Journal of Clinical Immunology (2020) 40:66–81 https://doi.org/10.1007/s10875-020-00758-x

ORIGINAL ARTICLE

Human Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical Classification

Aziz Bousfiha1,2 & Leila Jeddane3 & Capucine Picard4,5 & Waleed Al-Herz6 & Fatima Ailal1 & Talal Chatila7 & Charlotte Cunningham-Rundles8 & Amos Etzioni9 & Jose Luis Franco10 & Steven M Holland11 & Christoph Klein12 & Tomohiro Morio13 & Hans D. Ochs14 & Eric Oksenhendler15 & Jennifer Puck16 & Troy R. Torgerson14 & Jean-Laurent Casanova17,18,19,20 & Kathleen E. Sullivan21 & Stuart G. Tangye22,23

Received: 12 December 2019 /Accepted: 22 January 2020 /Published online: 11 February 2020 # The Author(s) 2020

Abstract Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classifi- cation into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algo- rithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.

Keywords IUIS . primary immune deficiency . inborn errors of immunity . immune dysregulation . autoinflammatory disorders . classification

Introduction of which groups IEI sharing a given pathogenesis. However, with the growing number of IEI included in this catalog, these Human inborn errors of immunity (IEI) are caused by monogenic tables are not always easy to use at the bedside. We thus germline mutations resulting in loss or gain of function of the reported from 2013 onward a more user-friendly classification encoded protein. They can be dominant or recessive, autosomal adapted for the clinician, based on the clinical and laboratory or X-linked, and with complete or incomplete penetrance. They features observed in these patients. This phenotypic classifi- manifest as increased susceptibility to a broad or narrow spec- cation proved to be as popular as the genotypic classification trum of infectious diseases, as well as a growing diversity of (15 k vs 12 k downloads on publisher site) [3] and has been autoimmune, autoinflammatory, allergic, and/or malignant phe- adapted in a smartphone application [4]. notypes. They now comprise 406 distinct disorders with 430 Here, we present an update of the phenotypic classi- different gene defects listed in the 2019 International Union of fication of IEI, based on the 2019 IEI classical classifi- Immunological Societies (IUIS) classical classification [1]. If cation [1]. This tree-based decision-making process is most IEI are individually rare, they are collectively more com- aimed to physicians, regardless of their familiarity with mon than generally thought [2]. IEI. It aims at helping them to reach a diagnosis based The (IUIS) expert committee on IEI proposes every other on simple clinical and biological phenotypes. year a genotypic classification of all these disorders [1], which facilitates both research on, and diagnosis of, these conditions worldwide. This classification is organized in ten tables, each Methodology

We included in our figures all disorders indexed in the * Aziz Bousfiha 2019 update of the IUIS IEI classification [1]. A phe- [email protected] notypic algorithm was assigned to each of the ten main groups of the classification and the same color was used Extended author information available on the last page of the article for each group of similar conditions. Given the high J Clin Immunol (2020) 40:66–81 67

Fig. 1 Immunodeficiencies affecting cellular and humoral immunity. a variable immunodeficiency, def deficiency, EBV Epstein-Barr virus, Eo Severe combined immunodeficiencies defined by T cell lymphopenia. b eosinophilia, GOF gain-of-function mutation, HHV8 human herpes virus Combined immunodeficiencies. * T cell lymphopenia in SCID is defined 8, HIGM hyper IgM syndrome, HPV human papillomavirus, HSM by CD3+ T cells < 300/μL. AD autosomal dominant transmission, ADA hepatosplenomegaly, Ig immunoglobulins, MHC major adenosine deaminase, Adp adenopathies, Ag antigen, AR autosomal histocompatibility complex, Nl normal, NK natural killer, SCID severe recessive transmission, β2m bêta-2 microglobulin, Bc B cells, CBC combined immunodeficiency, Tc T cells, TCR T cell receptor, Treg complete blood count, CD cluster of differentiation, CVID common regulatory T cells, XL X-linked transmission number of diseases, several categories have been split Discussion since last update [3] in two sub-figures to be more informative. These algorithms are aimed to guide clinicians to diag- Disease names are presented in red and genes in bold italic. nose patients presenting typical phenotype. However, An asterisk is added to highlight extremely rare disorders (less readers should be aware of the limitations of such a than 10 reported cases to date). However, the reader should work. keep in mind that some genes have been very recently de- More and more reports show a spectrum of atypical scribed and that true prevalence is unknown. A double asterisk presentations related to hypomorphic mutations of is added when only one case or one kindred has been reported those genes. Omenn syndrome (OMIM #603554) is a to date. In these cases, it is difficult to confirm than observed good example of such an atypical presentation, as phenotype would be reproducible in other patients carrying well as “leaky SCID” and RAG deficiency spectrum the same defect, or if it is an exception. [5]. Moreover, readers should be extremely cautious with descriptions of disease when only one patient or kindred have been reported. We are aware that Results these reports may not reflect the typical phenotype of such defects, but the exception; however, we Algorithms for the 2019 update of IUIS phenotypical classifi- thought that it was needed to be mentioned in these cation are presented in Figs. 1, 2, 3, 4, 5, 6, 7, 8, 9,and10. classifications. 68 J Clin Immunol (2020) 40:66–81

