The 2024 update of IUIS phenotypic classification of human inborn errors of immunity

Abstract

Here, we report the 2024 update of the phenotypic classification by the International Union of Immunological Societies (IUIS) expert committee (EC) on inborn errors of immunity (IEI), which accompanies and complements the 2024 genotypic classification. The aim of this classification is to help diagnosis for clinicians at the bedside and focuses on clinical features and basic laboratory phenotypes of specific IEI. In this update, 559 IEI are described, including 67 novel monogenic defects and 2 new phenocopies. This phenotypic classification is presented in the form of decision trees when possible, with essential clinical or immunological phenotype entries.

Figure 1.

Decision tree orienting through IEI classification categories. MDS: myelodysplasia; N: No; TRECS: T cell receptor excision circles; Y: Yes. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 2.

Immunodeficiencies affecting cellular and humoral immunity. Severe combined immunodeficiencies (SCID) defined by T cell lymphopenia. *T cell lymphopenia in SCID is defined by CD3⁺ T cells <300/μl. Ab: antibody; AD: autosomal dominant inheritance; ADA: adenosine deaminase; Adp: adenopathies; Ag: antigen; AR: autosomal recessive; Bc: B cells; CD: cluster of differentiation; CID: combined immunodeficiency; def: deficiency; GOF: gain-of-function mutation; HSCT: hematopoietic stem cell transplantation; Ig: immunoglobulins; LOF: loss-of-function mutation; Nl: normal; NK: natural killer cells; SCID: severe combined immunodeficiency; Tc: T cells; TCR: T cell receptor; TREC: T cell receptor excision circles; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 3.

Immunodeficiencies affecting cellular and humoral immunity. Combined immunodeficiencies (2). *T cell lymphopenia in SCID is defined by CD3⁺ T cells <300/μl. Ab: antibody; AD: autosomal dominant inheritance; AD DN: autosomal dominant inheritance with dominant negative effect; Adp: adenopathies; Ag: antigen; AR: autosomal recessive; β2m: β-2 microglobulin; Bc: B cells; CD: cluster of differentiation; CID: combined immunodeficiency; def: deficiency; EBV: Epstein-Barr virus; Eo: eosinophils; GOF: gain-of-function mutation; HSM: hepatosplenomegaly; Ig: immunoglobulins; LOF: loss-of-function mutation; MHC: major histocompatibility complex; Nl: normal; NK: natural killer cells; PRCA: pure red cell aplasia; SCID: severe combined immunodeficiency; Tc: T cells; T_EM: effector memory T cells; T_EMRA: effector memory T cells expressing CD45RA; Tfh: follicular helper T cells; Treg: regulatory T cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 4.

Immunodeficiencies affecting cellular and humoral immunity. Combined immunodeficiencies (3). *T cell lymphopenia in SCID is defined by CD3⁺ T cells <300/μl. Ab: antibody; AD: autosomal dominant inheritance; Ag: antigen; AR: autosomal recessive; Bc: B cells; CD: cluster of differentiation; CID: combined immunodeficiency; def: deficiency; Eo: eosinophils; HLH: hemophagocytic lymphohistiocytosis; HPV: human papillomavirus; Ig: immunoglobulins; LOF: loss-of-function mutation; Nl: normal; NK: natural killer cells; SCID: severe combined immunodeficiency; SLE: systemic lupus erythematosus; Tc: T cells; TCR: T cell receptor; Tfh: follicular helper T cells; TREC: T cell receptor excision circles; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 5.

CID with associated or syndromic features (2). Ab: antibody; AD: autosomal dominant inheritance; AFP: α-fetoprotein; AR: autosomal recessive inheritance; Bc: B cells; BCG: Bacillus Calmette–Guerin; BMF: bone marrow failure; CD: cluster of differentiation; CID: combined immunodeficiency of T and B cells; def: deficiency; DNA: deoxyribonucleic acid; Eo: eosinophils; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; FILS: facial dysmorphism, immunodeficiency, livedo and short stature; Ig: immunoglobulins; IUGR: intrauterine growth retardation; LOF: loss-of-function; Nl: normal; NK: natural killer; PPS: polysaccharides; SCID: severe combined immunodeficiency; sd: syndrome; Tc: T cells; TREC: T cell receptor excision circle; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 6.

CID with associated or syndromic features (3). Ab: antibody; AD: autosomal dominant inheritance; AR: autosomal recessive inheritance; Bc: B cells; BCR: B cell receptor; CD: cluster of differentiation; CID: combined immunodeficiency of T and B cells; CNS: central nervous system; def: deficiency; EDA: anhidrotic ectodermal dysplasia; GI: gastrointestinal; GOF: gain-of-function; HIES: hyper IgE syndrome; ID: immunodeficiency; Ig: immunoglobulins; IL-6: Interleukin-6; LOF: loss-of-function; Nl: normal; NK: natural killer; PJP: Pneumocystis jiroveci pneumonia; sd: syndrome; Tc: T cells; TCR: T cell receptor; Tfh: follicular helper T cells; TREC: T cell receptor excision circle; Treg: regulatory T cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 7.

