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 # 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 Human inborn errors of immunity (IEI) are caused bymonogenic germline mutations resulting in loss or gain of function of the encoded protein. They can be dominant or recessive, autosomal or X-linked, and with complete or incomplete penetrance. They manifest as increased susceptibility to a broad or narrow spec- trum of infectious diseases, as well as a growing diversity of autoimmune, autoinflammatory, allergic, and/or malignant phe- notypes. They now comprise 406 distinct disorders with 430 different gene defects listed in the 2019 International Union of Immunological Societies (IUIS) classical classification [1]. If most IEI are individually rare, they are collectively more com- mon than generally thought [2]. The (IUIS) expert committee on IEI proposes every other 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 of which groups IEI sharing a given pathogenesis. However, with the growing number of IEI included in this catalog, these tables are not always easy to use at the bedside. We thus reported from 2013 onward a more user-friendly classification adapted for the clinician, based on the clinical and laboratory features observed in these patients. This phenotypic classifi- cation proved to be as popular as the genotypic classification (15 k vs 12 k downloads on publisher site) [3] and has been adapted in a smartphone application [4]. Here, we present an update of the phenotypic classi- fication of IEI, based on the 2019 IEI classical classifi- cation [1]. This tree-based decision-making process is aimed to physicians, regardless of their familiarity with IEI. It aims at helping them to reach a diagnosis based on simple clinical and biological phenotypes. Methodology We included in our figures all disorders indexed in the 2019 update of the IUIS IEI classification [1]. A phe- notypic algorithm was assigned to each of the ten main groups of the classification and the same color was used for each group of similar conditions. Given the high * Aziz Bousfiha profbousfiha@gmail.com Extended author information available on the last page of the article Journal of Clinical Immunology (2020) 40:66–81 https://doi.org/10.1007/s10875-020-00758-x The Author(s) 2020 http://crossmark.crossref.org/dialog/?doi=10.1007/s10875-020-00758-x&domain=pdf mailto:profbousfiha@gmail.com number of diseases, several categories have been split since last update [3] in two sub-figures to be more informative. Disease names are presented in red and genes in bold italic. An asterisk is added to highlight extremely rare disorders (less than 10 reported cases to date). However, the reader should keep in mind that some genes have been very recently de- scribed and that true prevalence is unknown. A double asterisk is added when only one case or one kindred has been reported to date. In these cases, it is difficult to confirm than observed phenotype would be reproducible in other patients carrying the same defect, or if it is an exception. Results Algorithms for the 2019 update of IUIS phenotypical classifi- cation are presented in Figs. 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Discussion These algorithms are aimed to guide clinicians to diag- nose patients presenting typical phenotype. However, readers should be aware of the limitations of such a work. More and more reports show a spectrum of atypical presentations related to hypomorphic mutations of those genes. Omenn syndrome (OMIM #603554) is a good example of such an atypical presentation, as well as “leaky SCID” and RAG deficiency spectrum [5]. Moreover, readers should be extremely cautious with descriptions of disease when only one patient or kindred have been reported. We are aware that these reports may not reflect the typical phenotype of such defects, but the exception; however, we thought that it was needed to be mentioned in these classifications. 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, Adp adenopathies, 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, Eo eosinophilia, GOF gain-of-function mutation, HHV8 human herpes virus 8, HIGM hyper IgM syndrome, HPV human papillomavirus, HSM hepa tosp lenomega ly, Ig immunoglobu l in s , 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 J Clin Immunol (2020) 40:66–81 67 68 J Clin Immunol (2020) 40:66–81 Fig. 1 (continued) J Clin Immunol (2020) 40:66–81 69 Jacobsen Sd. 11q23del. Recurrent respiratory infec�ons; mul�ple warts; facial dysmorphism, growth retarda�on. Lymphopenia, Low NK, Bc and switched memory Bc. Hypogammaglobulinemia. Ataxia telangiectasia. ATM: Ataxia; telangiectasia; pulmonary infec�ons; lymphore�cular and other malignancies; increased α- fetoprotein; increased radiosensi�vity, chromosomal instability and transloca�ons. O�en decreased IgA, IgE and IgG subclasses; increased IgM; an�bodies variably decreased. Tc : Progressive decrease, abnormal prolif to Mitogens. IIa. CID with associated or syndromic features Car�lage Hair Hypoplasia RMRP. Short-limbed dwarfism with metaphyseal dysostosis, sparse hair, bone marrow failure; autoimmunity; suscep�bility to lymphoma and other cancers; impaired spermatogenesis; neuronal dysplasia of the intes�ne. Ig: Nl or ↓. Tc: Varies from ↓↓ (SCID) to Nl; impaired lymphocyte prolifera�on. Schimke Sd SMARCAL1 Short stature, spondilo- epiphyseal dysplasia, IUGR; nephropathy; bacterial, viral, fungal infec�ons; may present as SCID; bone marrow failure. Tc: ↓ Thymic Defects with Addi�onal Congenital Anomalies Congenital thrombocytopenia Bloom sd. BLM.Short stature; bird like face; sun-sensi�ve erythema; marrow failure; leukemia; lymphoma; chromosomal instability. Low Ig. PMS2 def. PMS2. Café-au-lait spots ; lymphoma, colorectal carcinoma, brain tumors. HIGM and abnormal an�body responses. Reduced Bc, switched and non-switched. Immunodeficiency with centromeric instabil�y and facial anomalies: ICF1. DNMT3B; ICF2:ZBTB24; ICF3:CDCA7; ICF4:HELLS.Facial dysmorphism; macroglossia; bacterial/opportunis�c infec�ons; malabsorp�on; malignancies. Cytopenias; mul�radial configura�ons of chromosomes 1,9,16; no DNA breaks. Ig: Hypogammaglobulinemia; Tc and Bc: decreased or Nl. RNF168 def* (RIDDLE sd). RNF168. Short stature; mild defect of motor control to ataxia; normal intelligence to learning difficul�es; mild facial dysmorphism to microcephaly; increased radiosensi�vity. Low IgG or IgA. DNA Repair Defects other than those listed in Table1: Karyotype XL: Wisko� Aldrich Sd or XL thrombocytopenia WAS (LOF). Recurrent bacterial and viral infec�ons; bloody diarrhea; eczema; lymphoma; autoimmune disease; IgA nephropathy; vasculi�s. Small platelets; Decreased IgM. Low an�body to polysaccharides; o�en increased IgA and IgE. Nl Bc. Tc: Progressive decrease in numbers; Low Tc responses to an�-CD3. Pa�ents with XL-thrombocytopenia have later onset of complica�ons and more favourable life expectancy but eventually develop similar complica�ons as observed in WAS AR: WIP deficiency*. WIPF1, WAS protein absent. +/- small platelets; increased IgE. Bc : Nl to low. Tc: Reduced; defec�ve lymphocyte responses to