Fig. 1 (continued) J Clin Immunol (2020) 40:66–81 69

IIa. CID with associated or syndromic features

Congenital thrombocytopenia DNA Repair Defects other than those listed in Table1: Karyotype Immuno- Thymic osseous Defects with XL: Wisko Aldrich Sd or XL thrombocytopenia WAS (LOF). Recurrent bacterial and viral infecons; bloody diarrhea; eczema; dysplasias Addional lymphoma; autoimmune disease; IgA nephropathy; vasculis. Small platelets; Decreased IgM. Low anbody to polysaccharides; Congenital o en increased IgA and IgE. Nl Bc. Tc: Progressive decrease in numbers; Low Tc responses to an-CD3. Paents with XL-thrombocytopenia have later onset of complicaons and more favourable life expectancy but eventually Carlage Hair Hypoplasia RMRP. Anomalies develop similar complicaons as observed in WAS Short-limbed dwarfism with AR: WIP deficiency*. WIPF1, WAS protein absent. +/- small platelets; increased IgE. Bc : Nl to low. Tc: Reduced; defecve metaphyseal dysostosis, sparse AD. Hypoparathyroidism, lymphocyte responses to an-CD3. hair, bone marrow failure; conotruncal cardiac autoimmunity; suscepbility to malformaon, velopalatal AR: Defecve Arp2/3-mediated filament branching. ARPC1B. Recurrent invasive infecons, colis, vasculis. Mild lymphoma and other cancers; insufficiency, facial dysmorphism, trombocytopenia, normal sized platelets; autoanbodies (ANA, ANCA); eosinophilia.High IgA and IgE. impaired spermatogenesis; intellectual disability . Ig : Normal neuronal dysplasia of the or decreased. Tc: ↓or Nl May Ataxia telangiectasia. ATM: Ataxia; telangiectasia; pulmonary infecons; lymphorecular and other malignancies; increased α- intesne. Ig: Nl or ↓. Tc: Varies have low TRECs at NBS. DiGeorge/velocardiofacial fetoprotein; increased radiosensivity, chromosomal instability and translocaons. O en decreased IgA, IgE and IgG subclasses; from ↓↓ (SCID) to Nl; impaired Sd. Chr22q11.2 deleon Sd. increased IgM; anbodies variably decreased. Tc : Progressive decrease, abnormal prolif to Mitogens. lymphocyte proliferaon. 22q11.2DS. TBX1 deficiency . TBX1 Nijmegen breakage Sd. NBS1. Microcephaly; bird-like face; lymphomas; solid tumors; increased radiosensivity; chromosomal instability. Schimke Sd SMARCAL1 O en decreased IgA, IgE and IgG subclasses;increased IgM; anbodies variably decreased. Bc: Variably reduced. Tc: progressive decrease. Short stature, spondilo- Chromosome 10p13-p14 epiphyseal dysplasia, IUGR; deleon Syndrome. Bloom sd. BLM.Short stature; bird like face; sun-sensive erythema; marrow failure; leukemia; lymphoma; chromosomal instability. Low Ig. nephropathy; bacterial, viral, 10p13-p14DS. AD. fungal infecons; may present as Hypoparathyroidism; renal PMS2 def. PMS2. Café-au-lait spots ; lymphoma, colorectal carcinoma, brain tumors. HIGM and abnormal anbody responses. Reduced SCID; bone marrow failure. Tc: ↓ disease; deafness; growth Bc, switched and non-switched. retardaon; facial dysmorphism; cardiac defects may be present Immunodeficiency with centromeric instabily and facial anomalies: ICF1. DNMT3B; ICF2:ZBTB24; ICF3:CDCA7; ICF4:HELLS.Facial MOPD1 Deficiency. dysmorphism; macroglossia; bacterial/opportunisc infecons; malabsorpon; malignancies. Cytopenias; mulradial configuraons of RNU4ATAC.Recurrent bacterial AD. CHARGE Sd. CHD7, chromosomes 1,9,16; no DNA breaks. Ig: Hypogammaglobulinemia; Tc and Bc: decreased or Nl. infecons, lymphadenopathy, SEMA3E. Coloboma, Spondyloepiphyseal dysplasia, heart anomaly, choanal atresia, MCM4 def. MCM4. Viral infecons:EBV,HSV,VZV.short stature.Bc lymphoma; Adrenal failure; NKc low number and funcon. IUGR, renal dystrophy, facial intellectual disability, genital and dysmorphism; +/- microcephaly. ear anomalies; CNS short stature. Ig: ↓ , specific malformaon; some are SCID-like RNF168 def* (RIDDLE sd). RNF168. Short stature; mild defect of motor control to ataxia; normal intelligence to learning difficules; mild anbodies variably decreased and have low TRECs. Ig: Normal facial dysmorphism to microcephaly; increased radiosensivity. Low IgG or IgA. or decreased. Tc: Decreased or normal; response to PHA may be Immunoskeletal dysplasia decreased POLE1 (Polymerase ε subunit 1) deficiency (FILS syndrome). POLE1.Recurrent respiratory infecons; meningis; facial dysmorphism, with neurodevelopmental livido, short stature. Low IgM, lack of anbody to PPS. Low memory Bc. Decreased Tc proliferaon. abnormalies. EXTL3. Short Jacobsen Sd. 11q23del. stature; cervical spinal stenosis, Recurrent respiratory infecons; POLE2 (Polymerase ε subunit 2) deficiency**. POLE2. Recurrent infecon, disseminated BCG infecons, autoimmunity (type 1 diabetes, neurodevelopmental mulple warts; facial hypothyroidism), facial dysmorphism; Low Ig; Very low Bc. Lymphopenia, lack of TRECS, absent proliferaon of angens. impairment. Eosinophilia; Ig: dysmorphism, growth variably ↓ Tc: ↓ retardaon. Lymphopenia, Low NK, Bc and switched memory Bc. NSMCE3 deficiency*. NSMCE3. Severe lung disease (possibly viral); thymic hypoplasia, Chromosomal breakage; radiaon sensivity. Ig: Hypogammaglobulinemia. Decreased Ab responses to PPS, normal IgG, IgA, normal to elevated IgM. Tc : Low, poor responses to mitogens and angens. MYSM1 def* MYSM1, AR Short stature, congenital bone FOXN1 haploinsufficiency. Ligase I deficiency *. LIGI Recurrent bacterial and viral infecons; growth retardaon; sun sensivity; lymphoma; radiaon sensivity. marrow failure, myelodysplasia. Skeletal anomalies; cataracts; FOXN1, AD Macrocyc red blood cells. Hypogammaglobulinemia. Reduced Ab response. Lymphopenia, increased γδTc, decreased mitogen response. Recurrent, viral and bacterial developmental delay. Affects respiratory tract infecons; skin GINS1 def*. GINS1. IUGR. Neutropenia, NK cells very low. Tc and Bc: low or normal. High IgA, Low IgG and IgM. granulocytes. Bc: immature. Tc: involvement (eczema, dermas), lymphopenia, reduced naïve Tc. nail dystrophy. T cell lymphopenia Hypogammaglobulinemia may normalize by adulthood. BMFS2 (Hebo def). ERCC6L2, AR. Facial dysmorphism; microcephaly, learning difficules. Bone marrow failure. Fig. 2 a, b CID with associated or syndromic features. Ab antibody, AD gain-of-function, HIES hyper IgE syndrome, FILS facial dysmorphism, autosomal dominant transmission, AD DN autosomal dominant immunodeficiency, livedo and short stature, ID immunodeficiency, Ig transmission with dominant negative effect, ANA anti-nuclear immunoglobulins, IL-6 interleukin-6, IUGR intrauterine growth antibodies, ANCA anti-neutrophil cytoplasm antibodies, AR autosomal retardation, LOF loss-of-function, MCC mucocutaneous candidiasis, Nl recessive transmission, Bc B cells, BCG bacillus Calmette-Guerin, BCR normal, NK natural killer, PHA phytohemagglutinin, PPS B cell receptor, CD cluster of differentiation, CID combined polysaccharides, SCID severe combined immunodeficiency, sd immunodeficiency of T and B cells, CMV cytomegalovirus, CNS syndrome, Tc T cells, TCR T cell receptor, TREC T cell receptor central nervous system, def deficiency, DNA deoxyribonucleic acid, excision circle, XL X-linked transmission EBV Epstein-Barr virus, EDA anhidrotic ectodermal dysplasia, GOF 70 J Clin Immunol (2020) 40:66–81

IIb. CID with associated or syndromic features

Hyper-IgE syndromes (HIES) Defects of Vitamin Anhidroc Others B12 and Folate Ectodermodysplasia AD-HIES (Job sd ). STAT3, AD LOF. Disncve facial features (broad Metabolism: with ID Purine nucleoside phosphorylase deficiency. PNP. Autoimmune nasal bridge); bacterial infecons (boils and pulmonary abscesses, haemolyc anemia, neurological impairment. Hypouricemia. Ig : Nl/Low. Bc: Nl. Tc: Progressive decrease pneumatoceles) due to S. aureus, Aspergillus, Pneumocyss jirovecii; Megaloblasc anemia, Ig: Anhidroc ectodermal eczema; mucocutaneous candidiasis; hyperextensible joints, decreased. dysplasia,various infecons osteoporosis and bone fractures, scoliosis, retenon of primary (bacteria, mycobacteria, viruses and Calcium Channel Defects. Autoimmunity, EDA, non-progressive myopathy. Transcobalamin 2 Ig and Bc: Nl. Tc: Normal, defecve TCR mediated acvaon. ORAI-1 teeth; aneurysm formaon. IgE ↑↑; specific anbody producon↓. fungi), colis, variable defects of deficiency. TCN2. skin, hair and teeth. deficiency*. ORAI1 . STIM1 deficiency*. STIM1 Bc:Normal; reduced switched and non-switched memory Bc; BAFF pancytopenia, if untreated for expression ↑. Tc:Nl overall; Th-17 & T-follicular helper cells ↓ prolonged periods results in NEMO deficiency. IKBKG (NEMO). ID with mulple intesnal atresias. TTC7A . Bacterial (sepsis), fungal, viral intellectual disability. XL, monocyte dysfuncon. Ig infecons, mulple intesnal atresias, o en with intrauterine ZNF341 deficiency. ZNF341. AR. Phenocopy of AD-HIES: Mild facial decreased, some with elevated IgA, polyhydramnios and early demise, some with SCID phenotype. Markedly dysmorphism, early onset eczema, MCC, bacterial skin infecons, Deficiency causing IgM, poor specific anbody decreased IgG, IgM, IgA. Bc:Nl/low.Tc: Variable/absent, low TRECs (may responses, absent anbody to hereditary folate present with SCID at birth) abscesses, recurrent bacterial respiratory infecons (S. aureus), lung polysaccharide angens. Bc: Nl, Low abscesses and pneumatoceles, hyperextensible joints, bone fractures malabsorbon. SLC46A1. memory and isotype switched Bc. and retenon of primary teeth failure to thrive, if untreated Tc: Nl/decreased, TCR acvaon Hepac veno-occlusive disease with immunodeficiency (VODI). SP110. for prolonged periods results impaired. Hepac veno-occlusive disease, Pneumocyss jirovecii pneumonia, CMV, Comel Netherton Sd; SPINK5; Congenital ichthyosis, bamboo in intellectual disability candida, thrombocytopenia, hepatosplenomegaly, cerebrospinal leukodystrophy. Decreased IgG, IgA, IgM, absent germinal centers and hair,atopic diathesis; ↑ bacterial infecons, failure to thrive. ↑ IgE EDA-ID due to IKBA GOF mutaon. NFKBIA (IKBA). AD Tc and ssue plasma cells. Decreased memory Bc . Decreased memory Tc. and IgA; Other Ig: variably decreased. Bc: Switched and non-switched Methylene- tetrahydrofolate monocyte dysfuncon Decreased Bc are↓. IgG and IgA, elevated IgM, poor dehydrogenase 1 STAT5b deficiency. STAT5B. AR. Growth-hormone insensive dwarfism, specific anbody responses, absent dysmorphic features, eczema, lymphocyc intersal pneumonis, deficiency MTHFD1. PGM3 deficiency. PGM3. Severe atopy; autoimmunity; skeletal anbody to polysaccharide autoimmunity. Hypergammaglobulinemia, High IgE. Recurrent bacterial infecon, anomalies: short stature, brachydactyly, dysmorphic facial angens. Normal Bc numbers, AD DN: Growth failure and eczema only. High IgE. Pneumocyss jirovecii; failure features. Recurrent pneumonia, recurrent skin abscesses,bacterial impaired BCR acvaon, low to thrive; neutropenia; and viral infecons; cognive impairment; delayed CNS myelinaon memory and isotype switched Bc. seizures, intellectual Normal total Tc, TCR acvaon BCL11B deficiency. BCL11B. AD. Congenital abnormalies: neonatal teeth, in some. Ig:Nl or elevated. Elevated IgE; eosinophilia. Reduced B and disability; folate-responsive impaired. dysmorphic facies; absent corpus callosum; neurocognive deficits. Tc : memory Bc. CD8 and CD4 Tc may be↓. ↓ Bc, ↓ anbody responses Low, poor proliferaon. to conjugated polysaccharide EDA-ID due to IKBK GOF mutaon* angens. IKBB. AD. Low Tc. Bc: Nl number, Hennekam-lymphangiectasia-lymphedema syndrome*. CCBE1, FAT4. CID with early-onset asthma, eczema and food allergies, poor funcon. Low Ig. autoimmunity ID with atopic dermas (CADINS)*. CARD11. AD LOF. Lymphangiectasia and lymphedema with facial abnormalies and other Variable atopy, cutaneous viral infecons, recurrent respiratory dysmorphic features. Ig: decreased. Bc and Tc: Variable. infecons, lymphoma. Eosinophilia, ↓Tc proliferaon. Nl to low Bc. Bacterial infecons, autoinflammaon, amylopecnosis.Bc: Nl,decreased memory Bc. HOIL1 deficiency. RBCK1. Poor Ab responses to polysaccharides. HOIP deficiency*. RNF31. Lymphangiectasia. Ig: decreased. ERBIN deficiency**. ERBB21P. Recurrent respiratory infecons, suscepbility to S. aureus, eczema, hyperextensible joints, scoliosis, Vici syndrome. EPG5. Agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmentaon, intellectual disability, microcephaly, CMC. arterial dilataon in some. Moderately increased IgE; increased Treg. Ig: Decreased IgG2. Bc: Defecve. Profound depleon of CD4+ cells.

