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Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency.

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  • 1. Department of Pediatrics, Kuwait University , Kuwait City , Kuwait ; Allergy and Clinical Immunology Unit, Department of Pediatrics, Al-Sabah Hospital , Kuwait City , Kuwait.
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    • Al-Herz W 1
    (1 author)
  • 2. Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Medical School, King Hassan II University , Casablanca , Morocco.
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    • Bousfiha A 2
    (1 author)
  • 3. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY , USA ; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Imagine Institut, Necker Medical School, University Paris Descartes , Paris , France.
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    • Casanova JL 3
    (1 author)
  • 4. Division of Immunology, Children's Hospital Boston , Boston, MA , USA.
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    • Chatila T 4
    (1 author)
  • 5. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University , New York, NY , USA.
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    • Conley ME 5
    (1 author)
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Frontiers in Immunology, 22 Apr 2014, 5:162
https://doi.org/10.3389/fimmu.2014.00162 PMID: 24795713 PMCID: PMC4001072

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This article has been corrected. See Front Immunol. 2014;5:460.

Abstract 

We report the updated classification of primary immunodeficiencies (PIDs) compiled by the Expert Committee of the International Union of Immunological Societies. In comparison to the previous version, more than 30 new gene defects are reported in this updated version. In addition, we have added a table of acquired defects that are phenocopies of PIDs. For each disorder, the key clinical and laboratory features are provided. This classification is the most up-to-date catalog of all known PIDs and acts as a current reference of the knowledge of these conditions and is an important aid for the molecular diagnosis of patients with these rare diseases.

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Front Immunol. 2014; 5: 162.
Published online 2014 Apr 22. https://doi.org/10.3389/fimmu.2014.00162
PMCID: PMC4001072
PMID: 24795713

Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency

Waleed Al-Herz,1,2 Aziz Bousfiha,3 Jean-Laurent Casanova,4,5 Talal Chatila,6 Mary Ellen Conley,4 Charlotte Cunningham-Rundles,7 Amos Etzioni,8 Jose Luis Franco,9 H. Bobby Gaspar,10,* Steven M. Holland,11 Christoph Klein,12 Shigeaki Nonoyama,13 Hans D. Ochs,14 Erik Oksenhendler,15,16 Capucine Picard,5,17 Jennifer M. Puck,18 Kate Sullivan,19 and Mimi L. K. Tang20,21,22
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Abstract

We report the updated classification of primary immunodeficiencies (PIDs) compiled by the Expert Committee of the International Union of Immunological Societies. In comparison to the previous version, more than 30 new gene defects are reported in this updated version. In addition, we have added a table of acquired defects that are phenocopies of PIDs. For each disorder, the key clinical and laboratory features are provided. This classification is the most up-to-date catalog of all known PIDs and acts as a current reference of the knowledge of these conditions and is an important aid for the molecular diagnosis of patients with these rare diseases.

Keywords: primary immunodeficiencies, IUIS, classification, genetic defects, genotype

Background

The International Union of Immunological Societies (IUIS) Expert Committee on Primary Immunodeficiency met in New York on 19th–21st April 2013 to update the classification of human primary immunodeficiencies (PIDs). This report represents the most current and complete catalog of known PIDs. It serves as a reference for these conditions and provides a framework to help in the diagnostic approach to patients suspected to have PID.

As in previous reports, we have classified the conditions into major groups of PIDs and these are now represented in nine different tables. In each table, we list the condition, its genetic defect if known, and the major immunological and in some conditions the non-immunological abnormalities associated with the disease. The classification this year differs slightly from the previous edition in that Table ​Table11 lists combined immunodeficiencies without non-immunologic phenotypes, whereas Table ​Table22 refers to combined immunodeficiencies with syndromic features, as increasing numbers of these are being identified. The title and classification of Tables ​Tables33–8 present the same major PID groups as in the previous report.

Table 1

Combined immunodeficiencies.