an�-CD3. AR: Defec�ve Arp2/3-mediated filament branching. ARPC1B. Recurrent invasive infec�ons, coli�s, vasculi�s. Mild trombocytopenia, normal sized platelets; autoan�bodies (ANA, ANCA); eosinophilia.High IgA and IgE. AD. Hypoparathyroidism, conotruncal cardiac malforma�on, velopalatal insufficiency, facial dysmorphism, intellectual disability . Ig : Normal or decreased. Tc: ↓or Nl May have low TRECs at NBS. DiGeorge/velocardiofacial Sd. Chr22q11.2 dele�on Sd. 22q11.2DS. TBX1 deficiency . TBX1 MCM4 def. MCM4. Viral infec�ons:EBV,HSV,VZV.short stature.Bc lymphoma; Adrenal failure; NKc low number and func�on. AD. CHARGE Sd. CHD7, SEMA3E. Coloboma, heart anomaly, choanal atresia, intellectual disability, genital and ear anomalies; CNS malforma�on; some are SCID-like and have low TRECs. Ig: Normal or decreased. Tc: Decreased or normal; response to PHA may be decreased POLE1 (Polymerase ε subunit 1) deficiency (FILS syndrome). POLE1.Recurrent respiratory infec�ons; meningi�s; facial dysmorphism, livido, short stature. Low IgM, lack of an�body to PPS. Low memory Bc. Decreased Tc prolifera�on. POLE2 (Polymerase ε subunit 2) deficiency**. POLE2. Recurrent infec�on, disseminated BCG infec�ons, autoimmunity (type 1 diabetes, hypothyroidism), facial dysmorphism; Low Ig; Very low Bc. Lymphopenia, lack of TRECS, absent prolifera�on of an�gens. Ligase I deficiency *. LIGI Recurrent bacterial and viral infec�ons; growth retarda�on; sun sensi�vity; lymphoma; radia�on sensi�vity. Macrocy�c red blood cells. Hypogammaglobulinemia. Reduced Ab response. Lymphopenia, increased γδTc, decreased mitogen response. Nijmegen breakage Sd. NBS1. Microcephaly; bird-like face; lymphomas; solid tumors; increased radiosensi�vity; chromosomal instability. O�en decreased IgA, IgE and IgG subclasses;increased IgM; an�bodies variably decreased. Bc: Variably reduced. Tc: progressive decrease. NSMCE3 deficiency*. NSMCE3. Severe lung disease (possibly viral); thymic hypoplasia, Chromosomal breakage; radia�on sensi�vity. Ig: Decreased Ab responses to PPS, normal IgG, IgA, normal to elevated IgM. Tc : Low, poor responses to mitogens and an�gens. Immuno- osseous dysplasias GINS1 def*. GINS1. IUGR. Neutropenia, NK cells very low. Tc and Bc: low or normal. High IgA, Low IgG and IgM. Immunoskeletal dysplasia with neurodevelopmental abnormali�es. EXTL3. Short stature; cervical spinal stenosis, neurodevelopmental impairment. Eosinophilia; Ig: variably ↓ Tc: ↓ MOPD1 Deficiency. RNU4ATAC.Recurrent bacterial infec�ons, lymphadenopathy, Spondyloepiphyseal dysplasia, IUGR, re�nal dystrophy, facial dysmorphism; +/- microcephaly. short stature. Ig: ↓ , specific an�bodies variably decreased MYSM1 def* MYSM1, AR Short stature, congenital bone marrow failure, myelodysplasia. Skeletal anomalies; cataracts; developmental delay. Affects granulocytes. Bc: immature. Tc: lymphopenia, reduced naïve Tc. Hypogammaglobulinemia Chromosome 10p13-p14 dele�on Syndrome. 10p13-p14DS. AD. Hypoparathyroidism; renal disease; deafness; growth retarda�on; facial dysmorphism; cardiac defects may be present FOXN1 haploinsufficiency. FOXN1, AD Recurrent, viral and bacterial respiratory tract infec�ons; skin involvement (eczema, derma��s), nail dystrophy. T cell lymphopenia may normalize by adulthood. BMFS2 (Hebo def). ERCC6L2, AR. Facial dysmorphism; microcephaly, learning difficul�es. Bone marrow failure. Fig. 2 a, b CID with associated or syndromic features. Ab antibody, AD autosomal dominant transmission, AD DN autosomal dominant transmission with dominant negative effect, 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, CID combined immunodeficiency of T and B cells, CMV cytomegalovirus, CNS central nervous system, def deficiency, DNA deoxyribonucleic acid, EBV Epstein-Barr virus, EDA anhidrotic ectodermal dysplasia, GOF gain-of-function, HIES hyper IgE syndrome, FILS facial dysmorphism, immunodeficiency, livedo and short stature, ID immunodeficiency, Ig immunoglobulins, IL-6 interleukin-6, IUGR intrauterine growth retardation, LOF loss-of-function, MCC mucocutaneous candidiasis, 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 70 J Clin Immunol (2020) 40:66–81 Others IIb. CID with associated or syndromic features Hyper-IgE syndromes (HIES) AD-HIES (Job sd ). STAT3, AD LOF. Dis�nc�ve facial features (broad nasal bridge); bacterial infec�ons (boils and pulmonary abscesses, pneumatoceles) due to S. aureus, Aspergillus, Pneumocys�s jirovecii; eczema; mucocutaneous candidiasis; hyperextensible joints, osteoporosis and bone fractures, scoliosis, reten�on of primary teeth; aneurysm forma�on. IgE ↑↑; specific an�body produc�on↓. Bc:Normal; reduced switched and non-switched memory Bc; BAFF expression ↑. Tc:Nl overall; Th-17 & T-follicular helper cells ↓ Comel Netherton Sd; SPINK5; Congenital ichthyosis, bamboo hair,atopic diathesis; ↑ bacterial infec�ons, failure to thrive. ↑ IgE and IgA; Other Ig: variably decreased. Bc: Switched and non-switched Bc are↓. PGM3 deficiency. PGM3. Severe atopy; autoimmunity; skeletal anomalies: short stature, brachydactyly, dysmorphic facial features. Recurrent pneumonia, recurrent skin abscesses,bacterial and viral infec�ons; cogni�ve impairment; delayed CNS myelina�on in some. Ig:Nl or elevated. Elevated IgE; eosinophilia. Reduced B and memory Bc. CD8 and CD4 Tc may be↓. Purine nucleoside phosphorylase deficiency. PNP. Autoimmune haemoly�c anemia, neurological impairment. Hypouricemia. Ig : Nl/Low. Bc: Nl. Tc: Progressive decrease Hepa�c veno-occlusive disease with immunodeficiency (VODI). SP110. Hepa�c veno-occlusive disease, Pneumocys�s jirovecii pneumonia, CMV, candida, thrombocytopenia, hepatosplenomegaly, cerebrospinal leukodystrophy. Decreased IgG, IgA, IgM, absent germinal centers and �ssue plasma cells. Decreased memory Bc . Decreased memory Tc. Vici syndrome. EPG5. Agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmenta�on, intellectual disability, microcephaly, CMC. Ig: Decreased IgG2. Bc: Defec�ve. Profound deple�on of CD4+ cells. Defects of Vitamin B12 and Folate Metabolism: Anhidro�c Ectodermodysplasia with ID Bacterial infec�ons, autoinflamma�on, amylopec�nosis.Bc: Nl,decreased memory Bc. HOIL1 deficiency. RBCK1. Poor Ab responses to polysaccharides. HOIP deficiency*. RNF31. Lymphangiectasia. Ig: decreased. Calcium Channel Defects. Autoimmunity, EDA, non-progressive myopathy. Ig and Bc: Nl. Tc: Normal, defec�ve TCR mediated ac�va�on. ORAI-1 deficiency*. ORAI1 . STIM1 deficiency*. STIM1 Hennekam-lymphangiectasia-lymphedema syndrome*. CCBE1, FAT4. Lymphangiectasia and lymphedema with facial abnormali�es and other dysmorphic features. Ig: decreased. Bc and Tc: Variable. Kabuki Sd. KMT2D (MLL2): AD. KDM6A: XL. Typical facial abnormali�es, cle� or high arched palate, skeletal abnormali�es, short stature, intellectual disability, congenital heart defects, recurrent infec�ons (o��s media, pneumonia) in 50% of pa�ents. Autoimmunity may be present. Low IgA and occasionally low IgG. ZNF341 deficiency. ZNF341. AR. Phenocopy of AD-HIES: Mild facial dysmorphism, early onset eczema, MCC, bacterial skin infec�ons, abscesses, recurrent bacterial respiratory infec�ons (S. aureus), lung