IL6R deficiency*. IL6R. Recurrent pyogenic infecons, cold Kabuki Sd. KMT2D (MLL2): AD. KDM6A: XL. abscesses, high circulang IL-6 Levels. Typical facial abnormalies, cle or high arched palate, skeletal abnormalies, short stature, intellectual disability, congenital heart defects, recurrent infecons (os media, pneumonia) in 50% of paents. Autoimmunity may be present. Low IgA and occasionally low IgG.

IL6ST deficiency*. IL6ST. Bacterial infecons, boiles, eczema, Wiedemann-Steiner Sd. KMT2A (MLL): AD Respiratory infecons; short stature; hypertelorism; hairy elbows; developmental delay, intellectual pulmonary abscesses, pneumatoceles, bone fractures, scoliosis, disability. Hypogammaglobulinemia, decreased memory Bc. retenon of primary teeth, craniosynostosis. ↓B-cell memory. Immunodeficiency, developmental delay and hypohomocysteinemia, IMDDHH*. Acvang de-novo mutaons in NFE2L2. AD. Recurrent respiratory and skin infecons, growth retardaon, developmental delay; white maer cerebral lesions, decreased level of homocysteine; increased expression of Loes-Dietz syndrome. TGFBR1, TGFBR2. Recurrent respiratory stress response genes. Hypogammaglobulinemia. Bc: Decreased switched-memory Bc. infectons, eczema, food allergies, hyperextensible joints, scoliosis, retenon of primary teeths; aorc aneurisms. Tricho-Hepato-Enteric syndrome. TTC37; SKIV2L* . Respiratory infecons, IUGR, wooly hair, early onset intractable diarrhea, liver cirrhosis, platelet abnormalies. Impaired IFNγ producon, Hypogammaglobulinemia, low anbody responses. Bc: Variably low switched-memory Bc. Fig. 2 (continued) J Clin Immunol (2020) 40:66–81 71

Fig. 3 Predominantly antibody deficiencies. a cell anergy, CD cluster of differentiation, CMF flow cytometry, COPD Hypogammaglobulinemias. b Other antibody deficiencies. AD chronic obstructive pulmonary disease, def deficiency, EBV Epstein-Barr autosomal dominant transmission, AR autosomal recessive virus, GOF gain-of-function, Hx patient history, Ig immunoglobulins, Nl transmission, Bc B cells, BENTA B cell expansion with NF-κBandT normal, XL X-linked transmission 72 J Clin Immunol (2020) 40:66–81

III. Predominantly Antibody deficiencies.

b: Other Anbody deficiencies

Severe Reducon in Serum IgG and IgA with Isotype, Light Chain, or Funconal Deficiencies High Bc numbers due to with Generally Nl Numbers of Bc constuve NF-κB acvaon Normal or elevated IgM Selecve IgA deficiency. Unknown. CARD11 GOF . and Normal Numbers of Bc : May be asymptomac. Bacterial infecons, autoimmunity

Hyper IgM Syndromes mildly increased. Very low to absent IgA with other isotypes CARD11. AD. BENTA syndrome normal, normal subclasses and specific anbodies.

AID deficiency. Transient hypogammaglobuliemia of infancy. Unknown. AICDA. AR or AD. Usually not associated with significant infecons, normal ability Splenomegaly, Bacterial infecons, enlarged lymph nodes and germinal to produce anbodies to vaccine angens. IgG and IgA decreased. centers. Nl memory Bc, but lacking somac lymphadenopathy, hypermutaon in AR form. IgG subclass deficiency with IgA deficiency. Unknown. poor vaccine responses. Recurrent bacterial infecons. May be asymptomac. Reduced UNG deficiency. UNG. IgA with decrease in one or more IgG subclass.

Enlarged lymph nodes and germinal centers. Isolated IgG subclass deficiency. Unknown. Usually asymptomac, a minority may have poor anbody response to specific angens and recurrent viral/bacterial infecons. Reducon in one or more IgG subclass. INO80 def*. INO80 . Specific anbody deficiency with normal Ig levels and normal B cells. Unknown. Severe bacterial infecons. Reduced ability to produce anbodies to specific angens. Ig: Nl.

MSH6*. MSH6 . Ig heavy chain mutaons and deleons. Mutaon or chromosomal deleon at 14q32. Family or personal history of cancer. Variable IgG, May be asymptomac. One or more IgG and/or IgA subclasses as well as IgE may be absent. Kappa chain deficiency*. IGKC. defects, increased IgM in some, Nl Bc, low switched Asymptomac. All immunoglobulins have lambda light chain.

memory Bc. Selecve IgM deficiency. Unknown. Pneumococcal / bacterial infecons. Absent serum IgM.