DiseaseGenetic defect/presumed pathogenesisInheritanceCirculating T cellsCirculating B cellsSerum IgAssociated featuresOMIM number
1. T−B+ severe combined immunodeficiency (SCID)
(a) γc deficiencyMutation of IL-2RGXLMarkedly decreasedNormal or increasedDecreasedMarkedly decreased NK cells300400
Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21
(b) JAK3 deficiencyMutation of JAK3ARMarkedly decreasedNormal or increasedDecreasedMarkedly decreased NK cells600173
Defect in Janus-activating kinase 3
(c) IL7Rα deficiencyMutation of IL7RAARMarkedly decreasedNormal or increasedDecreasedNormal NK cells146661
Defect in IL-7 receptor α chain
(d) CD45 deficiencyaMutation of PTPRCARMarkedly decreasedNormalDecreasedNormal γ/δ T cells151460
Defect in CD45
(e) CD3δ deficiencyMutation of CD3DARMarkedly decreasedNormalDecreasedNormal NK cells186790
Defect in CD3δ chain of T cell antigen receptor complexNo γ/δ T cells
(f) CD3ε deficiencyaMutation of CD3EARMarkedly decreasedNormalDecreasedNormal NK cells186830
Defect in CD3ε chain of T cell antigen receptor complexNo γ/δ T cells
(g) CD3ζ deficiencyaMutation of CD3ZARMarkedly decreasedNormalDecreasedNormal NK cells186740
Defect in CD3ζ chain of T cell antigen receptor complexNo γ/δ T cells
(h) Coronin-1A deficiencyaMutation of CORO1A defective thymic egress of T cells and defective T cell locomotionARMarkedly decreasedNormalDecreasedDetectable thymus EBV associated B cell lymphoproliferation605000
2. T−B−SCID
(i) DNA recombination defects
(a) RAG 1 deficiencyMutation of RAG1ARMarkedly decreasedMarkedly decreasedDecreased601457
Defective VDJ recombination; defect of recombinase activating gene (RAG) 1
(a) RAG 2 deficiencyMutation of RAG2ARMarkedly decreasedMarkedly decreasedDecreased601457
Defective VDJ recombination; defect of recombinase activating gene (RAG) 2
(b) DCLRE1C (artemis) deficiencyMutation of ARTEMISARMarkedly decreasedMarkedly decreasedDecreasedRadiation sensitivity602450
Defective VDJ recombination; defect in artemis DNA recombinase repair protein
(c) DNA PKcs deficiencyaMutation of PRKDC- Defective VDJ recombination; defect in DNA PKcsARMarkedly decreasedMarkedly decreasedDecreasedRadiation sensitivity, microcephaly, and developmental defects600899
Recombinase repair protein
(ii) Reticular dysgenesis, AK2 deficiencyMutation of AK2ARMarkedly decreasedDecreased or normalDecreasedGranulocytopenia and deafness103020
Defective maturation of lymphoid and myeloid cells (stem cell defect)
Defect in mitochondrial adenylate kinase 2
(iii) Adenosine deaminase (ADA) deficiencyMutation of ADA absent ADA activity, elevated lymphotoxic metabolites (dATP, S-adenosyl homocysteine)ARAbsent from birth (null mutations) or progressive decreaseAbsent from birth of progressive decreaseProgressive decreaseDecreased NK cells, often with costochondral junction flaring, neurological features, hearing impairment, lung and liver manifestations; partial ADA deficiency may lead to delayed or milder presentation102700
Combined immunodeficiencies generally less profound than severe combined immunodeficiency
3. CD40 ligand deficiencyMutation of CD40LG defects in CD40 ligand (CD40L; also called TNFSF5 or CD154) cause defective isotype switching and impaired dendritic cell signalingXLNormal; may progressively decreasesIgM+ and sIgD+ B cells present, other surface isotype positive B cells absentIgM increased or normal, other isotypes decreasedNeutropenia, thrombocytopenia; hemolytic anemia, biliary tract and liver disease, opportunistic infections300386
4. CD40 deficiencyaMutation of CD40 (also called TNFRSF5) defects in CD40 cause defective isotype switching and impaired dendritic cell signalingARNormalIgM+ and IgD+ B cells present, other isotypes absentIgM increased or normal, other isotypes decreasedNeutropenia, gastrointestinal and liver/biliary tract disease, opportunistic infections109535
5. Purine nucleoside phosphorylase (PNP) deficiencyMutation of PNP, absent PNP, and T cell and neurologic defects from elevated toxic metabolites, especially dGTPARProgressive decreaseNormalNormal or decreasedAutoimmune hemolytic anemia, neurological impairment164050
6. CD3γ deficiencyaMutation of CD3G defect in CD3 γ – component of the T cell antigen receptor complexARNormal, but reduced TCR expressionNormalNormal186740
7. CD8 deficiencyaMutation of CD8A, defects of CD8 α chain – important for maturation and function of CD8 T cellsARAbsent CD8, normal CD4 cellsNormalNormal186910
8. ZAP70 deficiencyMutation in ZAP70 intracellular signaling kinase, acts downstream of TCRARDecreased CD8, normal CD4 cellsNormalNormalAutoimmunity in some cases269840
9. MHC class I deficiencyMutations in TAP1, TAP2, or TAPBP (tapasin) genes giving MHC class I deficiencyARDecreased CD8, normal CD4NormalNormalVasculitis; pyoderma gangrenosum604571
10. MHC class II deficiencyMutation in transcription factors for MHC class II proteins (CIITA, RFX5, RFXAP, RFXANK genes)ARNormal number, decreased CD4 cellsNormalNormal or decreasedFailure to thrive, diarrhea, respiratory tract infections, liver/biliary tract disease209920
11. ITK deficiencyaMutations in ITK encoding IL-2-inducible T cell kinase required for TCR-mediated activationARProgressive decreaseNormalNormal or decreasedEBV-associated B cell lymphoproliferation, lymphoma613011
Normal or decreased IgG
12. SH2D1A deficiency (XLP1)Mutations in SH2D1A encoding an adaptor protein regulating intracellular signalsXLNormal or increased activated T cellsReduced memory B cellsPartially defective NK cell and CTL cytotoxic activityClinical and immunologic features triggered by EBV infection: HLH, lymphoproliferation, aplastic anemia, lymphoma308240
Hypogammaglobulinemia
Absent iNKT cells
13. Cartilage hair hypoplasiaMutations in RMRP (RNase MRP RNA) involved in processing of mitochondrial RNA and cell cycle controlARVaries from severely decreased (SCID) to normal; impaired lymphocyte proliferationNormalNormal or reduced. antibodies variably decreasedCan present just as combined immunodeficiency without other features of short-limbed dwarfism250250
Also see Table ​Table22
14. MAGT1 deficiencyaMutations in MAGT1, impaired Mg++ flux leading to impaired TCR signalingXLDecreased CD4 cells reduced numbers of RTE, impaired T cell proliferation in response to CD3NormalNormalEBV infection, lymphoma; viral infections, respiratory, and GI infections300715
15. DOCK8 deficiencyMutations in DOCK8 – regulator of intracellular actin reorganizationARDecreased impaired T lymphocyte proliferationDecreased, low CD27+ memory B cellsLow IgM, increased IgELow NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and bacterial (staph.) infections, susceptibility to cancer243700
16. RhoH deficiencyaMutations in RHOH – an atypical Rho GTPase transducing signals downstream of various membrane receptorsARNormalNormalNormalHPV infection, lymphoma, lung granulomas, molluscum contagiosum602037
Low naïve T cells and RTE, restricted T cell repertoire and impaired T cells proliferation in response to CD3 stimulation
17. MST1 deficiencyMutations in STK4 – a serine/threonine kinaseARDecreased/increased proportion of terminal differentiated effector memory cells (TEMRA), low naïve T cells, restricted T cell repertoire in the TEMRA population, and impaired T cells proliferationDecreasedHighRecurrent bacterial, viral, and candidal infections; intermittent neutropenia; EBV-driven lymphoproliferation; lymphoma; congenital heart disease, autoimmune cytopenias; HPV infection614868
18. TCRα deficiencyaMutations in TRAC – essential component of the T cell receptorARNormal all CD3 T cells expressed TCRγδ (or may be better to say: TCRαβ T cell deficiency), impaired T cells proliferationNormalNormalRecurrent viral, bacterial, and fungal infections, immune dysregulation autoimmunity, and diarrhea615387
19. LCK deficiencyaDefects in LCK – a proximal tyrosine kinase that interacts with TCRARNormal total numbers but CD4+ T cell lymphopenia, low Treg numbers, restricted T cell repertoire, and impaired TCR signalingNormalNormal IgG and IgA and increased IgMDiarrhea, recurrent infections, immune dysregulation autoimmunity153390
20. MALT1 deficiencyaMutations in MALT1 – a caspase-like cysteine protease that is essential for nuclear factor kappa B activationARNormal impaired T cells proliferationNormalNormalBacterial, fungal, and viral infections604860
Impaired antibody response
21. IL-21R deficiencyaDefects in IL-21R – together with common gamma chain binds IL-21ARAbnormal T cell cytokine production; abnormal T cell proliferation to specific stimuliNormalNormal but impaired specific responsesSusceptibility to cryptosporidium and pneumocystis and cholangitis605383
22. UNC119 deficiencyaDefects in UNC119 – an activator of src tyrosine kinasesADLow T cellsMostly lowNormalRecurrent bacterial, fungal, and viral infections604011
CD4+ T cell lymphopenia, impaired TCR signaling
23. CARD11 deficiencyaDefects in CARD11 – acts as a scaffold for NF-κB activity in the adaptive immune responseARNormal predominance of naive T lymphocyte, impaired T cells proliferationNormal predominance of transitional B lymphocytesAbsent/lowPneumocystis jiroveci pneumonia, bacterial infections615206
24. OX40 deficiencyaDefects in OX40 – a co-stimulatory molecule expressed on activated T cellsARNormal T cell numbersNormal B cell numbersNormalKaposi’s sarcoma; impaired immunity to HHV8615593
Low levels of antigen-specific memory CD4+ cellsLower frequency of memory B cells
25. IKBKB deficiencyaDefects in IKBKB – encodes IkB kinase 2 a component of the NF-κB pathwayARNormal total T cells; absent regulatory and gd T cells; impaired TCR activationNormal B cell numbers; impaired BCR activationDecreasedRecurrent bacterial, viral, and fungal infections; clinical phenotype of SCID615592
26. Activated PI3K-δMutation in PIK3CD, PI3K-δAD gain-of-functionDecreased total numbers of T cellsDecreased total peripheral B cell and switched memory B cells; increased transitional B cellsReduced IgG2 and impaired antibody to pneumococci and hemophilusRespiratory infections, bronchiectasis; autoimmunity; chronic EBV, and CMV infection602839
27. LRBA deficiencyMutations in LRBA (lipopolysaccharide responsive beige-like anchor protein)ARNormal or decreased CD4 numbers; T cell dysregulationLow or normal numbers of B cellsReduced I IgG and IgA in mostRecurrent infections, inflammatory bowel disease, autoimmunity; EBV infections606453
28. CD27 deficiencyaMutations in CD27, encoding TNF-R member superfamily required for generation and long-term maintenance of T cell immunityARNormalNo memory B cellsHypogamma globulinemia following EBV infectionClinical and immunologic features triggered by EBV infection, HLH615122
Aplastic anemia, lymphoma
Hypogammaglobulinemia
Low iNKT cells
29. Omenn syndromeHypomorphic mutations in RAG1, RAG2, artemis, IL7RA, RMRP, ADA, DNA ligase IV, IL-2RG, AK2, or associated with DiGeorge syndrome; some cases have no defined gene mutationPresent; restricted T cell repertoire, and impaired functionNormal or decreasedDecreased, except increased IgEErythroderma, eosinophilia, adenopathies, hepatosplenomegaly603554

XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; SCID, severe combined immune deficiencies; EBV, Epstein–Barr virus; Ca++, calcium; MHC, major histocompatibility complex, RTE, recent thymic emigrants, HPV, human papillomavirus.

aTen or fewer unrelated cases reported in the literature.

Infants with SCID who have maternal T cells engraftment may have T cells that do not function normally; these cells may cause autoimmune cytopenias or graft versus host disease. Hypomorphic mutations in several of the genes that cause SCID may result in Omenn syndrome (OS), or “leaky” SCID or a less profound CID phenotype. Both OS and leaky SCID can be associated with higher numbers of T cells and reduced rather than absent activation responses when compared with typical SCID caused by null mutations. A spectrum of clinical findings including typical SCID, OS, leaky SCID, granulomas with T lymphopenia, autoimmunity, and CD4+ T lymphopenia can be found with RAG gene defects. RAC2 deficiency is a disorder of leukocyte motility and is reported in Table ​Table5;5; however, one patient with RAC2 deficiency was found to have absent T cell receptor excision circles (TRECs) by newborn screening, but T cell numbers and mitogen responses were not impaired. For additional syndromic conditions with T cell lymphopenia, such as DNA repair defects, cartilage hair hypoplasia, IKAROS deficiency, and NEMO syndrome, see Tables ​Tables22 and ​and6;6; however, it should be noted that individuals with the most severe manifestations of these disorders could have clinical signs and symptoms of SCID. Severe folate deficiency (such as with malabsorption due to defects in folate carrier or transporter genes SLC10A1 or PCFT) and some metabolic disorders, such as methylmalonic aciduria, may present with reversible profound lymphopenia in addition to their characteristic presenting features.

Table 2

Combined immunodeficiencies with associated or syndromic features.