CID with associated or syndromic features (4). Ab: antibody; AD: autosomal dominant inheritance; AD DN: autosomal dominant inheritance with dominant negative effect; AIHA: autoimmune hemolytic anemia; AR: autosomal recessive inheritance; Bc: B cells; CD: cluster of differentiation; CID: combined immunodeficiency of T and B cells; DC: dendritic cells; def: deficiency; EBV: Epstein-Barr virus; EDA: anhidrotic ectodermal dysplasia; GOF: gain-of-function; Ig: immunoglobulins; IUGR: intrauterine growth retardation; LOF: loss-of-function; Nl: normal; NK: natural killer; PJP: Pneumocystis jiroveci pneumonia; SCID: severe combined immunodeficiency; sd: syndrome; Tc: T cells; TCR: T cell receptor; Treg: regulatory T cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 8.

Predominantly antibody deficiencies. Hypogammaglobulinemias. AD: autosomal dominant inheritance; ALL: acute lymphoblastic leukemia; AR: autosomal recessive inheritance; Bc: Bcells; CD: cluster of differentiation; CLL: chronic lymphocytic leukemia; CMV: cytomegalovirus; CNS: central nervous system; COPD: chronic obstructive pulmonary disease; def: deficiency; EBV: Epstein-Barr virus; FCM: flow cytometry; FTT: failure to thrive; GC: germinal centers; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; Hx: patient history; Ig: immunoglobulins; NKc: natural killer cells; Nl: normal; sw: switched; Tc: T cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 9.

Predominantly antibody deficiencies. Other antibody deficiencies. AD: autosomal dominant inheritance; AR: autosomal recessive inheritance; Bc: Bcells; BENTA: B cell expansion with NF-κB and T cell anergy; CD: cluster of differentiation; def: deficiency; GOF: gain-of-function; Ig: immunoglobulins; NKc: natural killer cells; Nl: normal; Tc: T cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 10.

Diseases of immune dysregulation (2). Hemophagocytic lymphohistiocytosis and EBV susceptibility. Ab: antibody; AD: autosomal dominant inheritance; Ag: antigen; AIHA: autoimmune hemolytic anemia; ALPS: autoimmune lymphoproliferative syndrome; AR: autosomal recessive inheritance; Bc: B cells; CD: cluster of differentiation; CNS: central nervous system; CTL: cytotoxic T lymphocytes; def: deficiency; DNT: double-negative T cells; EBV: Epstein-Barr virus; FHL: familial hemophagocytic lymphohistiocytosis; FTT: failure to thrive; GI: gastrointestinal; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; (H)SM: (hepato)splenomegaly; IBD: inflammatory bowel disease; Ig: immunoglobulin; LOF: loss-of-function; iNKT: invariant NK T cells; NK: natural killer cells; Nl: normal; RTE: recent thymic emigrant; sd: syndrome; Tc: T cells; Treg: regulatory T cells; VZV: varicella zona virus; WBC: white blood cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 11.

Diseases of immune dysregulation (3). Syndromes with autoimmunity and others. AD: autosomal dominant inheritance; ALPS: autoimmune lymphoproliferative syndrome; AR: autosomal recessive inheritance; Bc: B cells; BM: bone marrow; CD: cluster of differentiation; CMC: chronic mucocutaneous candidiasis; def: deficiency; DNT: double-negative T cells; EBV: Epstein-Barr virus; Eo: eosinophils; FTT: failure to thrive; GI: gastrointestinal; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; (H)SM: (hepato)splenomegaly; Ig: immunoglobulin; IL-10: interleukin-10; ITP: immune thrombocytopenic purpura; JIA: juvenile idiopathic arthritis; LOF: loss-of-function; NK: natural killer cells; NKTc: NK T cells; Nl: normal; sd: syndrome; SLE: systemic lupus erythematous disease; T1D: type 1 diabetes; Tc: T cells; Tfh: follicular helper T cells; Treg: regulatory T cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 12.

Diseases of immune dysregulation (4). Syndromes with autoimmunity and others. AD: autosomal dominant inheritance; AIHA: autoimmune hemolytic anemia; ALPS: autoimmune lymphoproliferative syndrome; AR: autosomal recessive inheritance; Bc: B cells; CD: cluster of differentiation; def: deficiency; EBV: Epstein-Barr virus; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; (H)SM: (hepato)splenomegaly; IBD: inflammatory bowel disease; Ig: immunoglobulin; IL-10: interleukin-10; LOF: loss-of-function; NK: natural killer cells; Nl: normal; sd: syndrome; Tc: T cells; Treg: regulatory T cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 13.