Fig. 3 (continued) J Clin Immunol (2020) 40:66–81 73

IV. Diseases of immune dysregulaon. a : Hemophagocyc Lymphohisocytosis HLH & EBV suscepbility

Hemophagocyc Lymphohisocytosis (HLH) Suscepbility to EBV

RASGRP1 deficiency*. RASGRP1. Familial Hemophagocytic EBV associated HLH Hypopigmentation: Recurrent pneumonia, herpes virus Lymphohistiocytosis infecons, EBV associated lymphoma. SH2DIA. Partial albinism . Decreased NK and CTL Syndromes: Decreased NK cell funcon; high IgA. Bc XL, XLP1. activities(cytotoxicity and/or degranulation). Bc and Tc: Poor acvaon, proliferaon, and Tc: Nl Clinical and immunologic Fever, HSM, cytopenias, molity features triggered by EBV Nl Bc. Increased activated Tc. CD70 deficiency*. CD70 (TNFSF7). infection: LYST Chediak Higashi Sd. Decreased to absent NK and CTL Hodgkin lymphoma, autoimmunity in lymphoproliferation, Aplastic activities (cytotoxicity and/or Recurrent infections, fever, HSM, bleeding some paents. Reduced IgM, IgG, IgA anemia, Lymphoma. degranulation) (75%) and reduced Ag-specific Ab tendency, progressive neurological responses (50%). Bc:poor anbody and PRF1. Hypogammaglobulinemia, Perforin deficiency (FHL2). memory responses. Tc:low Treg, poor dysfunction. Giant lysosomes (WBC), Absent iNKT cells. Impaired NK acvaon and funcon neutropenia, cytopenias, Specific hair UNC13D / Munc13-4 deficiency (FHL3). cell and CTL cytotoxic activity . UNC13D. CTPS1 deficiency. CTPS1. Reduced Memory B cells . shaft anomaly. Increased activated Tc. Syntaxin 11 deficiency (FHL4). STX11. Recurrent/chronic bacterial and viral STXBP2 / Munc18-2 deficiency (FHL5) infecons (EBV, VZV), EBV lympho- SAP deficiency (FCM). STXBP2. Enteropathy proliferaon, B cell non-Hodgkin Griscelli Sd type 2. RAB27A. lymphoma. Tc: poor proliferaon to Ag XL, XLP2. XIAP. Fever, HSM, cytopenias; Specific hair FAAP24 deficiency**. FAAP24. CD137 deficiency*. TNFRSF9. EBV Splenomegaly, lympho- shaft anomaly EBV-driven lymphoproliferative disease. lymphoproliferaon, B cell lymphoma, Increased activated Tc. Failure to kill proliferation, Colitis, IBD, chronic acve EBV infecon. Low IgA and hepatitis. autologous EBV transformed Bc. Nl NK IgG, poor response to angens, decreased T Hermansky Pudlak sd type 2. AP3B1. cell function. cell proliferaon Hypogammaglobulinemia, Low Recurrent infections, pulmonary fibrosis, iNKT cells. Increased T cells SLC7A7 deficiency. SLC7A7. RLTPR (CARMIL2) deficiency. RLTPR. susceptibility to apoptosis to increased bleeding, neutropenia; Specific Lysinuric protein intolerance, bleeding Recurrent bacterial, fungal and tendency, alveolar proteinosis Hyper- mycobacterial infecons, viral warts, CD95 and enhanced activation- hair shaft anomaly. inflammatory response of macrophages. Nl molluscum and EBV lymphoproliferave and induced cell death (AICD). Tc and NK cell function other malignancy, atopy. Ig Nl to ↓, poor T Normal NK and CTL cytotoxic dependent anbody response. Nl Bc. Tc: ↓ Treg, activity. XIAP def (FCM) Hermansky-Pudlak syndrome, type 10**. high CD4, poor funcon. AP3D1. XL magnesium EBV and neoplasia (XMEN)*. MAGT1.XL. EBV infecon, lymphoma, viral AR, CD27 deficiency . CD27 Oculocutaneous albinism, severe infecons, respiratory and GI infecons. Glycosylaon disorder. Some paents can present with (TNFRSF7). neurological manifestaons. Low CD4 Low recent thymic emigrant cells, poor proliferaon to CD3. neutropenia, recurrent infections, seizures, High B cells, high DN T cells.. Features triggered by EBV hearing loss and neurodevelopmental infection, aplastic anemia, PRKCD deficiency*. PRKCD. Recurrent infecons, EBV chronic infecon, lymphoproliferaon, delay . SLE-like autoimmunity (nephroc and anphospholipid Sd). Low IgG. Low memory Bc high CD5 Bc low iNKTc lymphoma. Low Ig

Fig. 4 Diseases of immune dysregulation. a Hemophagocytic familial hemophagocytic lymphohistiocytosis, GOF gain-of-function, lymphohistiocytosis. b Other diseases of immune dysregulation. Ab HLH hemophagocytic lymphohistiocytosis, (H)SM antibody, AD autosomal dominant transmission, Ag antigen, AIHA (hepato)splenomegalia, IBD inflammatory bowel disease, Ig autoimmune hemolytic anemia, ALPS autoimmune lymphoproliferative immunoglobulin, IL-10 interleukin-10, LOF loss-of-function, iNKT syndrome, APS autoimmune polyendocrinopathy syndrome, AR invariant NKT cells, NK natural killer cells, Nl normal, sd syndrome, autosomal recessive transmission, Bc B cells, CD cluster of SLE systemic lupus erythematous disease, Tc T cells, TCR T cell differentiation, CMF flow cytometry, CTL cytotoxicT lymphocytes, def receptor, XL X-linked transmission deficiency, DNT double negative T cells, EBV Epstein-Barr virus, FHL 74 J Clin Immunol (2020) 40:66–81

IV. Diseases of immune dysregulaon. b: Syndromes with Autoimmunity and Others

Syndromes with Autoimmunity Immune Dysregulaon with Colis: IBD Increased CD4- CD8- TCR αβ+ (double negative (DN) T cells) ? IL-10 deficiency*. IL10. AR. Yes: No : Folliculis, recurrent respiratory ALPS Regulatory T Cell Defects ? diseases, arthris. No funconal IL-10 Autoimmune secreon. Lymphoproliferative Sd No Yes IL-10R deficiency. AR. Folliculis, Chronic adenopathy recurrent respiratory diseases, arthris, lymphoma. Splenomegaly, defective Autoimmune polyendocrinopathy with candidiasis IPEX, immune dysregulaon, polyendocrinopathy, IL10RA Leukocytes unresponsive to IL- lymphocyte apoptosis. and ectodermal dystrophy: APECED (APS-1) . enteropathy X-linked. FOXP3. Autoimmune enteropathy, early onset diabetes, thyroidis hemolyc anemia, 10. IL10RB. Leukocytes unresponsive to AIRE. AR/ AD. thrombocytopenia, eczema, elevated IgE, IgA. Lack and/or ALPS-FAS. TNFRSF6. AD or AR. impaired funcon of CD4+ CD25+ FOXP3+ regulatory T cells (Tregs). IL10, IL22, IL26, IL28A, IL28B, IL29 Hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfuncon and NFAT5 haploinsufficiency**. NFAT5. Autoimmune cytopenias, other endocrine abnormalies, chronic CD25 deficiency*. IL2RA. AR. Lymphoproliferaon, AD. Recurrent Sinopulmonary increased lymphoma risk, IgG mucocutaneous candidiasis, dental enamel autoimmunity, impaired Tc proliferaon. No CD4+C25+ cells infecons. Decreased memory Bc and and IgA Nl or increased, elevated hypoplasia, alopecia, enteropathy, pernicious with impaired funcon of Tregs cells. plasmablasts. serum FasL, IL-10, vitamin B12. anemia. CTLA4 deficiency (ALPSV). CTLA4. AD. Autoimmune TGFB1 deficiency*. TGFB1. AR. ALPS-FASLG. TNFSF6.AR. ITCH deficiency. ITCH. AR. cytopenias, enteropathy, intersal lung disease, extra-lymphoid Recurrent viral infecons, microcephaly, lymphocyc infiltraon recurrent infecons . Impaired funcon and encephalopathy. Decreased T cell of Tregs. Tc and Bc decreased. proliferaon in response to an-CD3 Autoimmune cytopenias, SLE, Early-onset chronic lung disease (intersal pneumonis), thyroidis, type I diabetes, chronic soluble FasL is not elevated diarrhea/enteropathy, and hepas, developmental LRBA deficiency. LRBA. AR. Recurrent infecons, RIPK1 deficiency*. RIPK1. AR. delay, dysmorphic facial features . inflammatory bowel disease, autoimmunity. Reduced IgG Reccurrent infecons, progressive ALPS-Caspase10*. CASP10. AD. and IgA in most. Low or normal numbers of Bc. Normal or polyarthris. Low Tc , low or nl Bc. Tripepdyl-Pepdase II Deficiency**. TPP2.AR. decreased CD4 numbers, Tc dysregulaon. ALPS-Caspase 8**. CASP8. AR. Variable lymphoproliferaon, severe autoimmune STAT3 GOF mutaon. STAT3. AD. Lymphoproliferaon, solid organ autoimmunity, recurrent infecons. Bacterial and viral infecons, cytopenias, hypergammaglobulinemia, recurrent Enhanced STAT3 signaling, leading to increased Th17 cell differenaon, lymphoproliferaon and Hypogammaglobulinemia. infecons. autoimmunity. Decreased Tregs and impaired funcon. Tc and Bc decreased. Defecve lymphocyte acvaon. Decreased Tc and Bc. BACH2 deficiency. BACH2. AD. Lymphocyc colis, sinopulmonary infecons. Impaired memory Bc Slightly increased DNT cells. development. Progressive Tc lymphopenia. JAK1 GOF**. JAK1. AD GOF.

FADD deficiency.** FADD. AR. HSM, eosinophilic enteris, thyroid disease, poor CD122 deficiency. IL2RB. Lymphoproliferaon, lymphadenopathy, HSM, AIHA, dermas, enteropathy. Hypergammaglobulinemia, recurrent viral (EBV, CMV) infecons Funconal hyposplenism, growth, viral infecons. Eosinophilia, bacterial and viral infecons, DEF6 deficiency*. DEF6. HSM, enteropathy, cardiomyopathy, recurrent infecons. Low Tc, low or normal Bc recurrent episodes of Prolidase deficiency. PEPD. AR. encephalopathy and liver FERMT1 deficiency. FERMT1. Dermatosis (congenital blistering, skin atrophy, photosensivity, skin fragility, dysfuncon. Chronic skin ulcers, eczema, infecons. Auto- and scaling). Intracellular accumulaon of IgG, IgM, IgA, and C3 in colloid bodies under the basement anbodies common. membrane

Fig. 4 (continued) J Clin Immunol (2020) 40:66–81 75

V. Congenital defects of phagocyte number, funcon, or both. a : Neutropenia (without an-PMN )

Syndrome associated No syndrome associated

Shwachman-Diamond Syndrome. DNAJC21.AR.EFL1*.AR. Pancytopenia, exocrine pancreac insufficiency. SBDS.AR.+chondrodysplasia Elastase deficiency. (SCN1). ELANE. AD. SRP54 SRP54 deficiency*. . AD. Neutropenia and exocrine pancreac insufficiency . Suscepbility to MDS/leukemia. Severe congenital G6PC3 deficiency (SCN4). G6PC3. AR. Structural heart defects, urogenital abnormalies, inner ear neutropenia or cyclic neutropenia (perform CBC deafness, and venous angiectasias of trunks and limbs. Affected foncons: Myeloid differenaon, - twice weekly/ 4 weeks). chemotaxis, O2 producon.