DiseaseGenetic defect/presumed pathogenesisInheritanceCirculating T cellsCirculating B cellsSerum IgAssociated featuresOMIM number
1. Congenital thrombocytopenia
(a) Wiskott– Aldrich syndrome (WAS)Mutations in WAS; cytoskeletal, and immunologic synapse defect affecting hematopoietic stem cell derivativesXLProgressive decrease, abnormal lymphocyte responses to anti-CD3NormalDecreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgEThrombocytopenia with small platelets; eczema; lymphoma; autoimmune disease; IgA nephropathy; bacterial and viral infections. XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASP301000
(b) WIP deficiencyaMutations in WIPF1; cytoskeletal and immunologic synapse defect affecting hematopoietic stem cell derivativesARReduced, defective lymphocyte responses to anti-CD3LowNormal, except for increased IgERecurrent infections; eczema; thrombocytopenia. WAS-like phenotype614493
2. DNA repair defects (other than those in Table ​Table11)
(a) Ataxia–telangiectasiaMutations in ATM; disorder of cell cycle checkpoint; and DNA double-strand break repairARProgressive decreaseNormalOften decreased IgA, IgE, and IgG subclasses; increased IgM monomers; antibodies variably decreasedAtaxia; telangiectasia; pulmonary infections; lymphoreticular and other malignancies; increased alpha fetoprotein and increased radiosensitivity; chromosomal instability208900
(b) Ataxia–telangiectasia-like disease (ATLD)aHypomorphic mutations in MRE11; disorder of cell cycle checkpoint and DNA double-strand break repairARProgressive decreaseNormalAntibodies variably decreasedModerate ataxia; pulmonary infections; severely increased radiosensitivity604391
(c) Nijmegen breakage syndromeHypomorphic mutations in NBS1 (Nibrin); disorder of cell cycle checkpoint and DNA double-strand break repairARProgressive decreaseVariably reducedOften decreased IgA, IgE, and IgG subclasses; increased IgM; antibodies variably decreasedMicrocephaly; bird-like face; lymphomas; solid tumors; increased radiosensitivity; chromosomal instability251260
(d) Bloom syndromeMutations in BLM; RecQ-like helicaseARNormalNormalReducedShort stature; bird-like face; sun-sensitive erythema; marrow failure; leukemia; lymphoma; chromosomal instability210900
(e) Immunodeficiency with centromeric instability and facial anomalies (ICF)Mutations in DNA methyltransferase DNMT3B (ICF1) resulting in defective DNA methylationARDecreased or normal; responses to PHA may be decreasedDecreased or normalHypogamma globulinemia; variable antibody deficiencyFacial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks242860
(f) Immunodeficiency with centromeric instability and facial anomalies (ICF)Mutations in ZBTB24 (ICF2)ARDecreased or normal; responses to PHA may be decreasedDecreased or normalHypogamma globulinemia; variable antibody deficiencyFacial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; cytopenias; malignancies; multiradial configurations of chromosomes 1, 9, 16242860
(g) PMS2 deficiencyMutations in PMS2, resulting in class switch recombination deficiency due to impaired mismatch repairARNormalSwitched and non-switched B cells are reducedLow IgG and IgA, elevated IgM, abnormal antibody responsesRecurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumor600259
(h) RNF168 deficiencyaMutations in RNF168, resulting in defective DNA double-strand break repairARNormalNormalLow IgG or low IgAShort stature; mild motor control to ataxia and normal intelligence to learning difficulties; mild facial dysmorphism to microcephaly; increased radiosensitivity611943
(i) MCM4 deficiencyMutations in MCM4 (minichromosome maintenance complex component 4) gene involved in DNA replication and repairARNormalNormalNormalViral infections (EBV, HSV, VZV) Adrenal failure Short stature609981
3. Thymic defects with additional congenital anomalies
(a) DiGeorge anomalyContiguous gene defect in 90% affecting thymic development; may also be due to heterozygous mutation in TBX1 (chromosome 22q11.2 deletion or TBX1 haploinsufficient syndrome)De novo defect (majority) or ADDecreased or normal; 5% have <1500 CD3 T cells/μLNormalNormal or decreasedHypoparathyroidism, conotruncal malformation; abnormal facies; large deletion (3 Mb) in 22q11.2 (or rarely a deletion in 10p)188400
(b) CHARGE syndromeVariable defects of the thymus and associated T cell abnormalities often due to deletions or mutations in CHD7, SEMA3E, or as yet unknown genesDe novo defect (majority) or ADDecreased or normal; some have <1500 CD3 T cells/μLNormalNormal or decreasedColoboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies214800 608892
4. Immune-osseous dysplasias
(a) Cartilage hair hypoplasiaMutations in RMRP (RNase MRP RNA) involved in processing of mitochondrial RNA and cell cycle controlARVaries from severely decreased (SCID) to normal; impaired lymphocyte proliferationNormalNormal or reduced. Antibodies variably decreasedShort-limbed dwarfism with metaphyseal dysostosis, sparse hair, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine250250
(b) Schimke syndromeMutations in SMARCAL1 involved in chromatin remodelingARDecreasedNormalNormalShort stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy; bacterial, viral, and fungal infections; may present as SCID; bone marrow failure242900
5. Hyper-IgE syndromes (HIES)
(a) AD-HIES (Job’s syndrome)Dominant-negative heterozygous mutations in STAT3AD Often de novo defectNormal Th-17 and T follicular helper cells decreasedNormal Switched and non-switched memory B cells are reduced; BAFF level increasedElevated IgE; specific antibody production decreasedDistinctive facial features (broad nasal bridge), eczema, osteoporosis, and fractures, scoliosis, delay of shedding primary teeth, hyperextensible joints, bacterial infections (skin and pulmonary abscesses, pneumatoceles) due to Staphylococcus aureus, candidiasis, aneurysm formation147060
(i) Tyk2 deficiencyaMutation in TYK2ARNormal, but multiple cytokine signaling defectNormal(±) Elevated IgESusceptibility to intracellular bacteria (Mycobacteria, Salmonella), fungi, and viruses611521
(ii) DOCK8 deficiencyMutations in DOCK8 – regulator of intracellular actin reorganizationARDecreased impaired T lymphocyte proliferationDecreased, low CD27+ memory B cellsLow IgM, increased IgELow NK cells with impaired function, hypereosinophilia, recurrent infections; severe atopy, extensive cutaneous viral and bacterial (staph.) infections, susceptibility to cancer243700
6. Dyskeratosis congenital (DKC)
(a) XL-DKCMutations in dyskerin (DKC1) (Hoyeraal–Hreidarsson syndrome)XLProgressive decreaseProgressive decreaseVariableIntrauterine growth retardation, microcephaly, nail dystrophy, recurrent infections, digestive tract involvement, pancytopenia, reduced number and function of NK cells305000
(b) AR-DKC due to NHP2 deficiencyMutation in NOLA2 (NHP2)ARDecreasedVariableVariablePancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails613987
(c) AR-DKC due to NOP10 deficiencyMutation in NOLA3 (NOP10 PCFT)ARDecreasedVariableVariablePancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails224230
(d) AR-DKC due to RTEL1 deficiencyMutation in (RTEL1)ARDecreasedVariableVariablePancytopenia, sparse scalp hair and eyelashes, prominent periorbital telangiectasia, and hypoplastic/dysplastic nails608833
(e) AD-DKC due to TERC deficiencyMutation in TERCADVariableVariableVariableReticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia127550
(f) AD-DKC due to TERT deficiencyMutation in TERTADVariableVariableVariableReticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia614742
(g) AD-DKC due to TINF2 deficiencyMutation in TINF2ADVariableVariableVariableReticular hyperpigmentation of the skin, dystrophic nails, osteoporosis premalignant leukokeratosis of the mouth mucosa, palmar hyperkeratosis, anemia, pancytopenia613990
7. Defects of vitamin B12 and folate metabolism
(a) TCN2 deficiencyMutation in TCN2; encodes transcobalamin, a transporter of cobalamin into blood cellsARNormalVariableDecreasedMegaloblastic anemia, pancytopenia, untreated for prolonged periods results in mental retardation275350
(b) SLC46A1 deficiencyMutation in SLC46A1; a proton coupled folate transporterARVariable numbers and activation profileVariableDecreasedMegaloblastic anemia, failure to thrive untreated for prolonged periods results in mental retardation229050
(c) MTHFD1a deficiencyMutations in MTHFD1; essential for processing of single-carbon folate derivativesARLowLowDecreasedMegaloblastic anemia, failure to thrive neutropenia, seizures, mental retardation
8. Comel–Netherton syndromeMutations in SPINK5 resulting in lack of the serine protease inhibitor LEKTI, expressed in epithelial cellsARNormalSwitched and non-switched B cells are reducedElevated IgE and IgACongenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive256500
Antibody variably decreased
9. Winged helix deficiency (Nude)aDefects in forkhead box N1 transcription factor encoded by FOXN1ARMarkedly decreasedNormalDecreasedAlopecia, abnormal thymic epithelium, impaired T cell maturation600838
10. ORAI-I deficiencyaMutation in ORAI1, a Ca++ release-activated channel (CRAC) modulatory componentARNormal number, but defective TCR-mediated activationNormalNormalAutoimmunity, anhydrotic ectodermic dysplasia, non-progressive myopathy defective TCR-mediated activation610277
11. STIM1 deficiencyaMutations in STIM1, a stromal interaction molecule 1ARNormal number, but defective TCR-mediated activationNormalNormalAutoimmunity, anhydrotic ectodermal dysplasia, non-progressive myopathy defective TCR-mediated activation605921
12. STAT5b deficiencyaMutations in STAT5B, signal transducer, and transcription factor, essential for normal signaling from IL-2 and 15, key growth factors for T and NK cellsARModestly decreasedNormalNormalGrowth-hormone insensitive dwarfism245590
Dysmorphic features
Eczema
Lymphocytic interstitial pneumonitis, autoimmunity
13. Hepatic veno-occlusive disease with immunodeficiency (VODI)Mutations in SP110ARNormal (decreased memory T cells)Normal (decreased memory B cells)Decreased IgG, IgA, IgM, absent germinal centers, absent tissue plasma cellsHepatic veno-occlusive disease; Pneumocystis jiroveci pneumonia; susceptibility to CMV, Candida; thrombocytopenia; hepatosplenomegaly235550
14. IKAROS deficiencyaMutation in IKAROSAD de novoNormal, but impaired lymphocyte proliferationAbsentPresumably decreasedAnemia, neutropenia, thrombocytopeniaNot assigned
15. FILS syndromeaMutation in POLE1; defective DNA replicationARLow naïve T cells; decreased T cell proliferationLow memory B cellsDecreased IgM and IgG; lack of antibodies to polysaccharide antigensMild facial dysmorphism (malar hypoplasia, high forehead), livedo, short stature; recurrent upper and lower respiratory tract infections, recurrent pulmonary infections, and recurrent meningitis615139
16. Immunodeficiency with multiple intestinal atresiasMutation in TTC7A [tetratricopeptide repeat (TPR) domain 7A] protein of unknown functionARVariable, but sometimes absentNormalDecreasedMultiple intestinal atresias, often with intrauterine polyhydramnios and early demise; some with SCID phenotype243150