abscesses and pneumatoceles, hyperextensible joints, bone fractures and reten�on of primary teeth ERBIN deficiency**. ERBB21P. Recurrent respiratory infec�ons, suscep�bility to S. aureus, eczema, hyperextensible joints, scoliosis, arterial dilata�on in some. Moderately increased IgE; increased Treg. IL6ST deficiency*. IL6ST. Bacterial infec�ons, boiles, eczema, pulmonary abscesses, pneumatoceles, bone fractures, scoliosis, reten�on of primary teeth, craniosynostosis. ↓B-cell memory. Loes-Dietz syndrome. TGFBR1, TGFBR2. Recurrent respiratory infectons, eczema, food allergies, hyperextensible joints, scoliosis, reten�on of primary teeths; aor�c aneurisms. Immunodeficiency, developmental delay and hypohomocysteinemia, IMDDHH*. Ac�va�ng de-novo muta�ons in NFE2L2. AD. Recurrent respiratory and skin infec�ons, growth retarda�on, developmental delay; white ma�er cerebral lesions, decreased level of homocysteine; increased expression of stress response genes. Hypogammaglobulinemia. Bc: Decreased switched-memory Bc. Tricho-Hepato-Enteric syndrome. TTC37; SKIV2L* . Respiratory infec�ons, IUGR, wooly hair, early onset intractable diarrhea, liver cirrhosis, platelet abnormali�es. Impaired IFNγ produc�on, Hypogammaglobulinemia, low an�body responses. Bc: Variably low switched-memory Bc. IL6R deficiency*. IL6R. Recurrent pyogenic infec�ons, cold abscesses, high circula�ng IL-6 Levels. CID with early-onset asthma, eczema and food allergies, autoimmunity ID with atopic derma��s (CADINS)*. CARD11. AD LOF. Variable atopy, cutaneous viral infec�ons, recurrent respiratory infec�ons, lymphoma. Eosinophilia, ↓Tc prolifera�on. Nl to low Bc. Anhidro�c ectodermal dysplasia,various infec�ons (bacteria, mycobacteria, viruses and fungi), coli�s, variable defects of skin, hair and teeth. NEMO deficiency. IKBKG (NEMO). XL, monocyte dysfunc�on. Ig decreased, some with elevated IgA, IgM, poor specific an�body responses, absent an�body to polysaccharide an�gens. Bc: Nl, Low memory and isotype switched Bc. Tc: Nl/decreased, TCR ac�va�on impaired. EDA-ID due to IKBA GOF muta�on. NFKBIA (IKBA). AD Tc and monocyte dysfunc�on Decreased IgG and IgA, elevated IgM, poor specific an�body responses, absent an�body to polysaccharide an�gens. Normal Bc numbers, impaired BCR ac�va�on, low memory and isotype switched Bc. Normal total Tc, TCR ac�va�on impaired. EDA-ID due to IKBK GOF muta�on* IKBB. AD. Low Tc. Bc: Nl number, poor func�on. Low Ig. BCL11B deficiency. BCL11B. AD. Congenital abnormali�es: neonatal teeth, dysmorphic facies; absent corpus callosum; neurocogni�ve deficits. Tc : Low, poor prolifera�on. STAT5b deficiency. STAT5B. AR. Growth-hormone insensi�ve dwarfism, dysmorphic features, eczema, lymphocy�c inters��al pneumoni�s, autoimmunity. Hypergammaglobulinemia, High IgE. AD DN: Growth failure and eczema only. High IgE. ID with mul�ple intes�nal atresias. TTC7A . Bacterial (sepsis), fungal, viral infec�ons, mul�ple intes�nal atresias, o�en with intrauterine polyhydramnios and early demise, some with SCID phenotype. Markedly decreased IgG, IgM, IgA. Bc:Nl/low.Tc: Variable/absent, low TRECs (may present with SCID at birth) Wiedemann-Steiner Sd. KMT2A (MLL): AD Respiratory infec�ons; short stature; hypertelorism; hairy elbows; developmental delay, intellectual disability. Hypogammaglobulinemia, decreased memory Bc. Megaloblas�c anemia, Ig: decreased. Transcobalamin 2 deficiency. TCN2. pancytopenia, if untreated for prolonged periods results in intellectual disability. Deficiency causing hereditary folate malabsorb�on. SLC46A1. failure to thrive, if untreated for prolonged periods results in intellectual disability Methylene- tetrahydrofolate dehydrogenase 1 deficiency MTHFD1. Recurrent bacterial infec�on, Pneumocys�s jirovecii; failure to thrive; neutropenia; seizures, intellectual disability; folate-responsive ↓ Bc, ↓ an�body responses to conjugated polysaccharide an�gens. Fig. 2 (continued) J Clin Immunol (2020) 40:66–81 71 F i g . 3 P r e d o m i n a n t l y a n t i b o d y d e f i c i e n c i e s . 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 72 J Clin Immunol (2020) 40:66–81 III. Predominantly Antibody deficiencies. b: Other An�body deficiencies Severe Reduc�on in Serum IgG and IgA with Normal or elevated IgM and Normal Numbers of Bc : Hyper IgM Syndromes AID deficiency. AICDA. AR or AD. Bacterial infec�ons, enlarged lymph nodes and germinal centers. Nl memory Bc, but lacking soma�c hypermuta�on in AR form. UNG deficiency. UNG. Enlarged lymph nodes and germinal centers. INO80 def*. INO80 . Severe bacterial infec�ons. MSH6*. MSH6 . Family or personal history of cancer. Variable IgG, defects, increased IgM in some, Nl Bc, low switched memory Bc. Isotype, Light Chain, or Func�onal Deficiencies with Generally Nl Numbers of Bc Ig heavy chain muta�ons and dele�ons. Muta�on or chromosomal dele�on at 14q32. May be asymptoma�c. One or more IgG and/or IgA subclasses as well as IgE may be absent. Kappa chain deficiency*. IGKC. Asymptoma�c. All immunoglobulins have lambda light chain. Isolated IgG subclass deficiency. Unknown. Usually asymptoma�c, a minority may have poor an�body response to specific an�gens and recurrent viral/bacterial infec�ons. Reduc�on in one or more IgG subclass. IgG subclass deficiency with IgA deficiency. Unknown. Recurrent bacterial infec�ons. May be asymptoma�c. Reduced IgA with decrease in one or more IgG subclass. Selec�ve IgA deficiency. Unknown. May be asymptoma�c. Bacterial infec�ons, autoimmunity mildly increased. Very low to absent IgA with other isotypes normal, normal subclasses and specific an�bodies. Specific an�body deficiency with normal Ig levels and normal B cells. Unknown. Reduced ability to produce an�bodies to specific an�gens. Ig: Nl. Transient hypogammaglobuliemia of infancy. Unknown. Usually not associated with significant infec�ons, normal ability to produce an�bodies to vaccine an�gens. IgG and IgA decreased. CARD11 GOF . CARD11. AD. BENTA syndrome Splenomegaly, lymphadenopathy, poor vaccine responses. Selec�ve IgM deficiency. Unknown. Pneumococcal / bacterial infec�ons. Absent serum IgM. High Bc numbers due to cons�tu�ve NF-κB ac�va�on Fig. 3 (continued) J Clin Immunol (2020) 40:66–81 73 XL magnesium EBV and neoplasia (XMEN)*. MAGT1.XL. EBV infec�on, lymphoma, viral infec�ons, respiratory and GI infec�ons. Glycosyla�on disorder. Some pa�ents can present with neurological manifesta�ons. Low CD4 Low recent thymic emigrant cells, poor prolifera�on to CD3. High B cells, high DN T cells.. Fever, HSM, cytopenias, Nl Bc. Increased activated Tc. Decreased to absent NK and CTL activities (cytotoxicity and/or degranulation) Perforin deficiency (FHL2).PRF1. UNC13D / Munc13-4 deficiency (FHL3). UNC13D. Syntaxin 11 deficiency (FHL4). STX11. STXBP2 / Munc18-2 deficiency (FHL5) STXBP2. Enteropathy Familial Hemophagocytic Lymphohistiocytosis Syndromes: IV. Diseases of immune dysregula�on. a : Hemophagocy�c Lymphohis�ocytosis HLH & EBV suscep�bility Chediak Higashi Sd. LYST Recurrent infections, fever, HSM, bleeding tendency, progressive neurological dysfunction. Giant lysosomes (WBC), neutropenia, cytopenias, Specific hair shaft anomaly. Increased activated Tc. Griscelli Sd type 2. RAB27A. Fever, HSM, cytopenias; Specific hair shaft anomaly Hermansky Pudlak sd type 2. AP3B1. Recurrent infections, pulmonary fibrosis, increased bleeding, neutropenia; Specific hair shaft anomaly. Hypopigmentation: Partial albinism . Decreased NK and CTL activities(cytotoxicity and/or degranulation). Bc and Tc: Nl Hermansky-Pudlak syndrome, type 10**. AP3D1. Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss and neurodevelopmental delay . FAAP24 deficiency**. FAAP24. EBV-driven lymphoproliferative disease. Increased activated Tc. Failure to kill autologous EBV transformed Bc. Nl NK cell function. Hemophagocy�c Lymphohis�ocytosis (HLH) XL, XLP2. XIAP. Splenomegaly, lympho- proliferation, Colitis, IBD, hepatitis. Hypogammaglobulinemia, Low iNKT cells. Increased T cells susceptibility to apoptosis to CD95 and enhanced activation- induced cell death (AICD). Normal NK and CTL cytotoxic activity. XIAP def (FCM) XL, XLP1. SH2DIA. Clinical and immunologic features triggered by EBV infection: lymphoproliferation, Aplastic anemia, Lymphoma. Hypogammaglobulinemia, Absent iNKT cells. Impaired NK cell and CTL cytotoxic activity . Reduced Memory B cells . SAP deficiency (FCM). EBV associated HLH AR, CD27 deficiency . CD27 (TNFRSF7). Features triggered by EBV infection, aplastic anemia, low iNKTc lymphoma. Low Ig Suscep�bility to EBV CTPS1 deficiency. CTPS1. Recurrent/chronic bacterial and viral infec�ons (EBV, VZV), EBV lympho- prolifera�on, B cell non-Hodgkin lymphoma. Tc: poor prolifera�on to Ag RLTPR (CARMIL2) deficiency. RLTPR. Recurrent bacterial, fungal and mycobacterial infec�ons, viral warts, molluscum and EBV lymphoprolifera�ve and other malignancy, atopy. Ig Nl to ↓, poor T dependent an�body response. Nl Bc. Tc: ↓ Treg, high CD4, poor func�on. CD70 deficiency*. CD70 (TNFSF7). Hodgkin lymphoma, autoimmunity in some pa�ents. Reduced IgM, IgG, IgA (75%) and reduced Ag-specific Ab responses (50%). Bc:poor an�body and memory responses. Tc:low Treg, poor ac�va�on and func�on PRKCD deficiency*. PRKCD. Recurrent infec�ons, EBV chronic infec�on, lymphoprolifera�on, SLE-like autoimmunity (nephro�c and an�phospholipid Sd). Low IgG. Low memory Bc high CD5 Bc SLC7A7 deficiency. SLC7A7. Lysinuric protein intolerance, bleeding tendency, alveolar proteinosis Hyper- inflammatory response of macrophages. Nl Tc and NK cell function CD137 deficiency*. TNFRSF9. EBV lymphoprolifera�on, B cell lymphoma, chronic ac�ve EBV infec�on. Low IgA and IgG, poor response to an�gens, decreased T cell prolifera�on RASGRP1 deficiency*. RASGRP1. Recurrent pneumonia, herpes virus infec�ons, EBV associated lymphoma. Decreased NK cell func�on; high IgA. Bc and Tc: Poor ac�va�on, prolifera�on, mo�lity Fig. 4 Diseases of immune dysregulation. a Hemophagocytic lymphohistiocytosis. b Other diseases of immune dysregulation. Ab antibody, AD autosomal dominant transmission, Ag antigen, AIHA autoimmune hemolytic anemia, ALPS autoimmune lymphoproliferative syndrome, APS autoimmune polyendocrinopathy syndrome, AR autosomal recessive transmission, Bc B cells, CD cluster of differentiation, CMF flow cytometry, CTL cytotoxicT lymphocytes, def deficiency, DNT double negative T cells, EBV Epstein-Barr virus, FHL familial hemophagocytic lymphohistiocytosis, GOF gain-of-function, HLH h emo p h a g o c y t i c l ym p h o h i s t i o c y t o s i s , ( 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 74 J Clin Immunol (2020) 40:66–81 IV. Diseases of immune dysregula�on. b: Syndromes with Autoimmunity and Others Syndromes with Autoimmunity Increased CD4- CD8- TCR αβ+ (double negative (DN) T cells) ? Yes: ALPS Autoimmune Lymphoproliferative Sd Chronic adenopathy Splenomegaly, defective lymphocyte apoptosis. ALPS-FAS. TNFRSF6. AD or AR. Autoimmune cytopenias, increased lymphoma risk, IgG and IgA Nl or increased, elevated serum FasL, IL-10, vitamin B12. ALPS-Caspase 8**. CASP8. AR. Bacterial and viral infec�ons, Hypogammaglobulinemia. Defec�ve lymphocyte ac�va�on. Slightly increased DNT cells. ALPS-FASLG. TNFSF6.AR. Autoimmune cytopenias, SLE, soluble FasL is not elevated ALPS-Caspase10*. CASP10. AD. FADD deficiency.** FADD. AR. Func�onal hyposplenism, bacterial and viral infec�ons, recurrent episodes of encephalopathy and liver dysfunc�on. No : Regulatory T Cell Defects ? Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy: APECED (APS-1) . AIRE. AR/ AD. Hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunc�on and other endocrine abnormali�es, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia, enteropathy, pernicious anemia. JAK1 GOF**. JAK1. AD GOF. HSM, eosinophilic enteri�s, thyroid disease, poor growth, viral infec�ons. Eosinophilia, ITCH deficiency. ITCH. AR. Early-onset chronic lung disease (inters��al pneumoni�s), thyroidi�s, type I diabetes, chronic diarrhea/enteropathy, and hepa��s, developmental delay, dysmorphic facial features . Tripep�dyl-Pep�dase II Deficiency**. TPP2. AR. Variable lymphoprolifera�on, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infec�ons. Decreased Tc and Bc. IPEX, immune dysregula�on, polyendocrinopathy, enteropathy X-linked. FOXP3. Autoimmune enteropathy, early onset diabetes, thyroidi�s hemoly�c anemia, thrombocytopenia, eczema, elevated IgE, IgA. Lack and/or impaired func�on of CD4+ CD25+ FOXP3+ regulatory T cells (Tregs). CTLA4 deficiency (ALPSV). CTLA4. AD. Autoimmune cytopenias, enteropathy, inters��al lung disease, extra-lymphoid lymphocy�c infiltra�on recurrent infec�ons . Impaired func�on of Tregs. Tc and Bc decreased. CD25 deficiency*. IL2RA. AR. Lymphoprolifera�on, autoimmunity, impaired Tc prolifera�on. No CD4+C25+ cells with impaired func�on of Tregs cells. STAT3 GOF muta�on. STAT3. AD. Lymphoprolifera�on, solid organ autoimmunity, recurrent infec�ons. Enhanced STAT3 signaling, leading to increased Th17 cell differen�a�on, lymphoprolifera�on and autoimmunity. Decreased Tregs and impaired func�on. Tc and Bc decreased. LRBA deficiency. LRBA. AR. Recurrent infec�ons, inflammatory bowel disease, autoimmunity. Reduced IgG and IgA in most. Low or normal numbers of Bc. Normal or decreased CD4 numbers, Tc dysregula�on. BACH2 deficiency. BACH2. AD. Lymphocy�c coli�s, sinopulmonary infec�ons. Impaired memory Bc development. Progressive Tc lymphopenia. Immune Dysregula�on with Coli�s: IBD IL-10 deficiency*. IL10. AR. Folliculi�s, recurrent respiratory diseases, arthri�s. No func�onal IL-10 secre�on. IL-10R deficiency. AR. Folliculi�s, recurrent respiratory diseases, arthri�s, lymphoma. IL10RA Leukocytes unresponsive to IL- 10. IL10RB. Leukocytes unresponsive to IL10, IL22, IL26, IL28A, IL28B, IL29 NFAT5 haploinsufficiency**. NFAT5. AD. Recurrent Sinopulmonary infec�ons. Decreased memory Bc and plasmablasts. No Yes Prolidase deficiency. PEPD. AR. Chronic skin ulcers, eczema, infec�ons. Auto- an�bodies common. CD122 deficiency. IL2RB. Lymphoprolifera�on, lymphadenopathy, HSM, AIHA, derma��s, enteropathy. Hypergammaglobulinemia, recurrent viral (EBV, CMV) infec�ons DEF6 deficiency*. DEF6. HSM, enteropathy, cardiomyopathy, recurrent infec�ons. Low Tc, low or normal Bc FERMT1 deficiency. FERMT1. Dermatosis (congenital