Glycogen storage disease type 1b. G6PT1.AR. HAX1 deficiency (Kostmann Disease) (SCN3). HAX1. Fasng hypoglycemia, lacc acidosis, hyperlipidemia, hepatomegaly. AR. Cognive and neurological defects in paents Cohen syndrome. COH1. AR. Dysmorphism, mental retardaon, obesity, deafness. with defects in both HAX1 isoforms, suscepbility to 3-Methylglutaconic aciduria. CLPB.AR.Neurocognive developmental aberraons, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR. MDS/leukemia

TAZ. XL. Barth Syndrome (3-Methylglutaconic aciduria type II). GFI1. AD. Cardiomyopathy, myopathy, growth retardaon. GFI 1 deficiency (SCN2)**. B/T lymphopenia Clericuzio syndrome (Poikiloderma with neutropenia). C16ORF57 (USB1). AR. Renopathy, developmental delay, facial dysmorphism, poikiloderma. X-linked neutropenia/ myelodysplasia WAS GOF. VPS45 deficiency (SCN5). VPS45. AR. Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly. WAS. XL GOF. JAGN1.AR. JAGN1 deficiency. Osteopenia. Myeloid maturaon arrest. Myeloid maturaon arrest, monocytopenia, variable WDR1 deficiency. WDR1. AR. lymphoid anomalies . Poor wound healing, severe stomas, neutrophil nuclei herniate. Mild neutropenia.

SMARCD2 deficiency*. SMARCD2.AR. G-CSF receptor deficiency*. CSF3R. AR. Developmental aberraons, bones defect, myelodysplasia Stress granulopoiesis disturbed Specific granule deficiency*. CEBPE. AR. Neutrophils with bilobed nuclei. Chronic neutropenia. Neutropenia with combined immune deficiency *. HYOU1 deficiency**. HYOU1. AR. Hypoglycemia, inflammatory complicaons. MKL1. AR. P14/LAMTOR2 deficiency**. LAMTOR2.AR. Paral albinism, growth failure. Hypogammaglobulinemia, reduced CD8 cytotoxicity. Mild thrombocytopenia. Lymphopenia.

V. Congenital defects of phagocyte. b : Functional defects

Syndrome associated No Syndrome associated: DHR assay (or NBT test) ? Leukocyte adhesion deficiency Cystic fibrosis. Normal Abnormal CFTR. AR. Skin infections evolve to large ulcers. GATA2 def. GATA2, AD. CGD: Leukocytosis with neutrophilia Early onset of severe and (WBC > 25000) natural barriers of the organism ( lungs, Pancreatic insufficiency, recurrent infections affecting initially the Susceptibility to Respiratory infections, lymph nodes, skin), and eventually inner LAD I . Mycocbacteria, Papilloma structures (liver, spleen, bones, brain, and elevated sweat chloride ITGB2 +++ hepatic abscess). Autoinflammatory Delayed cord separation with Viruses, Histoplasmosis, phenotype, IBD omphalitis+++, no pus formation, lack Lymphedema. Alveolar CTSC. Granulomata obstructing respiratory, Papillon-Lefèvre . of inflammation is observed in urinary or gastrointestinal tracts. infection area. Periodontitis leads to proteinosis, Inflammatory bowel disease (Crohn’s like early loss of teeth. Severity of the disease) and perianal disease : up to 30 % disease correlates with the degree of myelodysplasia/ AML/ Pathogens : typically catalase negative Periodons, palmoplantar deficiency in CD18 (FCM). (WBC CMML . Multi lineage – – bacteria (S. aureus and gram-negative 20,000 150,000 with 60 85 % bacilli, Aspergillus, Candida); other: hyperkeratosis in some paents neutrophils) cytopenias. Low NK. Burkholderia cepacia,Chromobacterium violaceum, Nocardia, and invasive Serratia Pulmonary alveolar marcescens. In developing countries, BCG Localized juvenile LAD II (Congenital disorder of : adverse effects in up to 20 %. glycosylation, type IIc) SLC35C1 proteinosis. Microscopic granulomas. periodontitis . Recurrent infections. Mild LAD type 1 CYBB phox features with hh-blood group, growth CSF2RA, AR. CSF2RB*, XL CGD: (gp91 ) NCF1 (p47phox) , AR FPR1. retardation, developmental XL. CYBA (p22phox), AR delay , facial dysmorphism NCF4 (p40phox), AR Periodontitis only (depressed nasal bridge). NCF2 (p67phox), AR CYBC1** , AR Affected cells: Alveolar β-Actin . ACTB LAD III FERMT3 macrophages. Affected Rac 2 def** . RAC2. Poor wound healing. LAD phenotype Severe bacterial infections and fonction: GM-CSF (leukocytosis). severe bleeding disorder. Platelet signaling Mental retardaon, short stature aggregation assay. G6PD def Class I. G6PD. Infections. Fig. 5 Congenital defects of phagocyte number, function, or both. a DHR dihydrorhodamine-1,2,3, GM-CSF granulocytes/monocytes Neutropenia. b Functional defects of phagocytes. AD autosomal colony stimulation factor, GOF gain-of-function, IBD inflammatory dominant transmission, AML acute myeloid leukemia, AR autosomal bowel disease, IUGR intrauterine growth retardation, LAD leukocyte recessive transmission, BCG bacillus Calmette-Guerin, CD cluster of adhesion deficiency, MDS myelodysplasia, NBT nitroblue of differentiation, CGD chronic granulomatous disease, CMF flow tetrazolium, NK natural killer cells, WBC white blood cells, XL: X- cytometry, CMML chronic myelomonocytic leukemia, def deficiency, linked transmission 76 J Clin Immunol (2020) 40:66–81

VI. Defects in Intrinsic and Innate immunity. a : Bacterial and Parasic Infecons :

Predisposion to Predisposion to Parasic and Fungal Others Invasive Bacterial infecons (pyogens): infecons meningis, sepsis, arthris, osteomyelis and Osteopetrosis. Mucocutaneous TNFRSF11A, PLEKHM1 AR. abscesses, o en in the absence of fever. CARD9 def. Candidiasis (CMC) TCIRG1, AR. + CARD9, AR. Predominant pathogens (S. pneumoniae, S. aureus and hypocalcemia Chronic Mucocutaneous Pseudomonas aeruginosa). Non-invasive bacterial infecons (skin Candidiasis without ectodermal CLCN7, OSTM1, AR. + hypocalcemia, neurologic infecons and upper respiratory tract infecons). Improve with dysplasia features age. Roune Usual screening tests are normal. Specific Predisposion to SNX10, AR. + visual screening tests (lack of proinflammatory cytokine producon and INVASIVE Fungal STAT1 GOF. STAT1, AD impairment CD62L shedding) : available only in specialized clinical various fungal, bacterial and viral Diseases. TNFSF11, AR. + severe immunology laboratories. (HSV) infecons, autoimmunity (thyroidis, diabetes, cytopenias), growth retardaon IRAK4 def . IRAK4, AR enteropathy Invasive Hydradenis suppurava. MyD88 def . MYD88, AR. candidiasis IL-17F deficiency*. PSENEN, AD. IL17F, AD. Folliculis. infecon, deep NCSTN, AD. + acne IRAK-1 def**. IRAK1, XL. PSEN, AD. + dermatophytoses, X-linked MECP2 deficiency-related syndrome due to a large de IL-17RA deficiency. hyperpigmentaon other invasive novo Xq28 chromosomal deleon encompassing both MECP2 and IL17RA, AR Predisposion to Acute liver failure due to IRAK1 Folliculis. Suscepbility to S. fungal infecons. NBAS def. NBAS, AR. aureus (skin infecons) and Fever induces liver failure chronic bacterial infecons. TIRAP def**. TIRAP, AR. Trypanosomiasis Acute necrozing Staphylococcal disease during childhood. encephalopathy. RANBP2, IL-17RC deficiency. APOL1, AD AD. IL17RC, AR. Fever induces acute Isolated congenital asplenia. encephalopathy Bacteremia (encapsulated bacteria). No spleen. ACT1 deficiency*. ACT1, AR. IRF4 haploinsufficiency*. RPSA, AD Blepharis, folliculis and IRF4, AD. Trypanosomiasis. HMOX*, AR. Hemolysis, nephris, inflammaon macroglossia. Whipple’s disease