Congenital defects of phagocyte number, function, or both. Neutropenia. AD: autosomal dominant inheritance; AR: autosomal recessive inheritance; CBC: complete blood count; CD: cluster of differentiation; def: deficiency; GM-CSF: granulocyte/monocyte colony stimulation factor; GOF: gain-of-function; IUGR: intra uterine growth retardation; MDS: myelodysplasia; NK: natural killer cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 14.

Congenital defects of phagocyte number, function, or both. Functional defects of phagocytes. AD: autosomal dominant inheritance; AR: autosomal recessive inheritance; BCG: Bacillus Calmette–Guerin; CD: cluster of differentiation; CGD: chronic granulomatous disease; FCM: flow cytometry; def: deficiency; DHR: dihydrorhodamine-1,2,3; GM-CSF: granulocyte/monocyte colony stimulation factor; IBD: inflammatory bowel disease; LAD: leukocyte adhesion deficiency; NBT: nitroblue tetrazolium; NK: natural killer cells; WBC: white blood cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 15.

Defects in intrinsic and innate immunity. Predisposition to viral infections. AD: autosomal dominant inheritance; AR: autosomal recessive inheritance; CD: cluster of differentiation; CMV: cytomegalovirus; EBV: Epstein-Barr virus; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; HPV: human papillomavirus; HSV: herpes simplex virus; LOF: loss-of-function; MIS-C: multisystem inflammatory syndrome in children; 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 inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 16.

Defects in intrinsic and innate immunity. Predisposition to bacterial, fungal, and parasitic infections and other defects. AD: autosomal dominant inheritance; AML: acute myeloid leukemia; AR: autosomal recessive inheritance; BCG: Bacillus Calmette–Guerin; CD: cluster of differentiation; CMC: chronic mucocutaneous candidiasis; CMML: chronic myelomonocytic leukemia; GOF: gain-of-function; IFN-γ: interferon-γ; HPV: human papillomavirus; HSV: herpes simplex virus; LOF: loss-of-function; MSMD: Mendelian susceptibility to mycobacterial disease; NK: natural killer cells; Tc: T cells; VZV: varicella zoster virus; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 17.

Autoinflammatory disorders (2). AD: autosomal dominant inheritance; AR: autosomal recessive inheritance; Bc: B cells; CAPS: cryopyrin-associated periodic syndrome; DA: duration of acute inflammation episode; def: deficiency; DNT: double-negative T cells; FA: frequency of acute inflammation episode; GI: gastrointestinal; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; HSM: hepatosplenomegaly; IL: interleukin; Ig: immune serum globulin; LOF: loss-of-function; Nl: normal; sd: syndrome; Tc: T cells; TNF: tumor necrosis factor; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 18.

Autoinflammatory disorders (3). Ab: antibody; AD: autosomal dominant inheritance; AIHA: autoimmune hemolytic anemia; AR: autosomal recessive inheritance; Bc: B cells; CSF: cerebrospinal fluid; def: deficiency; DN: double-negative effect; FCL: familial chilblain lupus; GOF: gain-of-function; HSM: hepatosplenomegaly; ICC: intracranial calcifications; IFN: interferon; IL: interleukin; Ig: immune serum globulin; KREC: κ-deleting element recombination circle; LOF: loss-of-function; Nl: normal; sd: syndrome; SLE: systemic lupus erythematosus; Tc: T cells; TORCH: toxoplasmosis, other, rubella, cytomegalovirus, and herpes infection; TREC: T cell recombination excision circles; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 19.

Autoinflammatory disorders (4). AD: autosomal dominant inheritance; AR: autosomal recessive inheritance; Bc: B cells; CNS: central nervous system; DA: duration of acute inflammation episode; def: deficiency; DN: double-negative effect; FA: frequency of acute inflammation episode; GOF: gain-of-function; HLH: hemophagocytic lymphohistiocytosis; HSM: hepatosplenomegaly; IFN: interferon; IL: interleukin; Ig: immune serum globulin; LOF: loss-of-function; Nl: normal; sd: syndrome; Tc: T cells; TNF: tumor necrosis factor; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 20.

Complement deficiencies. AD: autosomal dominant inheritance; AH50: alternate pathway hemolytic activity; AutoAb: autoantibodies; AR: autosomal recessive inheritance; CHAPLE: complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy; CH50: complement hemolytic activity; def: deficiency; GOF: gain-of-function; LOF: loss-of-function; sd: syndrome; SLE: systemic lupus erythematosus; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.

Figure 21.

Bone marrow failure disorders. AD: autosomal dominant inheritance; AML: acute myeloid leukemia; AR: autosomal recessive inheritance; Bc: B cells; BMF: bone marrow failure; def: deficiency; DKC: Dyskeratosis congenita; GOF: gain-of-function; IUGR: intrauterine growth retardation; LOF: loss-of-function; MDS: myelodysplasia; sd: syndrome; Tc: T cells; XL: X-linked inheritance. A searchable PDF file containing all figures in this article can be found under the “Supplements” tab.