blistering, skin atrophy, photosensi�vity, skin fragility, and scaling). Intracellular accumula�on of IgG, IgM, IgA, and C3 in colloid bodies under the basement membrane TGFB1 deficiency*. TGFB1. AR. Recurrent viral infec�ons, microcephaly, and encephalopathy. Decreased T cell prolifera�on in response to an�-CD3 RIPK1 deficiency*. RIPK1. AR. Reccurrent infec�ons, progressive polyarthri�s. Low Tc , low or nl Bc. Fig. 4 (continued) V. Congenital defects of phagocyte number, func�on, or both. a : Neutropenia (without an�-PMN ) No syndrome associatedSyndrome associated GFI 1 deficiency (SCN2)**. GFI1. AD. B/T lymphopenia Elastase deficiency. (SCN1). ELANE. AD. Suscep�bility to MDS/leukemia. Severe congenital neutropenia or cyclic neutropenia (perform CBC twice weekly/ 4 weeks). HAX1 deficiency (Kostmann Disease) (SCN3). HAX1. AR. Cogni�ve and neurological defects in pa�ents with defects in both HAX1 isoforms, suscep�bility to MDS/leukemia G6PC3 deficiency (SCN4). G6PC3. AR. Structural heart defects, urogenital abnormali�es, inner ear deafness, and venous angiectasias of trunks and limbs. Affected fonc�ons: Myeloid differen�a�on, chemotaxis, O2 - produc�on. Glycogen storage disease type 1b. G6PT1. AR. Fas�ng hypoglycemia, lac�c acidosis, hyperlipidemia, hepatomegaly. VPS45 deficiency (SCN5). VPS45. AR. Extramedullary hematopoiesis, bone marrow fibrosis, nephromegaly. G-CSF receptor deficiency*. CSF3R. AR. Stress granulopoiesis disturbed P14/LAMTOR2 deficiency**. LAMTOR2. AR. Par�al albinism, growth failure. Hypogammaglobulinemia, reduced CD8 cytotoxicity. X-linked neutropenia/ myelodysplasia WAS GOF. WAS. XL GOF. Myeloid matura�on arrest, monocytopenia, variable lymphoid anomalies . Barth Syndrome (3-Methylglutaconic aciduria type II). TAZ. XL. Cardiomyopathy, myopathy, growth retarda�on. Cohen syndrome. COH1. AR. Dysmorphism, mental retarda�on, obesity, deafness. Clericuzio syndrome (Poikiloderma with neutropenia). C16ORF57 (USB1). AR. Re�nopathy, developmental delay, facial dysmorphism, poikiloderma. JAGN1 deficiency. JAGN1. AR. Osteopenia. Myeloid matura�on arrest. 3-Methylglutaconic aciduria. CLPB. AR. Neurocogni�ve developmental aberra�ons, microcephaly, hypoglycemia, hypotonia, ataxia, seizures, cataracts, IUGR. SMARCD2 deficiency*. SMARCD2. AR. Developmental aberra�ons, bones defect, myelodysplasia Shwachman-Diamond Syndrome. DNAJC21. AR. EFL1*. AR. Pancytopenia, exocrine pancrea�c insufficiency. SBDS. AR. +chondrodysplasia SRP54 deficiency*. SRP54. AD. Neutropenia and exocrine pancrea�c insufficiency . WDR1 deficiency. WDR1. AR. Poor wound healing, severe stoma��s, neutrophil nuclei herniate. Mild neutropenia. HYOU1 deficiency**. HYOU1. AR. Hypoglycemia, inflammatory complica�ons. Neutropenia with combined immune deficiency *. MKL1. AR. Mild thrombocytopenia. Lymphopenia. Specific granule deficiency*. CEBPE. AR. Neutrophils with bilobed nuclei. Chronic neutropenia. Rac 2 def** . RAC2. Poor wound healing. LAD phenotype (leukocytosis). V. Congenital defects of phagocyte. b : Functional defects Leukocyte adhesion deficiency Skin infections evolve to large ulcers. Leukocytosis with neutrophilia (WBC > 25000) LAD I . ITGB2 Delayed cord separation with omphalitis+++, no pus formation, lack of inflammation is observed in infection area. Periodontitis leads to early loss of teeth. Severity of the disease correlates with the degree of deficiency in CD18 (FCM). (WBC 20,000–150,000 with 60–85 % neutrophils) LAD II (Congenital disorder of glycosylation, type IIc) SLC35C1 Recurrent infections. Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay , facial dysmorphism (depressed nasal bridge). LAD III FERMT3 Severe bacterial infections and severe bleeding disorder. Platelet aggregation assay. Papillon-Lefèvre . CTSC. Periodon��s, palmoplantar hyperkeratosis in some pa�ents β-Actin . ACTB Mental retarda�on, short stature Localized juvenile periodontitis . FPR1. Periodontitis only Pulmonary alveolar proteinosis. CSF2RA, AR. CSF2RB*, XL. Affected cells: Alveolar macrophages. Affected fonction: GM-CSF signaling CGD: Early onset of severe and recurrent infections affecting initially the natural barriers of the organism ( lungs, lymph nodes, skin), and eventually inner structures (liver, spleen, bones, brain, and +++ hepatic abscess). Autoinflammatory phenotype, IBD Granulomata obstructing respiratory, urinary or gastrointestinal tracts. Inflammatory bowel disease (Crohn’s like disease) and perianal disease : up to 30 % Pathogens : typically catalase negative bacteria (S. aureus and gram-negative bacilli, Aspergillus, Candida); other: Burkholderia cepacia,Chromobacterium violaceum, Nocardia, and invasive Serratia marcescens. In developing countries, BCG : adverse effects in up to 20 %. Microscopic granulomas. XL CGD: CYBB (gp91phox) NCF1 (p47phox) , AR CYBA (p22phox), AR NCF4 (p40phox), AR NCF2 (p67phox), AR CYBC1** , AR GATA2 def. GATA2, AD. Susceptibility to Mycocbacteria, Papilloma Viruses, Histoplasmosis, Lymphedema. Alveolar proteinosis, myelodysplasia/ AML/ CMML . Multi lineage cytopenias. Low NK. Abnormal Syndrome associated No Syndrome associated: DHR assay (or NBT test) ? NormalCystic fibrosis. CFTR. AR. Pancreatic insufficiency, Respiratory infections, elevated sweat chloride G6PD def Class I. G6PD. Infections. Fig. 5 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, GM-CSF granulocytes/monocytes colony stimulation factor, GOF gain-of-function, IBD inflammatory bowel disease, IUGR intrauterine growth retardation, LAD leukocyte adhesion deficiency, MDS myelodysplasia, NBT nitroblue of tetrazolium, NK natural killer cells, WBC white blood cells, XL: X- linked transmission J Clin Immunol (2020) 40:66–81 75 76 J Clin Immunol (2020) 40:66–81 Predominant pathogens (S. pneumoniae, S. aureus and Pseudomonas aeruginosa). Non-invasive bacterial infec�ons (skin infec�ons and upper respiratory tract infec�ons). Improve with age. Rou�ne Usual screening tests are normal. Specific screening tests (lack of proinflammatory cytokine produc�on and CD62L shedding) : available only in specialized clinical immunology laboratories. IRAK4 def . IRAK4, AR MyD88 def . MYD88, AR. VI. Defects in Intrinsic and Innate immunity. a : Bacterial and Parasi�c Infec�ons : Isolated congenital asplenia. Bacteremia (encapsulated bacteria). No spleen. RPSA, AD HMOX*, AR. Hemolysis, nephri�s, inflamma�on Predisposi�on to Invasive Bacterial infec�ons (pyogens): meningi�s, sepsis, arthri�s, osteomyeli�s and abscesses, o�en in the absence of fever. IRAK-1 def**. IRAK1, XL. X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal dele�on encompassing both MECP2 and IRAK1 Predisposi�on to Mucocutaneous Candidiasis (CMC) Chronic Mucocutaneous Candidiasis without ectodermal dysplasia IL-17RA deficiency. IL17RA, AR Folliculi�s. Suscep�bility to S. aureus (skin infec�ons) and chronic bacterial infec�ons. STAT1 GOF. STAT1, AD various fungal, bacterial and viral (HSV) infec�ons, autoimmunity (thyroidi�s, diabetes, cytopenias), enteropathy CARD9 def. CARD9, AR. Predisposi�on to INVASIVE Fungal Diseases. Invasive candidiasis infec�on, deep dermatophytoses, other invasive fungal infec�ons. Trypanosomiasis