VI. Defects in Intrinsic and Innate immunity. b : MSMD and Viral infecon

Mendelian Suscepbility to mycobacterial disease (MSMD) Predominant suscepbility to viral infecon

Severe phenotypes. Moderate phenotypes. Epidermodysplasia Predisposion to Herpes simplex Severe Viral Infecon Encephalis With Suscepbility to Salmonella verruciformis (HPV) Complete IFNGR1 Def STAT1 Def (AR LOF). STAT1. Dominant clinical IL-12 and IL-23 receptor b1 chain deficiency. (+ Mycobacteria) phenotype is Herpes IL12RB1 .AR. HPV (group B1) simplex encephalis (HSE) and IFNGR2 Def : IL-12p40 (IL-12 and IL-23) def. IL12B .AR. STAT2 deficiency*. STAT2. during primary infecon IL-12Rb2 deficiency**. IL12RB2. AR infecons and cancer of AR. Disseminated vaccine- with herpes simplex virus IL-23R deficiency**. IL23R. AR. strain measles IFNGR1, IFNGR2. AR. type 1 (HSV1), usually the skin between 3 months and 6 STAT1 LOF STAT1(AD) IRF7 deficiency**. IRF7. AR. years of age. Incomplete M IRF9 deficiency*. IRF9. AR. Paral IFNγR1, IFNGR1. AR. EVER1 def. T C6.AR. clinical penetrance for all Severe influenza disease. Paral IFNγR2, IFNGR2.AR. eologies listed here. Serious disseminated EVER2 def. TMC8. AR. IFNAR1 deficiency*. IFNAR1 AD IFNGR1 IFNGR1. AD. Mycobacterial AR. Severe disease caused by Roune screening tests osteomyelis CIB1 def. CIB1. AR. BCG and environmental Yellow Fever vaccine and are normal. SPPL2a deficiency*. SPPL2A. AR. Measles vaccine Specific tests examining mycobacterial infecons WHIM (Warts, Tyk2 deficiency, TYK2. AR. IFNAR2 deficiency**. the TLR3 pathway : Suscepbility to viruses, +/- elevated IgE. mulple IFNAR2 AR. Disseminated marked decrease in the Hypogammaglobuline (so ssue, bone cytokine signaling defect. P1104A TYK2 vaccine-strain measles, ability of paent’s homozygosity MSMD or tuberculosis. HHV6. No response to IFN-α. fibroblasts to produce IFN- mia, infecons, myelo- α and β in response to marrow, lungs, skin, Macrophage gp91 phox deficiency CYBB, XL CD16 deficiency*. FCGR3A. HSV1 infecon. IRF8 deficiency, IRF8 AD kathexis) sd AR. Severe herpes viral infecons, parcularly VZV, bones and lymph nodes), ISG15 Def, ISG15. AR. Brain calcificaon. CXCR4 AD GOF. EBV, and HPV. UNC93B1 (AR), TRAF3** IFNg producon defect. (AD), TICAM1 (TRIF)* MDA5 deficiency (LOF)*. (AR,AD), TBK1* (AD), IRF8 deficiency, IRF8 AR Mulple other infecous IFIH1. AR. Rhinovirus and IRF3* (AD) agents. Myeloproliferaon Warts (HPV) infecon, Salmonella spp., Listeria other RNA viruses neutropenia, low B cell TLR3 (AD,AR), + severe RORγt deficiency*. RORC AR. Suscepbility to RNA poymerase III def*. monocytogenes and Candida. IFNg producondefect, POLR3A. POLR3C. POLR3F. pulmonary influenza, VZV complete absence of IL-17A/F-producing Tc number, hypogamma- AD. Severe VZV infecon. DBR1* (AR) +other viral infecons of the viruses JAK1 (LOF)*, JAK1. AR. Suscepbility to viruses, globulinemia. urothelial carcinoma. ↓ IFNg producon. IL-18BP def**. IL18BP. AR. brainstem Fulminant viral hepas

Fig. 6 Defects in intrinsic and innate immunity. a Bacterial and parasitic HPV human papillomavirus, HSV herpes simplex virus, LOF loss-of- infections. b MSMD and viral infection. AD autosomal dominant function, MSMD Mendelian susceptibility to mycobacterial disease, transmission, AR autosomal recessive transmission, BCG bacillus NK natural killer cells, RNA ribonucleic acid, sd syndrome, Tc T cells, Calmette-Guerin, CD cluster of differentiation, CMC chronic TLR3 Toll-like receptor type 3, VZV varicella zoster virus, XL X-linked mucocutaneous candidiasis, EBV Epstein-Barr virus, GOF gain-of- transmission function, IFNg interferon gamma, HHV6 human herpes virus type 6, J Clin Immunol (2020) 40:66–81 77

VIIa. Auto-inflammatory disorders

Recurrent inflammaon Systemic inflammaon with urcaria rash Others

Recurrent fever Familial Cold Autoinflammatory Syndrome (CAPS) * . CANDLE sd (chronic atypical neutrophilic NLRP3, NLRP12. AD GOF DA: 24-48H dermas with lipodystrophy). Familial Mediterranean Fever (FMF) * PSMB8, AR and AD. Contractures, MEFV. AR or AD (Usually M694del variant) Non-pruric urcaria, arthris, chills, fever and panniculis, ICC, fevers. leukocytosis a er cold exposure. PSMG2, AR. Panniculis, lipodystrophy, DA: 1–4 days FA : Variable. AIHA. Muckle Wells syndrome (CAPS) * NLRP3. AD GOF. (Variants in PSMB4, PSMB9, PSMA3, and POMP have been proposed to cause a similar CANDLE phenotype in Polyserosis, Abdominal pain, Arthris, compound heterozygous monogenic , digenic,and AD Amyloidosis. Erysipelas-like erythema. Ethnic group : North European monogenic models). Predisposes to vasculis and inflammatory bowel disease . Connuous fever. O en worse in the evenings. COPA defect. COPA. AD Urcaria, Deafness (SNHL), Conjuncvis, Amyloidosis. Autoimmune inflammatory arthris and intersal lung disease with Th17 Colchicine-responsive +++. Neonatal onset mulsystem inflammatory disease dysregulaon and autoanbody producon (NOMID) or chronic infanle neurologic cutaneous and Mevalonate kinase def* (Hyper IgD sd). arcular syndrome (CINCA) *. NLRP3. AD GOF. MVK. AR NLRC4-MAS (macrophage acvang syndrome)*. NLRC4. Neonatal onset rash, with connuous fever and AD GOF. Severe enterocolis and DA: 3–7 days FA: 1–2 monthly. inflammaon. Asepc and chronic meningis, chronic macrophage acvaon syndrome (HLH). arthropathy. Mental retardaon, Sensorineural deafness. Triggered by cold exposure. Cervical adenopathy. Oral aphtosis. and Visual loss in some paents. Diarrhea. Mevalonate aciduria during NLRP1 GOF. NLRP1. AD GOF. aacks. Leukocytosis with high IgD levels. A20 haploinsufficiency TNFAIP3. AD LOF. Arthralgia, Palmoplantar carcinoma, corneal scarring; recurrent respiratory papillomatosis. TNF receptor-associated periodic mucosal ulcers, ocular inflammaon. Increased IL1β. syndrome; TRAPS. TNFRSF1A. AD. PLAID (PLCg2 associated anbody deficiency and ALPI deficiency*. ALP1. AR. DA: 1-4 weeks FA : Variable immune dysregulaon), or APLAID*. PLC2G. AD GOF. TRIM22 def*. TRIM22. AR Inflammatory bowel disease. Prolonged fever. Serosis, rash, Periorbital Cold Urcaria. Impaired humoral immunity. edema and conjuncvis. Hypogammaglobulinemia, autoinflammaon. T-cell lymphoma subcutaneous panniculis-like (TIM3 deficiency). HAVCR2. NLRP1 deficiency*. NLRP1. AR. Amyloidosis. Joint inflammaon. AR. Panniculis, HLH, polyclonal cutaneous Dyskeratosis, autoimmunity and arthris. T cell infiltrates or T-cell lymphoma