SCID, severe combined immune deficiencies; XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; MSMD, Mendelian susceptibility of mycobacterial disease.

aTen or fewer unrelated cases reported in the literature.

T and B cell number and function in these disorders exhibit a wide range of abnormality; the most severely affected cases meet diagnostic criteria for SCID or leaky SCID and require immune system restoring therapy such as allogeneic hematopoietic cell transplantation. While not all DOCK8-deficient patients have elevated serum IgE, most have recurrent viral infections and malignancies as a result of combined immunodeficiency. AR-HIES due to Tyk2 deficiency is also listed in Table ​Table6,6, because of its association with atypical mycobacterial disease resulting in MSMD. Riddle syndrome is caused by mutations in a gene involved in DNA double-strand break repair and is associated with hypogammaglobulinemia. Autosomal dominant and autosomal recessive forms of dyskeratosis congenita are included in this table. IKAROS-deficiency represents a single prematurely born infant who died at the age of 87 days and who had absent B and NK cells and non-functional T cells.

Table 3

Predominantly antibody deficiencies.

DiseaseGenetic defect/presumed pathogenesisInheritanceSerum IgAssociated featuresOMIM number
1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells
(a) BTK deficiencyMutations in BTK, a cytoplasmic tyrosine kinase activated by crosslinking of the BCRXLAll isotypes decreased in majority of patients; some patients have detectable immunoglobulinsSevere bacterial infections; normal numbers of pro-B cells300300
(b) μ Heavy chain deficiencyMutations in μ heavy chain; essential component of the pre-BCRARAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cells147020
(c) λ5 DeficiencyaMutations in l5; part of the surrogate light chain in the pre-BCRARAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cells146770
(d) Igα deficiencyaMutations in Iga (CD79a); part of the pre-BCR and BCRARAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cells112205
(e) Igβ deficiencyaMutations in Igb (CD79β); part of the pre-BCR and BCRARAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cells147245
(f) BLNK deficiencyaMutations in BLNK; a scaffold protein that binds to BTKARAll isotypes decreasedSevere bacterial infections; normal numbers of pro-B cells604615
(g) PI3 kinase deficiencyaMutations in PIK3R1; a kinase involved in signal transduction in multiple cell typesARAll isotypes decreasedSevere bacterial infections; decreased or absent pro-B cells171833
(h) E47 transcription factor deficiencyaMutations in TCF3; a transcription factor required for control of B cell developmentADAll isotypes decreasedRecurrent bacterial infections147141
(i) Myelodysplasia with hypogammaglobulinemiaMay have monosomy 7, trisomy 8, or dyskeratosis congenitaVariableOne or more isotypes may be decreasedInfections; decreased number of pro-B cellsNot assigned
(j) Thymoma with immunodeficiencyUnknownNoneOne or more isotypes may be decreasedBacterial and opportunistic infections; autoimmunity; decreased number of pro-B cellsNot assigned
2. Severe reduction in at least two serum immunoglobulin isotypes with normal or low number of B cells
(a) Common variable immunodeficiency disordersUnknownVariableLow IgG and IgA and/or IgMClinical phenotypes vary: most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias, and/or granulomatous diseaseNot assigned
(b) ICOS deficiencyaMutations in ICOS; a co-stimulatory molecule expressed on T cellsARLow IgG and IgA and/or IgMRecurrent infections; autoimmunity, gastroenteritis, granuloma in some604558
(c) CD19 deficiencyaMutations in CD19; transmembrane protein that amplifies signal through BCRARLow IgG and IgA and/or IgMRecurrent infections; may have glomerulonephritis107265
(d) CD81 deficiencyaMutations in CD81; transmembrane protein that amplifies signal through BCRARLow IgG, low or normal IgA and IgMRecurrent infections; may have glomerulonephritis186845
(e) CD20 deficiencyaMutations in CD20; a B cell surface receptor involved in B cell development and plasma cell differentiationARLow IgG, normal or elevated IgM and IgARecurrent infections112210
(f) CD21 deficiencyaMutations in CD21; also known as complement receptor 2 and forms part of the CD19 complexARLow IgG; impaired anti-pneumococcal responseRecurrent infections614699
(g) TACI deficiencyMutations in TNFRSF13B (TACI); a TNF receptor family member found on B cells and is a receptor for BAFF and APRILAD or AR or complexLow IgG and IgA and/or IgMVariable clinical expression604907
(h) LRBA deficiencyMutations in LRBA (lipopolysaccharide responsive beige-like anchor protein)ARReduced I IgG and IgA in mostRecurrent infections, inflammatory bowel disease, autoimmunity; EBV infections606453
(i) BAFF receptor deficiencyaMutations in TNFRSF13C (BAFF-R); a TNF receptor family member found on B cells and is a receptor for BAFFARLow IgG and IgMVariable clinical expression606269
(j) TWEAKaMutations in TWEAKADLow IgM and IgA; lack of anti-pneumococcal antibodyPneumonia, bacterial infections, warts; thrombocytopenia. neutropenia602695
(k) NFKB2 deficiencyaMutations in NFKB2; an essential component of the non-canonical NF-κB pathwayADLow IgG and IgA and IgMRecurrent infections615577
(l) Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndromeGain-of-function mutations of CXCR4, the receptor for CXCL12ADPanhypogammaglobulinemia, decreased B cellsWarts/human papilloma virus (HPV) infection Neutropenia Reduced B cell number Hypogammaglobulinemia193670
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells
(a) CD40L deficiencyMutations in CD40LG (also called TNFSF5 or CD154)XLIgG and IgA decreased; IgM may be normal or increased; B cell numbers may be normal or increasedBacterial and opportunistic infections, neutropenia, autoimmune disease300386
(b) CD40 deficiencyaMutations in CD40 (also called TNFRSF5)ARLow IgG and IgA; normal or raised IgMBacterial and opportunistic infections, neutropenia, autoimmune disease109535
(c) AID deficiencyMutations in AICDA geneARIgG and IgA decreased; IgM increasedBacterial infections, enlarged lymph nodes, and germinal centers605257
(d) UNG deficiencyMutations in UNGARIgG and IgA decreased; IgM increasedEnlarged lymph nodes and germinal centers191525
4. Isotype or light chain deficiencies with generally normal numbers of B cells
(a) Ig heavy chain mutations and deletionsMutation or chromosomal deletion at 14q32AROne or more IgG and/or IgA subclasses as well as IgE may be absentMay be asymptomaticNot assigned
(b) κ Chain deficiencyaMutations in Kappa constant geneARAll immunoglobulins have lambda light chainAsymptomatic147200
(c) Isolated IgG subclass deficiencyUnknownVariableReduction in one or more IgG subclassUsually asymptomatic; a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infectionsNot assigned
(d) IgA with IgG subclass deficiencyUnknownVariableReduced IgA with decrease in one or more IgG subclassRecurrent bacterial infectionsNot assigned
(e) PRKC δ deficiencyaMutation in PRKCD; encoding a member of the protein kinase C family critical for regulation of cell survival, proliferation, and apoptosisARLow IgG levels; IgA and IgM above the normal rangeRecurrent infections; EBV chronic infection Lymphoproliferation SLE-like autoimmunity (nephrotic and antiphospholipid syndromes)615559
(f) Activated PI3K-δMutation in PIK3CD, PI3K-δAD gain-of-functionReduced IgG2 and impaired antibody to pneumococci and hemophilusRespiratory infections, bronchiectasis; autoimmunity; chronic EBV, CMV infection602839
(g) Selective IgA deficiencyUnknownVariableIgA decreased/absentUsually asymptomatic; may have recurrent infections with poor antibody responses to carbohydrate antigens; may have allergies or autoimmune disease. A very few cases progress to CVID, others coexist with CVID in the family137100
5. Specific antibody deficiency with normal Ig concen-trations and normal numbers of B cellsUnknownVariableNormalReduced ability to produce antibodies to specific antigensNot assigned
6. Transient hypogammaglobulinemia of infancy with normal numbers of B cellsUnknownVariableIgG and IgA decreasedNormal ability to produce antibodies to vaccine antigens, usually not associated with significant infectionsNot assigned

XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; BTK, Bruton tyrosine kinase; BLNK, B cell linker protein; AID, activation-induced cytidine deaminase; UNG, uracil-DNA glycosylase; ICOS, inducible costimulator; Ig(κ), immunoglobulin or κ light chain type.

aTen or fewer unrelated cases reported in the literature.

Several autosomal recessive disorders that might previously have been called CVID have been added to Table ​Table3.3. CD81 is normally co-expressed with CD19 on the surface of B cells. As for CD19 mutations, mutations in CD81 result in normal numbers of peripheral blood B cells, low serum IgG, and an increased incidence of glomerulonephritis. Single patient with a homozygous mutation in CD20 and CD21 has been reported.

Common variable immunodeficiency disorders (CVID) include several clinical and laboratory phenotypes that may be caused by distinct genetic and/or environmental factors. Some patients with CVID and no known genetic defect have markedly reduced numbers of B cells as well as hypogammaglobulinemia. Alterations in TNFRSF13B (TACI) and TNFRSF13C (BAFF-R) sequences may represent disease-modifying mutations rather than disease causing mutations. CD40L and CD40 deficiency are included in Table ​Table11 as well as this table. A small minority of patients with XLP (Table ​(Table4),4), WHIM syndrome (Table ​(Table6),6), ICF (Table ​(Table2),2), VOD1 (Table ​(Table2),2), thymoma with immunodeficiency (Good syndrome), or myelodysplasia are first seen by an immunologist because of recurrent infections, hypogammaglobulinemia, and normal or reduced numbers of B cells. Patients with GATA2 mutations (Table ​(Table5)5) may have markedly reduced numbers of B cells, as well as decreased monocytes and NK cells, and a predisposition to myelodysplasia but they do not usually have an antibody deficiency.

Table 8

Complement deficiencies.