APOL1, AD Trypanosomiasis. Predisposi�on to Parasi�c and Fungal infec�ons TIRAP def**. TIRAP, AR. Staphylococcal disease during childhood. ACT1 deficiency*. ACT1, AR. Blephari�s, folliculi�s and macroglossia. IL-17F deficiency*. IL17F, AD. Folliculi�s. IL-17RC deficiency. IL17RC, AR. Others Osteopetrosis. TNFRSF11A, PLEKHM1 AR. TCIRG1, AR. + hypocalcemia CLCN7, OSTM1, AR. + hypocalcemia, neurologic features SNX10, AR. + visual impairment TNFSF11, AR. + severe growth retarda�on Hydradeni�s suppura�va. PSENEN, AD. NCSTN, AD. + acne PSEN, AD. + hyperpigmenta�on Acute liver failure due to NBAS def. NBAS, AR. Fever induces liver failure Acute necro�zing encephalopathy. RANBP2, AD. Fever induces acute encephalopathy IRF4 haploinsufficiency*. IRF4, AD. Whipple’s disease VI. Defects in Intrinsic and Innate immunity. b : MSMD and Viral infec�on Mendelian Suscep�bility to mycobacterial disease (MSMD) Severe phenotypes. Moderate phenotypes. Complete IFNGR1 Def and IFNGR2 Def : IFNGR1, IFNGR2. AR. Serious disseminated BCG and environmental mycobacterial infec�ons (so� �ssue, bone marrow, lungs, skin, bones and lymph nodes), Salmonella spp., Listeria monocytogenes and viruses Dominant clinical phenotype is Herpes simplex encephali�s (HSE) during primary infec�on with herpes simplex virus type 1 (HSV1), usually between 3 months and 6 years of age. Incomplete clinical penetrance for all e�ologies listed here. Rou�ne screening tests are normal. Specific tests examining the TLR3 pathway : marked decrease in the ability of pa�ent’s fibroblasts to produce IFN- α and β in response to HSV1 infec�on. UNC93B1 (AR), TRAF3** (AD), TICAM1 (TRIF)* (AR,AD), TBK1* (AD), IRF3* (AD) TLR3 (AD,AR), + severe pulmonary influenza, VZV DBR1* (AR) +other viral infec�ons of the brainstem Predominant suscep�bility to viral infec�on Epidermodysplasia verruciformis (HPV) HPV (group B1) infec�ons and cancer of the skin EVER1 def. TMC6.AR. EVER2 def. TMC8. AR. CIB1 def. CIB1. AR. WHIM (Warts, Hypogammaglobuline mia, infec�ons, myelo- kathexis) sd CXCR4 AD GOF. Warts (HPV) infec�on, neutropenia, low B cell number, hypogamma- globulinemia. Predisposi�on to Severe Viral Infec�on STAT1 Def (AR LOF). STAT1. (+ Mycobacteria) IRF7 deficiency**. IRF7. AR. IRF9 deficiency*. IRF9. AR. Severe influenza disease. STAT2 deficiency*. STAT2. AR. Disseminated vaccine- strain measles IFNAR2 deficiency**. IFNAR2 AR. Disseminated vaccine-strain measles, HHV6. No response to IFN-α. CD16 deficiency*. FCGR3A. AR. Severe herpes viral infec�ons, par�cularly VZV, EBV, and HPV. MDA5 deficiency (LOF)*. IFIH1. AR. Rhinovirus and other RNA viruses Herpes simplex Encephali�s Macrophage gp91 phox deficiency CYBB, XL IRF8 deficiency, IRF8 AD ISG15 Def, ISG15. AR. Brain calcifica�on. IFNg produc�on defect. IRF8 deficiency, IRF8 AR Mul�ple other infec�ous agents. Myeloprolifera�on RORγt deficiency*. RORC AR. Suscep�bility to Candida. IFNg produc�ondefect, complete absence of IL-17A/F-producing Tc JAK1 (LOF)*, JAK1. AR. Suscep�bility to viruses, urothelial carcinoma. ↓ IFNg produc�on. With Suscep�bility to Salmonella IL-12 and IL-23 receptor b1 chain deficiency. IL12RB1 .AR. IL-12p40 (IL-12 and IL-23) def. IL12B .AR. IL-12Rb2 deficiency**. IL12RB2. AR IL-23R deficiency**. IL23R. AR. STAT1 LOF STAT1(AD) Par�al IFNγR1, IFNGR1. AR. Par�al IFNγR2, IFNGR2.AR. AD IFNGR1 IFNGR1. AD. Mycobacterial osteomyeli�s SPPL2a deficiency*. SPPL2A. AR. Tyk2 deficiency, TYK2. AR. Suscep�bility to viruses, +/- elevated IgE. mul�ple cytokine signaling defect. P1104A TYK2 homozygosity MSMD or tuberculosis. IFNAR1 deficiency*. IFNAR1 AR. Severe disease caused by Yellow Fever vaccine and Measles vaccine RNA poymerase III def*. POLR3A. POLR3C. POLR3F. AD. Severe VZV infec�on. IL-18BP def**. IL18BP. AR. Fulminant viral hepa��s 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, EBV Epstein-Barr virus, GOF gain-of- function, IFNg interferon gamma, HHV6 human herpes virus type 6, HPV human papillomavirus, 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 J Clin Immunol (2020) 40:66–81 77 T-cell lymphoma subcutaneous panniculi�s-like (TIM3 deficiency). HAVCR2. AR. Panniculi�s, HLH, polyclonal cutaneous T cell infiltrates or T-cell lymphoma VIIa. Auto-inflammatory disorders OthersRecurrent inflamma�on Recurrent fever Systemic inflamma�on with ur�caria rash Familial Mediterranean Fever (FMF) * MEFV. AR or AD (Usually M694del variant) DA: 1–4 days FA : Variable. Polyserosi�s, Abdominal pain, Arthri�s, Amyloidosis. Erysipelas-like erythema. Predisposes to vasculi�s and inflammatory bowel disease . Colchicine-responsive +++. Mevalonate kinase def* (Hyper IgD sd). MVK. AR DA: 3–7 days FA: 1–2 monthly. Cervical adenopathy. Oral aphtosis. Diarrhea. Mevalonate aciduria during a�acks. Leukocytosis with high IgD levels. TNF receptor-associated periodic syndrome; TRAPS. TNFRSF1A. AD. DA: 1-4 weeks FA : Variable Prolonged fever. Serosi�s, rash, Periorbital edema and conjunc�vi�s. Amyloidosis. Joint inflamma�on. Familial Cold Autoinflammatory Syndrome (CAPS) * . NLRP3, NLRP12. AD GOF DA: 24-48H Non-pruri�c ur�caria, arthri�s, chills, fever and leukocytosis a�er cold exposure. Muckle Wells syndrome (CAPS) * NLRP3. AD GOF. Ethnic group : North European Con�nuous fever. O�en worse in the evenings. Ur�caria, Deafness (SNHL), Conjunc�vi�s, Amyloidosis. Neonatal onset mul�system inflammatory disease (NOMID) or chronic infan�le neurologic cutaneous and ar�cular syndrome (CINCA) *. NLRP3. AD GOF. Neonatal onset rash, with con�nuous fever and inflamma�on. Asep�c and chronic meningi�s, chronic arthropathy. Mental retarda�on, Sensorineural deafness. and Visual loss in some pa�ents. NLRC4-MAS (macrophage ac�va�ng syndrome)*. NLRC4. AD GOF. Severe enterocoli�s and macrophage ac�va�on syndrome (HLH). Triggered by cold exposure. PLAID (PLCg2 associated an�body deficiency and immune dysregula�on), or APLAID*. PLC2G. AD GOF. Cold Ur�caria. Impaired humoral immunity. Hypogammaglobulinemia, autoinflamma�on. NLRP1 deficiency*. NLRP1. AR. Dyskeratosis, autoimmunity and arthri�s. COPA defect. COPA. AD Autoimmune inflammatory arthri�s and inters��al lung disease with Th17 dysregula�on and autoan�body produc�on A20 haploinsufficiency TNFAIP3. AD LOF. Arthralgia, mucosal ulcers, ocular inflamma�on. NLRP1 GOF. NLRP1. AD GOF. Palmoplantar carcinoma, corneal scarring; recurrent respiratory papillomatosis. Increased IL1β. ALPI deficiency*. ALP1. AR. TRIM22 def*. TRIM22. AR Inflammatory bowel disease. CANDLE sd (chronic atypical neutrophilic derma��s with lipodystrophy). PSMB8, AR and AD. Contractures, panniculi�s, ICC, fevers. PSMG2, AR. Panniculi�s, lipodystrophy, AIHA. (Variants in PSMB4, PSMB9, PSMA3, and POMP have been proposed to cause a similar CANDLE phenotype in compound heterozygous monogenic , digenic,and AD monogenic models). Sterile inflamma�on ( skin / bone / joints ) VIIb. Auto-inflammatory disorders CAMPS CARD14. AD. Psoriasis. Progressive encephalopathy, ICC, Cerebral atrophy, HSMG, leukodystrophy , Thrombocytopenia, Elevated hepa�c transaminases . Chronic cerebrospinal fluid (CSF) lymphocytosis Aicardi-Gou�eres Syndromes : TREX1 AR-AD (+SLE, FCL), RNASEH2A, RNASEH2B (+SP), RNASEH2C, SAMHD1 (+ FCL), ADAR1 (+BSN, SP), IFIH1 GOF AD (+ SLE, SP, SMS), DNASE2 Type 1 Interferonopathies Spondyloenchondro-dysplasia with immune dysregula�on (SPENCDI). ACP5. Short stature, SP, ICC, SLE-like auto-immunity (Sjögren's syndrome, hypothyroidism, inflammatory myosi�s, Raynaud's disease and vi�ligo), hemoly�c anemia, thrombocytopenia, skeletal dysplasia, possibly recurrent bacterial and viral infec�ons. STING-associated vasculopathy, infan�le-onset. TMEM173. Early-onset inflammatory disease, Skin vasculopathy, inflammatory lung disease, systemic autoinflamma�on and ICC, FCL. ADA2 deficiency. CECR1. Polyarteri�s nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever, Livedo racemosa, some pa�ents develop hypogammaglobulinemia XL re�culate pigmentary disorder. POLA1. Hyper- pigmenta�on, re�culate pa�ern. Inflammatory lung and Gastroenteri�sor coli�s. Corneal scarring, characteris�cfacies USP18 def *. USP18. TORCH like syndrome. Pyogenic sterile arthri�s, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia and hyper- calprotec�nemia. PSTPIP1 (C2BP1). AD DA: 5 days FA: Fixed interval : 4-6 weeks Destruc�ve arthri�s, Pyoderma gangrenosum, inflammatory skin rash, Myosi�s. Acute-phase response during a�acks Chronic recurrent mul�focal osteomyeli�s and congenital dyserythropoie�canemia (Majeed syndrome). LPIN2. AR DA : Few days FA : 1-3 / month Chronic recurrent mul�focal osteomyeli�s, severe pain, tender so� �ssue swelling, Transfusion-dependent anemia, cutaneous inflammatory disorders Blau syndrome. NOD2 (CARD15). AD. Con�nuous inflamma�on. Uvei�s, Granulomatous synovi�s, Camptodactyly, Rash, Cranial neuropathies, 30% develop Crohn coli�s. Sustained modest acute-phase response. ADAM17 deficiency*. ADAM17 . AR. Early onset diarrhea and skin lesions. Severe bacteremia. Defec�ve TNFα produc�on. Cherubism. SH3BP2. AR. Bone degenera�on in jaws SLC29A3 muta�on. SLC29A3 . AR. Hyperpigmenta�on hypertrichosis, his�ocytosis- lymphadenopathy plus syndrome DITRA. (Deficiency of IL-36 receptor antagonist). IL-36RN. AR . Life-threatening, mul�systemic inflammatory disease characterized by episodic widespread, pustular psoriasis, malaise, and leukocytosis. DIRA (Deficiency of the Interleukin 1 Receptor Antagonist) IL1RN. AR Con�nuous inflamma�on. Neonatal onset of sterile mul�focal osteomyeli�s, perios��s and pustulosis. Otulipenia/ORAS*. OTULIN. AR. Neonatal onset of recurrent fever, Arthralgia, lipodystrophy. Derma��s, diarrhea, Neutrophilia Predominant on the skinPredominant on the bone / joints AP1S3 deficiency*. AP1S3. AR. Pustular psoriasis Pediatric systemic lupus erythematosus. DNASE1L3. Very early onset SLE, reduced complement levels, autoan�bodies (dsDNA, ANCA), lupus nephri�s, hypocomplementemic ur�carial vasculi�s syndrome. OAS1 def*. OAS1. AD GOF. Pulmonary alveolar proteinosis, skin rash. Fig. 7 a, b Autoinflammatory disorders. AD autosomal dominant transmission, ANCA anti-neutrophilic cytoplasmic autoantibody, AR autosomal recessive transmission, BSN bilateral striatal necrosis, CAPS cryopyrin-associated periodic syndrome, DA duration of acute inflammation episode, dsDNA double-stranded deoxyribonucleic acid, FA frequency of acute inflammation episode, FCL familial chilblain l u p u s , GOF g a i n - o f - f u n c t i o n , HLH hemoph a g o c y t i c 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 78 J Clin Immunol (2020) 40:66–81 VIII. Complement deficiencies C9 def. C9. Mild suscep�bility. Atypical Hemoly�c Uremic Syndrome Factor D def. CFD. AR. C1inhibitor. SERPING1. AD, Hereditary angioedema. Spontaneous ac�va�on of the complement pathway with consump�on of C4/C2 Properdin def. PFC. XL C1s def.C1S. Mul�ple autoimmune diseases; Ehlers Danlos phenotype SLE-like syndrome. Infec�ons with encapsulated organisms Absent CH50 hemoly�c ac�vity C2 def. C2. Vasculi�s, Polymyosi�s, atherosclerosis C1q def. C1QA, C1QB, C1QC. C1r def. C1R. Ehlers Danlos phenotype Complete C4 def . C4A+C4B.AR. Par�al deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense MASP2 def. MASP2. AR. Inflammatory lung disease, autoimmunity Disseminated Neisserial infec�ons C5 def. C5 C6 def. C6 C7 def . C7. + Vasculi�s C8 def. C8A, C8B, C8G Recurrent pyogenic infec�ons Membrane A�ack Complex Inhibitor deficiency. CD59. Hemoly�c anemia. Polyneuropathy. Ficolin 3 def. FCN3. AR. Infec�ons mainly in the lungs; abscesses, necro�zing entero- coli�s in infancy; selec�ve an�body defect to Pneumo- coccal polysaccharides. Absence of complement ac�va�on by the Ficolin 3 pathway Suscep�bility to infec�ons High Low Others Factor B. CFB LOF. AR. Infec�ons with encapsulated organisms. Deficient ac�va�on of the alterna�ve pathway C3 GOF. C3. AD. Glomerulonephri�s. Increased ac�va�on of complementC3 LOF. C3. AR. Absent CH50 and AH50 hemoly�c ac�vity, defec�ve opsoniza�on and humoral response Factor B GOF. CFB. AD. Increased spontaneous AH50 Factor H def. CFH. AR or AD. Infec�ons, disseminated neisserial infec�ons, preeclampsia. Spontaneous ac�va�on of the alterna�ve complement pathway with consump�on of C3 Thrombomodulin def. THBD. AD. Normal CH50, AH50 Factor I deficiency. AR. Infec�ons, disseminated neisserial infec�ons, preeclampsia. Spontaneous ac�va�on of the alterna�ve complement pathway with consump�on of C3 Factor H –related protein deficiencies. CFHR1-5. AR or AD. Later onset, disseminated neisserial infec�ons. Normal CH50, AH50, autoan�bodies to Factor H. Membrane Cofactor Protein deficiency. CD46.AD,Glomerulone- phri�s. Infec�ons, preeclampsia . Inhibitor of complement alternate pathway, decreased C3b binding Absent CH50 and AH50 hemoly�c ac�vity. Defec�ve bactericidal ac�vity. Normal CH50. Absent AH50 hemoly�c ac�vity CD55 deficiency (CHAPLE disease). CD55. AR. Protein losing enteropathy, thrombosis Periodontal Ehlers Danlos. C1R,C1S. AD GOF. Hyperpigmenta�on skin fragility. Normal CH50. Fig. 8 Complement deficiencies. AD autosomal dominant transmission, AH50 alternate pathway hemolytic activity, AR autosomal recessive transmission, CH50 complement hemolytic activity, def deficiency, GOF gain-of-function, LOF loss-of-function, sd syndrome, SLE systemic lupus erythematosus, XL X-linked transmission J Clin Immunol (2020) 40:66–81 79 Dyskeratosis congenita : IUGR, microcephaly, pulmonary and hepa�c fibrosis, nail dystrophy, sparse scalp hair and eyelashes; re�culate skin pigmenta�on; palmar hyperkeratosis; premalignant oral leukoplakia; pancytopenia; +/- recurrent infec�ons. DKC1: XL, Bc and Tc: Progressive decrease. NOLA2 (NHP2), NOLA3 (NOP10): AR, Tc: Decreased. RTEL1 : AD, Tc: Decreased. TERC, TINF2, ACD : AD,Tc: variable. TERT, TPP1: AD/AR, Tc: variable. DCLRE1B/ SNM1/APOLLO, WRAP53*, DCAB1: AR,Tc: variable. Hoyeraal-Hreidarsson Syndrome (HHS) Severe phenotype with developmental delay and cerebellar hypoplasia. AR, RTEL1, PARN, ACD Dyskeratosis congenita (DKC) Myelodysplasia, short telomeres. Exclude other causes: Fanconi anemia, Blackfan-Diamond COATS plus Sd: Intracranial calcifica�on, abnormal telomeres, IUGR, gastrointes�nal hemorrhage due to vascular ectasia, hypocellular bone marrow. pancytopenia STN1: premature aging, CTC1 : sparse graying hair, dystrophic