VIIb. Auto-inflammatory disorders

Sterile inflammaon ( skin / bone / joints ) Type 1 Interferonopathies

Predominant on the bone / joints Predominant on the skin Progressive encephalopathy, ICC, Cerebral atrophy, HSMG, leukodystrophy , Thrombocytopenia, Elevated hepac Pyogenic sterile arthris, pyoderma Blau syndrome. NOD2 (CARD15). AD. transaminases . Chronic cerebrospinal fluid (CSF) lymphocytosis gangrenosum, acne (PAPA) syndrome, Connuous inflammaon. Aicardi-Goueres Syndromes : hyperzincemia and hyper- TREX1 AR-AD (+SLE, FCL), RNASEH2A, RNASEH2B (+SP), calprotecnemia. PSTPIP1 (C2BP1). AD Uveis, Granulomatous synovis, Camptodactyly, RNASEH2C, SAMHD1 (+FCL),ADAR1 (+BSN, SP), IFIH1 GOF AD (+ Rash, Cranial neuropathies, 30% develop Crohn SLE, SP, SMS), DNASE2 DA: 5 days FA: Fixed interval : 4-6 weeks colis. Sustained modest acute-phase response. Spondyloenchondro-dysplasia with immune dysregulaon Destrucve arthris, Pyoderma CAMPS CARD14. AD. Psoriasis. (SPENCDI). ACP5. gangrenosum, inflammatory skin rash, Short stature, SP, ICC, SLE-like auto-immunity (Sjögren's Myosis. Acute-phase response during DITRA. (Deficiency of IL-36 receptor antagonist). syndrome, hypothyroidism, inflammatory myosis, Raynaud's aacks IL-36RN. AR . disease and viligo), hemolyc anemia, thrombocytopenia, skeletal dysplasia, possibly recurrent bacterial and viral infecons. Chronic recurrent mulfocal osteomyelis Life-threatening, mulsystemic inflammatory and congenital dyserythropoiecanemia disease characterized by episodic widespread, STING-associated vasculopathy, infanle-onset. TMEM173. (Majeed syndrome). LPIN2. AR pustular psoriasis, malaise, and leukocytosis. Early-onset inflammatory disease, Skin vasculopathy, inflammatory lung disease, systemic autoinflammaon and ICC, FCL. DA : Few days FA : 1-3 / month ADAM17 deficiency*. ADAM17 . AR. ADA2 deficiency. CECR1. Polyarteris nodosa, childhood-onset, Chronic recurrent mulfocal osteomyelis, Early onset diarrhea and skin lesions. Severe early-onset recurrent ischemic stroke and fever, Livedo racemosa, severe pain, tender so ssue swelling, bacteremia. some paents develop hypogammaglobulinemia Transfusion-dependent anemia, cutaneous Defecve TNFα producon. inflammatory disorders XL reculate pigmentary disorder. POLA1. Hyper- SLC29A3 mutaon. SLC29A3 . AR. pigmentaon, reculate paern. Inflammatory lung and DIRA (Deficiency of the Interleukin 1 Gastroenteris or colis. Corneal scarring, characteriscfacies Hyperpigmentaon hypertrichosis, hisocytosis- Receptor Antagonist) IL1RN. AR lymphadenopathy plus syndrome Connuous inflammaon. USP18 def *. USP18. TORCH like syndrome. Neonatal onset of sterile mulfocal osteomyelis, perioss and pustulosis. Otulipenia/ORAS*. OTULIN. AR. Pediatric systemic lupus erythematosus. DNASE1L3. Very Neonatal onset of recurrent fever, Arthralgia, early onset SLE, reduced complement levels, autoanbodies lipodystrophy. Dermas, diarrhea, Neutrophilia (dsDNA, ANCA), lupus nephris, hypocomplementemic Cherubism. SH3BP2. urcarial vasculis syndrome. AR. AP1S3 deficiency*. AP1S3. AR. OAS1 def*. OAS1. AD GOF. Pulmonary alveolar proteinosis, Bone degeneraon in jaws Pustular psoriasis skin rash.

Fig. 7 a, b Autoinflammatory disorders. AD autosomal dominant lupus, GOF gain-of-function, HLH hemophagocytic transmission, ANCA anti-neutrophilic cytoplasmic autoantibody, AR lymphohistiocytosis, HSM hepatosplenomegalia, ICC intracranial autosomal recessive transmission, BSN bilateral striatal necrosis, CAPS calcifications, IL interleukin, LOF loss-of-function, sd syndrome, SLE cryopyrin-associated periodic syndrome, DA duration of acute systemic lupus erythematosus, SMS Singleton-Merten syndrome, inflammation episode, dsDNA double-stranded deoxyribonucleic acid, SNHL sensorineural hearing loss, SP spastic paraparesis, TORCH FA frequency of acute inflammation episode, FCL familial chilblain toxoplasmosis, other, rubella, cytomegalovirus, and herpes infections 78 J Clin Immunol (2020) 40:66–81

VIII. Complement deficiencies

Suscepbility to infecons

High Low

Disseminated Recurrent SLE-like syndrome. Atypical Hemolyc Others Neisserial infecons pyogenic Infecons with encapsulated Uremic Syndrome infecons organisms Absent CH50 and AH50 C3 GOF. C3. AD. Normal CH50. . Absent CH50 hemolyc acvity Glomerulonephris. Increased acvaon of C1inhibitor. C3 LOF. C3.AR complement hemolyc acvity. Absent CH50 and AH50 SERPING1. hemolyc acvity, AD, Hereditary Defecve bactericidal Absent AH50 defecve opsonizaon C1q def. C1QA, C1QB, C1QC. Factor B GOF. CFB. AD. Increased angioedema. and humoral response spontaneous AH50 Spontaneous acvity. acvaon of the C1r def. C1R. Ehlers Danlos Factor H def. CFH. AR or AD. hemolyc MASP2 def. complement pathway phenotype Infecons, disseminated neisserial with consumpon of MASP2. AR. infecons, preeclampsia. Spontaneous C5 def. C5 acvaon of the alternave complement C4/C2 acvity Inflammatory lung pathway with consumpon of C3 disease, autoimmunity C1s def.C1S. Membrane Aack Factor H –related protein C6 def. C6 Mulple autoimmune diseases; Complex Inhibitor Ficolin 3 def. deficiencies. CFHR1-5. deficiency. Properdin FCN3. AR. Ehlers Danlos phenotype AR or AD. Later onset, disseminated CD59. Hemolyc Infecons mainly in neisserial infecons. Normal CH50, AH50, autoanbodies to Factor H. anemia. C7 def . C7. the lungs; abscesses, C2 def. C2. Polyneuropathy. def. necrozing entero- colis in infancy; Vasculis, Polymyosis, Factor I deficiency. AR. Infecons, + Vasculis selecve anbody disseminated neisserial infecons, CD55 deficiency PFC. XL defect to Pneumo- atherosclerosis preeclampsia. Spontaneous acvaon (CHAPLE disease). coccal polysaccharides. of the alternave complement CD55. AR. Protein C8 def. Absence of Complete C4 def . pathway with consumpon of C3 losing enteropathy, complement acvaon thrombosis by the Ficolin 3 C4A+C4B.AR. Thrombomodulin def. THBD. AD. C8A, C8B, C8G Factor D pathway Normal CH50, AH50 Paral deficiency is common Periodontal Ehlers Danlos. C1R,C1S. Factor B. CFB LOF. (either C4A or C4B) and appears Membrane Cofactor Protein def. AD GOF. AR. Infecons with deficiency. CD46.AD,Glomerulone- Hyperpigmentaon C9 def. C9. to have a modest effect on host phris. Infecons, preeclampsia . Inhibitor encapsulated skin fragility. organisms. Deficient of complement alternate pathway, defense Normal CH50. Mild suscepbility. CFD. AR. acvaon of the decreased C3b binding alternave pathway

Fig. 8 Complement deficiencies. AD autosomal dominant transmission, GOF gain-of-function, LOF loss-of-function, sd syndrome, SLE AH50 alternate pathway hemolytic activity, AR autosomal recessive systemic lupus erythematosus, XL X-linked transmission transmission, CH50 complement hemolytic activity, def deficiency, J Clin Immunol (2020) 40:66–81 79

IX. Bone marrow failure

Fanconi anemia Dyskeratosis congenita (DKC) Others CNS, skeletal, skin, Myelodysplasia, short telomeres. Bone marrow failure sd cardiac, GI, MIRAGE sd ,AD. SAMD9 (GOF) : urogenital anomalies. Exclude other causes: (BMFS) Fanconi anemia, IUGR with gonadal abnormalies, Increased Blackfan-Diamond Myelodysplasia adrenal failure, MDS with chromosomal breakage, Dyskeratosis congenita : chromosome 7 aberraons, pancytopenia. predisposion to infecons, IUGR, microcephaly, pulmonary and SRP72- deficiency**. Fanconi anemia Type hepac fibrosis, nail dystrophy, sparse enteropathy, absent spleen scalp hair and eyelashes; reculate skin A-W: SRP72, AD pigmentaon; palmar hyperkeratosis; Ataxia pancytopenia sd. AD. premalignant oral leukoplakia; SAMD9L. (GOF) :Cytopenia, AR pancytopenia; +/- recurrent infecons. predisposion to MDS with Bone marrow failure and congenital FANCA, FANCC, chromosome 7 aberraons and DKC1: XL, Bc and Tc: Progressive progressive cerebellar dysfuncon BRCA2, FANCD2, decrease. nerve deafness FANCE, FANCF, NOLA2 (NHP2), NOLA3 (NOP10): AR, COATS plus Sd: Intracranial XRCC9,FANCI, BRIP1, Tc: Decreased. RTEL1 : AD, Tc: calcificaon, abnormal telomeres, FANCL, FANCM, Decreased. TERC, TINF2, ACD : AD,Tc: BMFS5* variable. TERT, TPP1: AD/AR, Tc: IUGR, gastrointesnal hemorrhage PALB2, RAD51C, variable. DCLRE1B/ SNM1/APOLLO, due to vascular ectasia, hypocellular WRAP53*, DCAB1: AR,Tc: variable. SLX4,ERCC4, RAD51, TP53, AD bone marrow. pancytopenia BRCA1, UBE2T, XRCC2, Hoyeraal-Hreidarsson Syndrome (HHS) STN1: premature aging, MAD2L2,RFWD3, Severe phenotype with developmental Erythroid hypoplasia, delay and cerebellar hypoplasia. CTC1 : sparse graying hair, XL dystrophic nails, osteopenia, renal AR, RTEL1, PARN, ACD FANCB B-cell deficiency telangiectasia,