DiseaseGenetic defect; presumed pathogenesisInheritanceFunctional defectAssociated featuresOMIM number
1. C1q deficiencyMutation in C1QA, C1QB, C1QC: classical complement pathway componentsARAbsent CH50 hemolytic activity, defective activation of the classical pathwaySLE, infections with encapsulated organisms120550; 601269; 120575
Diminished clearance of apoptotic cells
2. C1r deficiencyMutation in C1R: classical complement pathway componentARAbsent CH50 hemolytic activity, defective activation of the classical pathwaySLE, infections with encapsulated organisms216950
3. C1s deficiencyMutation in C1S: classical complement pathway componentARAbsent CH50 hemolytic activity, defective activation of the classical pathwaySLE, infections with encapsulated organisms120580
4. C4 deficiencyMutation in C4A, C4B: classical complement pathway componentsARAbsent CH50 hemolytic activity, defective activation of the classical pathway, defective humoral immune response to carbohydrate antigens in some patientsSLE, infections with encapsulated organisms120810; 120820
5. C2 deficiencyMutation in C2: classical complement pathway componentARAbsent CH50 hemolytic activity, defective activation of the classical pathwaySLE, infections with encapsulated organisms, atherosclerosis217000
6. C3 deficiencyMutation in C3: central complement componentAR, gain-of-function ADAbsent CH50 and AH50 hemolytic activity defective opsonizationInfections; glomerulonephritis120700
Defective humoral immune responseAtypical hemolytic–uremic syndrome with gain-of-function mutations
7. C5 deficiencyMutation in C5: terminal complement componentARAbsent CH50 and AH50 hemolytic activity; defective bactericidal activityNeisserial infections120900
8. C6 deficiencyMutation in C6: terminal complement componentARAbsent CH50 and AH50 hemolytic activity; defective bactericidal activityNeisserial infections217050
9. C7 deficiencyMutation in C7: terminal complement componentARAbsent CH50 and AH50 hemolytic activity; defective bactericidal activityNeisserial infections217070
10. C8 α–γ deficiencyMutation in C8A, C8G: terminal complement componentsARAbsent CH50 and AH50 hemolytic activity; defective bactericidal activityNeisserial infections120950
11. C8b deficiencyMutation in C8B: Terminal complement componentARAbsent CH50 and AH50 hemolytic activity; defective bactericidal activityNeisserial infections120960
12. C9 deficiencyMutation in C9: Terminal complement componentARReduced CH50 and AP50 hemolytic activity; deficient bactericidal activityMild susceptibility to Neisserial infections613825
13. C1 inhibitor deficiencyMutation in SERPING1: regulation of kinins and complement activationADSpontaneous activation of the complement pathway with consumption of C4/C2Hereditary angioedema138470
Spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen
14. Factor BaMutation in CFB: activation of the alternative pathwayADGain-of-function mutation with increased spontaneous AH50aHUS138470
15. Factor D deficiencyMutation in CFD: regulation of the alternative complement pathwayARAbsent AH50 hemolytic activityNeisserial infections134350
16. Properdin deficiencyMutation in CFP: regulation of the alternative complement pathwayXLAbsent AH50 hemolytic activityNeisserial infections312060
17. Factor I deficiencyMutation in CFI: regulation of the alternative complement pathwayARSpontaneous activation of the alternative complement pathway with consumption of C3Infections, Neisserial infections, aHUS, preeclampsia, membranoproliferative glomerulonephritis (MPGN)610984
18. Factor H deficiencyMutation in CFH: regulation of the alternative complement pathwayARSpontaneous activation of the alternative complement pathway with consumption of C3Infections, Neisserial infections, aHUS, preeclampsia, membranoproliferative glomerulonephritis (MPGN)609814
19. Factor H-related protein deficienciesMutation in CFHR1-5: bind C3bARNormal CH50, AH50, autoantibodies to Factor HaHUS235400
20. ThrombomodulinaMutation in THBD: regulates complement and coagulant activationADNormal CH50, AH50aHUS188040
21. MASP1 deficiencyMutation in MASP1: cleaves C2 and activates MASP2ARDeficient activation of the lectin activation pathway, cell migrationInfections, 3MC syndrome600521
22. MASP2 deficiencyaMASP2: cleavage of C2 and C4ARDeficient activation of the lectin activation pathwayPyogenic infections; inflammatory lung disease, autoimmunity605102
23. 3MC syndrome COLEC11 deficiencyaMutation in COLEC11: binds MASP1, MASP3ARLoss of neural crest cell migration signalsA developmental syndrome of facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability, and genital, limb, and vesicorenal anomalies (3MC syndrome)612502
24. Complement receptor 2 (CR2) deficiencyaMutation in CD21ARSee CD21 deficiency in Table ​Table33120650
25. Complement receptor 3 (CR3) deficiencyMutation in ITGB2ARSee LAD1 in Table ​Table55116920
Membrane cofactor protein (CD46) deficiencyMutation in CD46: dissociates C3b and C4bADInhibitor of complement alternate pathway, decreased C3b bindingaHUS, infections, preeclampsia120920
Membrane Attack Complex inhibitor (CD59) deficiencyaMutation in CD59: regulates the membrane attack complex formationARErythrocytes highly susceptible to complement-mediated lysisHemolytic anemia, polyneuropathy107271
Ficolin 3 deficiencyaMutation in FCN3: activates the classical complement pathwayARAbsence of complement activation by the Ficolin 3 pathwayRespiratory infections, abscesses604973

XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; MAC, membrane attack complex; SLE, systemic lupus erythematosus; MBP, mannose-binding protein; MASP2, MBP-associated serine protease 2.

aTen or fewer unrelated cases reported in the literature.

New entities added to Table ​Table88 demonstrate the important role of complement regulators in a group of well-described inflammatory disorders. In particular, we have added mutations in membrane bound as well as surface attached soluble complement regulatory proteins recognized in hemolytic–uremic syndrome, age-related macular degeneration, and preeclampsia. The connecting theme of these otherwise unrelated clinical events is excessive activation or insufficient regulation of C3; these events lead to recruitment of leukocytes and permit secretion of inflammatory and anti-angiogenic mediators that disrupt the vascular bed of the target organ. Alterations in the genes for Factor B (CFB), Factor I (CFI), Factor H (CFH), and CD46 act as susceptibility genes rather than disease causing mutations. Population studies reveal no detectable increase in infections in MBP (also known at mannose-binding lectin – MBL) deficient adults. The 3MC syndrome, a developmental syndrome, has been variously called Carnevale, Mingarelli, Malpuech, and Michels syndrome.

Table 5

Congenital defects of phagocyte number, function, or both.

