA, Faculty of Medicine and Pharmacy, King Hassan II University, Casablanca, Morocco. profbousfiha@gmail.com.
² Laboratory of Clinical Immunology, Inflammation and Allergy LICIA, Faculty of Medicine and Pharmacy, King Hassan II University, Casablanca, Morocco.
³ Laboratoire National de Référence, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco.
⁴ Center for the Study of Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris(APHP), Paris, France.
⁵ Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, Paris Descartes University, Paris, France.
⁶ UCL Great Ormond Street Institute of Child Health, London, UK.
⁷ Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
⁸ Division of Immunology, Children's Hospital Boston, Boston, MA, USA.
⁹ Laboratory of Neuroinflammation and Neurogenetics, Necker Branch, INSERM UMR1163, Sorbonne-Paris-Cité, Institut Imagine, Paris Descartes University, Paris, France.
¹⁰ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
¹¹ Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, NewYork, NY, USA.
¹² Ruth's Children's Hospital-Technion, Haifa, Israel.
¹³ Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia.
¹⁴ Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
¹⁵ Dr von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
¹⁶ Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
¹⁷ Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
¹⁸ Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
¹⁹ Department of Pediatrics, University of California San Francisco and UCSF Benioff Children's Hospital, San Francisco, CA, USA.
²⁰ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
²¹ Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
²² Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia.
²³ Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
²⁴ St Vincent's Clinical School, University of NSW, Sydney, Australia.
²⁵ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
²⁶ Howard Hughes Medical Institute, New York, NY, USA.
²⁷ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, University Paris Descartes, Paris, France.
²⁸ Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children APHP, Paris, France.
²⁹ Division of Allergy Immunology, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

PMID: 29226301
PMCID: PMC5742599
DOI: 10.1007/s10875-017-0465-8

Abstract

Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification of the inborn errors of immunity. This complete catalog serves as a reference for immunologists and researchers worldwide. However, it was unadapted for clinicians at the bedside. For those, the IUIS PID EC is now publishing a phenotypical classification since 2013, which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification.

Keywords: Classification; IUIS; Inborn errors of immunity; Phenotypic; Primary immunodeficiencies.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

**Fig. 1**
Immunodeficiencies affecting cellular and humoral immunity. a Severe combined immunodeficiencies defined by T cell lymphopenia. b Combined immunodeficiencies. * T cell lymphopenia in SCID is defined by CD3+ T cells < 300/µL. AD: autosomal dominant transmission; ADA: adenosine deaminase; Ag: antigen; AR: autosomal recessive transmission; β2m: bêta-2 microglobulin; Bc: B cells; CBC: complete blood count; CD: cluster of differentiation; CVID: common variable immunodeficiency; def: deficiency; EBV: Epstein Barr virus; HHV8: human herpes virus 8; HIGM: hyper IgM syndrome; HPV: human papillomavirus; Ig: immunoglobulins; MHC: major histocompatibility complex; Nl: normal; NK: natural killer; SCID: severe combined immunodeficiency; Tc: T cells; TCR: T cell receptor; Treg: regulatory T cells; XL: X-linked transmission

**Fig. 2**
a, b CID with associated or syndromic features. Ab: antibody; AD: autosomal dominant transmission; ANA: anti-nuclear antibodies; ANCA: anti-neutrophil cytoplasm antibodies; AR: autosomal recessive transmission; Bc: B cells; BCG: Bacillus Calmette-Guerin; BCR: B cell receptor; CD: cluster of differentiation; CMV: cytomegalovirus; CNS: central nervous system; def: deficiency; DNA: desoxyribonucleic acid; DKC: dyskeratosis congenita; EDA: anhidrotic ectodermal dysplasia; GOF: gain-of-function; HIES: hyper IgE syndrome; FILS: facial dysmorphism, immunodeficiency, livedo and short stature; ID: immunodeficiency; Ig: immunoglobulins; IUGR: intrauterine growth retardation; LOF: loss-of-function; MDS: myelodysplasia; Nl: normal; NK: natural killer; PHA: phytohemagglutinin; PPS: polysaccharides; SCID: severe combined immunodeficiency; sd: syndrome; Tc: T cells; TCR: T cell receptor; TREC: T cell receptor excision circle; XL: X-linked transmission

**Fig. 3**
Predominantly antibody deficiencies. a Hypogammaglobulinemias. b Other antibody deficiencies. AD: autosomal dominant transmission; AR: autosomal recessive transmission; Bc: B cells; BENTA: B cell expansion with NF-κB and T cell anergy; CD: cluster of differentiation; CMF: flow cytometry; COPD: chronic obstructive pulmonary disease; def: deficiency; EBV: Epstein Barr virus; GOF: gain-of-function; Hx: patient history; Ig: immunoglobulins; Nl: normal; XL: X-linked transmission