Fig. 9 Bone marrow failure disorders. AD autosomal dominant dyskeratosis congenita, GI gastrointestinal, GOF gain-of-function, transmission, AR autosomal recessive transmission, Bc B cells, BMFS IUGR intrauterine growth retardation, MDS myelodysplasia, sd bone marrow failure syndrome, CNS central nervous system, DKC syndrome, Tc T cells, XL X-linked transmission 80 J Clin Immunol (2020) 40:66–81

X. Phenocopies of PID

Associated with Associated with Somatic Mutations Auto-Antibodies

Chronic mucocutaneous candidiasis (isolated or with Splenomegaly, lymphadenopathy, APECED syndrome) AutoAb to IL-17 and/or IL-22. autoimmune cytopenias. Defective lymphocyte apoptosis. Endocrinopathy, chronic mucocutaneous candidiasis /CMC. Germline mutation in AIRE

Adult-onset immunodeficiency with susceptibility to ALPS-SFAS mycobacteria. Auto-Ab to IFNg. Mycobacterial, fungal, salmonella, VZV infections /MSMD or CID. (somatic mutations in TNFRSF6)/ ALPS-FAS (ALPS type Im) Recurrent skin infection. AutoAb to IL-6. Staphylococcal infections / STAT3 deficiency

RALD. RAS-associated autoimmune leukoproliferative Pulmonary alveolar proteinosis . AutoAb to GM-CSF. disease. (ALPS Like); N-RAS GOF, K-RAS GOF Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency Sporadic; granulocytosis, monocytosis/ALPS-like Acquired angiooedema . AutoAb to C1 inhibitor. Cryopyrinopathy, (Muckle-Wells /CINCA/NOMID-like Angioedema /C1 inhibitor deficiency syndrome). NRLP3. Atypical Hemolytic Uremic Syndrome . AutoAb to Factor H. Urticaria-like rash, arthropathy, neurological symptoms Spontaneous activation of the alternative complement pathway Hypereosinophilic syndrome due to somatic mutations Thymoma with hypogammaglobulinemia (Good syndrome). in STAT5b. STAT5b. GOF. AutoAb to various cytokines. Invasive bacterial, viral or opportunistic infections, autoimmunity, PRCA, lichen planus, Atopic dermatitis, urticarial rash, diarrhea. Eosinophilia. cytopenia, colitis, chronic diarrhea. No B cells.

Fig. 10 Phenocopies of PID. ALPS autoimmune lymphoproliferative syndrome, AutoAb autoantibodies, CID combined immunodeficiency, CMC chronic mucocutaneous candidiasis, GOF gain-of-function, MSMD Mendelian susceptibility to mycobacterial disease, PRCA pure red cell aplasia

Conclusion provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated oth- This phenotypic classification of IEI forms a diagnostic re- erwise in a credit line to the material. If material is not included in the source, aimed to complement the 2019 IUIS genotypic clas- article's Creative Commons licence and your intended use is not permitted sification. These figures serve as diagnostic orientation tools by statutory regulation or exceeds the permitted use, you will need to for patients with any of the typical phenotypic presentations of obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. IEI, whether clinical or biological. They were designed for, and will hopefully be useful to physicians and biologists who are not experts in the field of IEI. We hope that these figures can help them reach a diagnosis of IEI when encountering References patients whose clinical or biological phenotypes are evocative of IEI. 1. Tangye SG, Al-Herz W, Bousfiha A,Chatila T, Cunningham- Rundles C, Etzioni A, et al. Human Inborn Errors of Immunity: Compliance with Ethical Standards 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol (2020). https://doi.org/10.1007/s10875-019-00737-x Conflict of Interest The authors declare that they have no conflict of 2. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova interest. JL, et al. Primary immunodeficiency diseases worldwide: more com- – Open Access This article is licensed under a Creative Commons mon than generally thought. J Clin Immunol. 2013;33(1):1 7. Attribution 4.0 International License, which permits use, sharing, adap- 3. Bousfiha A, Jeddane L, Picard C, Ailal F, Gaspar HB, Al-Herz W, tation, distribution and reproduction in any medium or format, as long as et al. The 2017 IUIS phenotypic classification for primary immuno- you give appropriate credit to the original author(s) and the source, deficiencies. J Clin Immunol. 2018;38(1):129–43. J Clin Immunol (2020) 40:66–81 81

4. Jeddane L, Ouair H, Benhsaien I, El Bakkouri J, Bousfiha AA. the primary immune deficiency treatment consortium experience. J Primary immunodeficiency classification on smartphone. J Clin Allergy Clin Immunol. 2014;133(4):1092–8. Immunol. 2017;37(1):1–2. 5. Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan Publisher’sNoteSpringer Nature remains neutral with regard to jurisdic- BR, et al. Establishing diagnostic criteria for severe combined im- tional claims in published maps and institutional affiliations. munodeficiency disease (SCID), leaky SCID, and Omenn syndrome:

Affiliations

Aziz Bousfiha1,2 & Leila Jeddane 3 & Capucine Picard4,5 & Waleed Al-Herz6 & Fatima Ailal1 & Talal Chatila7 & Charlotte Cunningham-Rundles8 & Amos Etzioni9 & Jose Luis Franco10 & Steven M Holland11 & Christoph Klein12 & Tomohiro Morio13 & Hans D. Ochs14 & Eric Oksenhendler15 & Jennifer Puck16 & Troy R. Torgerson14 & Jean-Laurent Casanova17,18,19,20 & Kathleen E. Sullivan21 & Stuart G. Tangye22,23

1 Laboratoire d’Immunologie Clinique, d’Inflammation et d’Allergy 12 Dr von Hauner Children’s Hospital, Ludwig-Maximilians- LICIA, Faculty of Medecine and Pharmacy, King Hassan II University Munich, Munich, Germany University, Casablanca, Morocco 13 Department of Pediatrics and Developmental Biology, Tokyo 2 Clinical Immunology Unit, Pediatric Infectiouse Disease Medical and Dental University (TMDU), Tokyo, Japan Departmentn Children’s Hospital, Ibn Rochd University Hospital, 14 Department of Pediatrics, University of Washington and Seattle Casablanca, Morocco Children’s Research Institute, Seattle, USA 3 Laboratoire national de référence, University Mohamed VI of Health 15 Department of Clinical Immunology, Hôpital Saint-Louis, APHP, Sciences, Casablanca, Morocco University Paris Diderot, Sorbonne Paris, Cité, Paris, France 4 Study Center for Primary Immunodeficiencies, Necker Hospital for 16 Department of Pediatrics, University of California San Francisco Sick Children, APHP, Paris University, Paris, France and UCSF Benioff Children’s Hospital, San Francisco, USA 5 Laboratory of Lymphocyte Activation and Susceptibility to EBV, 17 St. Giles Laboratory of Human Genetics of Infectious Diseases, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Rockefeller Branch, The Rockefeller University, New York, USA Children, Paris University, Paris, France 18 Howard Hughes Medical Institute, New York, USA 6 Department of Pediatrics, Faculty of Medicine, Kuwait University, 19 Kuwait City, Kuwait Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital 7 Division of Immunology, Children’s Hospital Boston, Boston, USA for Sick Children, Paris University, Paris, France 8 Departments of Medicine and Pediatrics, Mount Sinai School of 20 Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Medicine, New York, USA Children Assistance Publique-Hôpitaux de Paris (APHP), 9 Ruth’sChildren’s Hospital-Technion, Haifa, Israel Paris, France

10 Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, 21 Division of Allergy Immunology, Department of Pediatrics, The Universidad de Antioquia UdeA, Medellin, Colombia Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA 11 Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of 22 Garvan Institute of Medical Research, Darlinghurst, Australia Health, Bethesda, USA 23 St Vincent’s Clinical School, Faculty of Medicine, UNSW, Sydney, Australia