nails, osteopenia, re�nal telangiectasia, MIRAGE sd ,AD. SAMD9 (GOF) : IUGR with gonadal abnormali�es, adrenal failure, MDS with chromosome 7 aberra�ons, predisposi�on to infec�ons, enteropathy, absent spleen Ataxia pancytopenia sd. AD. SAMD9L. (GOF) :Cytopenia, predisposi�on to MDS with chromosome 7 aberra�ons and progressive cerebellar dysfunc�on IX. Bone marrow failure Fanconi anemia CNS, skeletal, skin, cardiac, GI, urogenital anomalies. Increased chromosomal breakage, pancytopenia. Fanconi anemia Type A-W: AR FANCA, FANCC, BRCA2, FANCD2, FANCE, FANCF, XRCC9,FANCI, BRIP1, FANCL, FANCM, PALB2, RAD51C, SLX4,ERCC4, RAD51, BRCA1, UBE2T, XRCC2, MAD2L2,RFWD3, XL FANCB SRP72- deficiency**. SRP72, AD Bone marrow failure and congenital nerve deafness Bone marrow failure sd (BMFS) Myelodysplasia BMFS5* TP53, AD Erythroid hypoplasia, B-cell deficiency Others Fig. 9 Bone marrow failure disorders. AD autosomal dominant transmission, AR autosomal recessive transmission, Bc B cells, BMFS bone marrow failure syndrome, CNS central nervous system, DKC dyskeratosis congenita, GI gastrointestinal, GOF gain-of-function, IUGR intrauterine growth retardation, MDS myelodysplasia, sd syndrome, Tc T cells, XL X-linked transmission Conclusion This phenotypic classification of IEI forms a diagnostic re- source, aimed to complement the 2019 IUIS genotypic clas- sification. These figures serve as diagnostic orientation tools for patients with any of the typical phenotypic presentations of 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 patients whose clinical or biological phenotypes are evocative of IEI. Compliance with Ethical Standards Conflict of Interest The authors declare that they have no conflict of interest. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adap- tation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, 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- erwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. References 1. Tangye SG, Al-Herz W, Bousfiha A,Chatila T, Cunningham- Rundles C, Etzioni A, et al. Human Inborn Errors of Immunity: 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 2. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova JL, et al. Primary immunodeficiency diseases worldwide: more com- mon than generally thought. J Clin Immunol. 2013;33(1):1–7. 3. Bousfiha A, Jeddane L, Picard C, Ailal F, Gaspar HB, Al-Herz W, et al. The 2017 IUIS phenotypic classification for primary immuno- deficiencies. J Clin Immunol. 2018;38(1):129–43. 80 J Clin Immunol (2020) 40:66–81 X. Phenocopies of PID Splenomegaly, lymphadenopathy, autoimmune cytopenias. Defective lymphocyte apoptosis. ALPS-SFAS (somatic mutations in TNFRSF6)/ ALPS-FAS (ALPS type Im) RALD. RAS-associated autoimmune leukoproliferative disease. (ALPS Like); N-RAS GOF, K-RAS GOF Sporadic; granulocytosis, monocytosis/ALPS-like Associated with Somatic Mutations Recurrent skin infection. AutoAb to IL-6. Staphylococcal infections / STAT3 deficiency Adult-onset immunodeficiency with susceptibility to mycobacteria. Auto-Ab to IFNg. Mycobacterial, fungal, salmonella, VZV infections /MSMD or CID. Associated with Auto-Antibodies Chronic mucocutaneous candidiasis (isolated or with APECED syndrome) AutoAb to IL-17 and/or IL-22. Endocrinopathy, chronic mucocutaneous candidiasis /CMC. Germline mutation in AIRE Pulmonary alveolar proteinosis . AutoAb to GM-CSF. Pulmonary alveolar proteinosis, cryptococcal meningitis, disseminated nocardiosis/CSF2RA deficiency Acquired angiooedema . AutoAb to C1 inhibitor. Angioedema /C1 inhibitor deficiencyCryopyrinopathy, (Muckle-Wells /CINCA/NOMID-like syndrome). NRLP3. Urticaria-like rash, arthropathy, neurological symptoms Atypical Hemolytic Uremic Syndrome . AutoAb to Factor H. Spontaneous activation of the alternative complement pathway Hypereosinophilic syndrome due to somatic mutations in STAT5b. STAT5b. GOF. Atopic dermatitis, urticarial rash, diarrhea. Eosinophilia. Thymoma with hypogammaglobulinemia (Good syndrome). AutoAb to various cytokines. Invasive bacterial, viral or opportunistic infections, autoimmunity, PRCA, lichen planus, 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 http://creativecommons.org/licenses/by/4.0/ https://doi.org/10.1007/s10875-019-00737-x 4. Jeddane L, Ouair H, Benhsaien I, El Bakkouri J, Bousfiha AA. Primary immunodeficiency classification on smartphone. J Clin Immunol. 2017;37(1):1–2. 5. ShearerWT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, et al. Establishing diagnostic criteria for severe combined im- munodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the primary immune deficiency treatment consortium experience. J Allergy Clin Immunol. 2014;133(4):1092–8. Publisher’s Note Springer Nature remains neutral with regard to jurisdic- tional claims in published maps and institutional affiliations. Affiliations 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 1 Laboratoire d’Immunologie Clinique, d’Inflammation et d’Allergy LICIA, Faculty of Medecine and Pharmacy, King Hassan II University, Casablanca, Morocco 2 Clinical Immunology Unit, Pediatric Infectiouse Disease Departmentn Children’s Hospital, Ibn Rochd University Hospital, Casablanca, Morocco 3 Laboratoire national de référence, University Mohamed VI of Health Sciences, Casablanca, Morocco 4 Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, APHP, Paris University, Paris, France 5 Laboratory of Lymphocyte Activation and Susceptibility to EBV, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, Paris University, Paris, France 6 Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait 7 Division of Immunology, Children’s Hospital Boston, Boston, USA 8 Departments of Medicine and Pediatrics, Mount Sinai School of Medicine, New York, USA 9 Ruth’s Children’s Hospital-Technion, Haifa, Israel 10 Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia UdeA, Medellin, Colombia 11 Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA 12 Dr von Hauner Children’s Hospital, Ludwig-Maximilians- University Munich, Munich, Germany 13 Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan 14 Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, USA 15 Department of Clinical Immunology, Hôpital Saint-Louis, APHP, University Paris Diderot, Sorbonne Paris, Cité, Paris, France 16 Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’s Hospital, San Francisco, USA 17 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA 18 Howard Hughes Medical Institute, New York, USA 19 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institute, Necker Hospital for Sick Children, Paris University, Paris, France 20 Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children Assistance Publique-Hôpitaux de Paris (APHP), Paris, France 21 Division of Allergy Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA 22 Garvan Institute of Medical Research, Darlinghurst, Australia 23 St Vincent’s Clinical School, Faculty of Medicine, UNSW, Sydney, Australia J Clin Immunol (2020) 40:66–81 81 Human Inborn Errors of Immunity: 2019 Update �of the IUIS Phenotypical Classification Abstract Introduction Methodology Results Discussion Conclusion References