**Fig. 4**
Diseases of immune dysregulation. a Hemophagocytic lymphohistiocytosis. b Other diseases of immune dysregulation. Ab: antibody; AD: autosomal dominant transmission; Ag: antigen; ALPS: autoimmune lymphoproliferative syndrome; APS: autoimmune polyendocrinopathy syndrome; AR: autosomal recessive transmission; Bc: B cells; CD: cluster of differentiation; CMF: flow cytometry; CTL: cytotoxic T lymphocytes; def: deficiency; DNT: double negative T cells; EBV: Epstein Barr virus; FHL: familial hemophagocytic lymphohistiocytosis; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; (H)SM: (hepato)splenomegalia; IBD: inflammatory bowel disease; Ig: immunoglobulin; IL-10: interleukin-10; LOF: loss-of-function; iNKT: invariant NKT cells; NK: natural killer cells; Nl: normal; sd: syndrome; SLE: systemic lupus erythematous disease; Tc: T cells; TCR: T cell receptor; XL: X-linked transmission

None — Congenital defects of phagocyte number, function, or both. a Neutropenia. b Functional defects of phagocytes. AD: autosomal dominant transmission; AML: acute myeloid leukemia; AR: autosomal recessive transmission; BCG: Bacillus Calmette-Guerin; CD: cluster of differentiation; CGD: chronic granulomatous disease; CMF: flow cytometry; CMML: chronic myelomonocytic leukemia; def: deficiency; DHR: dihydrorhodamine-1,2,3; GOF: gain-of-function; IUGR: intrauterine growth retardation; MDS: myelodysplasia; NBT: nitroblue of tetrazolium; NK: natural killer cells; WBC: white blood cells; XL: X-linked transmission

**Fig. 6**
Defects in intrinsic and innate immunity. a Bacterial and parasitic infections. b MSMD and viral infection. AD: autosomal dominant transmission; AR: autosomal recessive transmission; BCG: Bacillus Calmette-Guerin; CD: cluster of differentiation; CMC: chronic mucocutaneous candidiasis; GOF: gain-of-function; IFNg: interferon-gamma; HHV6: human herpes virus type 6; HPV: human papilloma virus; HSV: herpes simplex virus; LOF: loss-of-function; MSMD: Mendelian susceptibility to mycobacterial disease; NK: natural killer cells; RNA: ribonucleic acid; sd: syndrome; Tc: T cells; TLR3: Toll-like receptor type 3; VZV: varicella zoster virus; XL: X-linked transmission

**Fig. 7**
a, b Autoinflammatory disorders. *Diseases affecting the inflammasome. AD: autosomal dominant transmission; AR: autosomal recessive transmission; BSN: bilateral striatal necrosis; CAPS: cryopirin-associated periodic syndrome; DA: duration of inflammation episode; FA: frequency of inflammation episode; FCL: familial chilblain lupus; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; HSM: hepatosplenomegalia; ICC: intracranial calcifications; IL: interleukin; LOF: loss-of-function; sd: syndrome; SLE: systemic lupus erythematosus; SMS: Singleton-Merten syndrome; SNHL: sensorineural hearing loss; SP: spastic paraparesis; TORCH: toxoplasmosis, other, rubella, cytomegalovirus, and herpes infections

**Fig. 8**
Complement deficiencies. AD: autosomal dominant transmission; AH50: alternate pathway hemolytic activity; AR: autosomal recessive transmission; CH50: complement hemolytic activity; def: deficiency; LOF: loss-of-function; sd: syndrome; SLE: systemic lupus erythematosus; XL: X-linked transmission

**Fig. 9**
Phenocopies of PID. ALPS: autoimmune lymphoproliferative syndrome; AutoAb: auto-antibodies; CID: combined immunodeficiency; CMC: chronic mucocutaneous candidiasis; GOF: gain-of-function; MSMD: Mendelian susceptibility to mycobacterial disease; PRCA: pure red cell aplasia

See this image and copyright information in PMC

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References

1. Picard C, Gaspar HB, Al-Herz W, Bousfiha A, Chatila T, Crow YJ, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee report on inborn errors of immunity. J Clin Immunol 2017(in Press). - PMC - PubMed
1. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova JL, Abel L. Primary immunodeficiency diseases worldwide: more common than generally thought. J Clin Immunol. 2013;33(1):1–7. doi: 10.1007/s10875-012-9751-7. - DOI - PubMed
1. Kobrynski L, Powell RW, Bowen S. Prevalence and morbidity of primary immunodeficiency diseases, United States 2001-2007. J Clin Immunol. 2014;34(8):954–961. doi: 10.1007/s10875-014-0102-8. - DOI - PMC - PubMed
1. Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol. 2013;33(6):1078–1087. doi: 10.1007/s10875-013-9901-6. - DOI - PMC - PubMed
1. Jeddane L, Ouair H, Benhsaien I, El Bakkouri J, Bousfiha AA. Primary immunodeficiency classification on smartphone. J Clin Immunol. 2017;37(1):1–2. doi: 10.1007/s10875-016-0354-6. - DOI - PubMed

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The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies

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The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies

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