DiseaseGenetic defect/presumed pathogenesisInheritanceAffected cellsAffected functionAssociated featuresOMIM number
1. Defects of neutrophil function
(a) Severe congenital neutropenia 1 (ELANE deficiency)Mutation in ELANE: misfolded protein response, increased apoptosisADNMyeloid differentiationSusceptibility to MDS/leukemia202700
(b) SCN2a (GFI 1 deficiency)Mutation in GFI1: loss of repression of ELANEADNMyeloid differentiationB/T lymphopenia613107
(c) SCN3 (Kostmann disease)Mutation in HAX1: control of apoptosisARNMyeloid differentiationCognitive and neurological defects in patients with defects in both HAX1 isoforms, susceptibility to MDS/leukemia610738
(d) SCN4 (G6PC3 deficiency)Mutation in G6PC3: abolished enzymatic activity of glucose-6-phosphatase, aberrant glycosylation, and enhanced apoptosis of N and FARN + FMyeloid differentiation, chemotaxis, O2−productionStructural heart defects, urogenital abnormalities, inner ear deafness, and venous angiectasias of trunks and limbs612541
(e) SCN5Mutation in VPS45 controls vesicular traffickingARN + FMyeloid differentiation, migrationExtramedullary hematopoiesis, bone marrow fibrosis, nephromegaly615285
(f) Glycogen storage disease type 1bMutation in G6PT1: glucose-6-phosphate transporter 1ARN + MMyeloid differentiation, chemotaxis, O2−productionFasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly232220
(g) Cyclic neutropeniaMutation in ELANE: misfolded protein responseADNDifferentiationOscillations of other leukocytes and platelets162800
(h) X-linked neutropenia/amyelodysplasiaMutation in WAS: regulator of actin cytoskeleton (loss of auto-inhibition)XL, gain-of-functionN + MMitosisMonocytopenia300299
(i) P14/LAMTOR2 deficiencyaMutation in ROBLD3/LAMTOR2: endosomal adaptor protein 14ARN + L MelEndosome biogenesisNeutropenia610389
Hypogammaglobulinemia
↓CD8 cytotoxicity
Partial albinism
Growth failure
(j) Barth syndromeMutation in tafazzin (TAZ) gene: abnormal lipid structure of mitochondrial membrane, defective carnitine metabolismXLNMyeloid differentiationCardiomyopathy, myopathy, growth retardation302060
(k) Cohen syndromeMutation in COH1 gene: Pg unknownARNMyeloid differentiationRetinopathy, developmental delay, facial dysmorphisms216550
(l) Clericuzio syndrome poikiloderma with neutropeniaMutation in C16ORF57, affects genomic integrityARNMyeloid differentiationPoikiloderma, neutropenia, MDS613276
2. Defects of motility
(a) Leukocyte adhesion deficiency type 1 (LAD1)Mutation in ITGB2: adhesion protein (CD18)ARN + M + L + NKAdherence, chemotaxis, endocytosis, T/NK cytotoxicityDelayed cord separation, skin ulcers Periodontitis Leukocytosis116920
(b) Leukocyte adhesion deficiency type 2 (LAD2)aMutation in FUCT1: GDP-fucose transporterARN + MRolling, chemotaxisMild LAD type 1 features plus hh-blood group plus mental and growth retardation266265
(c) Leukocyte adhesion deficiency type 3 (LAD3)Mutation in KINDLIN3: Rap1-activation of β1–3 integrinsARN + M + L + NKAdherence, chemotaxisLAD type 1 plus bleeding tendency612840
(d) Rac 2 deficiencyaMutation in RAC2: regulation of actin cytoskeletonADNAdherence, chemotaxis, O2−productionPoor wound healing, leukocytosis602049
(e) β-Actin deficiencyaMutation in ACTB: cytoplasmic actinADN + MMotilityMental retardation, short stature102630
(f) Localized juvenile periodontitisMutation in FPR1: chemokine receptorARNFormylpeptide induced chemotaxisPeriodontitis only136537
(g) Papillon–Lefèvre syndromeMutation in CTSC: cathepsin C activation of serine proteasesARN + MChemotaxisPeriodontitis, palmoplantar hyperkeratosis in some patients245000
(h) Specific granule deficiencyaMutation in C/EBPE: myeloid transcription factorARNChemotaxisNeutrophils with bilobed nuclei; absent secondary granules and defensins245480
(i) Shwachman–Diamond syndromeMutation in SBDS: defective ribosome synthesisARNChemotaxisPancytopenia, exocrine pancreatic insufficiency, chondrodysplasia260400
3. Defects of respiratory burst
(a) X-linked chronic granulomatous disease (CGD)Mutation in CYBB: electron transport protein (gp91phox)XLN + MKilling (faulty O2−production)Recurrent bacterial infection, susceptibility to fungal infection, inflammatory gut manifestations McLeod phenotype in patients with deletions extending into the contiguous Kell locus306400
(b) Autosomal recessive CGD – p22 phox deficiencyMutation in CYBA: electron transport protein (p22phox)ARN + MKilling (faulty O2−production)Recurrent bacterial infection, susceptibility to fungal infection, and inflammatory gut manifestations233690
(c) Autosomal recessive CGD – p47 phox deficiencyMutation in NCF1: adapter protein (p47phox)ARN + MKilling (faulty O2−production)Recurrent bacterial infection, susceptibility to fungal infection, and inflammatory gut manifestations233700
(d) Autosomal recessive CGD – p67 phox deficiencyMutation in NCF2: activating protein (p67phox)ARN + MKilling (faulty O2−production)Recurrent bacterial infection, susceptibility to fungal infection, inflammatory gut manifestations233710
(e) Autosomal recessive CGD – p40 phox deficiencyaMutation in NCF4: activating protein (p40phox)ARN + MKilling (faulty O2−production)Inflammatory gut manifestations only601488
4. Mendelian susceptibility to mycobacterial disease (MSMD)
(a) IL-12 and IL-23 receptor β1 chain deficiencyMutation in IL-12RB1: IL-12 and IL-23 receptor β1 chainARL + NKIFN-γ secretionSusceptibility to Mycobacteria and Salmonella209950
(b) IL-12p40 deficiencyMutation in IL-12B: subunit p40 of IL-12/IL-23ARMIFN-γ secretionSusceptibility to Mycobacteria and Salmonella161561
(c) IFN-γ receptor 1 deficiencyMutation in IFNGR1: IFN-γR ligand binding chainAR, ADM + LIFN-γ binding and signalingSusceptibility to Mycobacteria and Salmonella107470
(d) IFN-γ receptor 2 deficiencyMutation in IFNGR2: IFN-γR accessory chainARM + LIFN-γ signalingSusceptibility to Mycobacteria and Salmonella147569
(e) STAT1 deficiency (AD form)aMutation in STAT1 (loss of function)ADM + LIFN-γ signalingSusceptibility to Mycobacteria600555
(f) Macrophage gp91 phox deficiencyaMutation in CYBB: electron transport protein (gp 91 phox)XLMf onlyKilling (faulty O2−production)Isolated susceptibility to Mycobacteria306400
(g) IRF8-deficiency (AD form)aMutation in IRF8: IL-12 production by CD1c+ MDCADCD1c+ MDCDifferentiation of CD1c+ MDC subgroupSusceptibility to Mycobacteria601565
(h) ISG15Mutation in ISG15; an interferon (IFN) α/β-inducible, ubiquitin-like intracellular proteinARM + N + LIFN-γ secretionSusceptibility to Mycobacteria14751
5. Other defects
(a) IRF 8-deficiency (AR form)aMutation in IRF8: IL-12 productionARMonocytes peripheral DCCytopeniasSusceptibility to Mycobacteria, Candida, myeloproliferation614893
(b) GATA2 deficiency (Mono MAC syndrome)Mutation in GATA2: loss of stem cellsADMonocytes peripheral DC + NK + BMultilineage cytopeniasSusceptibility to Mycobacteria, papilloma viruses, histoplasmosis, alveolar proteinosis, MDS/AML/CMML137295
(c) Pulmonary alveolar proteinosisaMutation in CSF2RABiallelic mutations in pseudo-autosomal geneAlveolar macro-phagesGM-CSF signalingAlveolar proteinosis306250

XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; ACTB, actin beta; B, B lymphocytes; CEBPE, CCAAT/enhancer-binding protein epsilon; CMML, chronic myelomonocytic leukemia; CTSC, cathepsin C; CYBA, cytochrome b alpha subunit; CYBB, cytochrome b beta subunit; DC, dendritic cells; ELANE, elastase neutrophil-expressed; GATA2, GATA binding protein 2; IFN, interferon; IFNGR1, interferon-gamma receptor subunit 1; IFNGR2, interferon-gamma receptor subunit 2; IL-12B, interleukin-12 beta subunit; IL-12RB1, interleukin-12 receptor beta 1; IFR8, interferon regulatory factor 8; F, fibroblasts; FPR1, formylpeptide receptor 1; FUCT1, fucose transporter 1; GFI1, growth factor independent 1; HAX1, HLCS1-associated protein X1; ITGB2, integrin beta-2; L, lymphocytes; M, monocytes–macrophages; MDC, myeloid dendritic cells; MDS, myelodysplasia; Mel, melanocytes; Mϕ, macrophages; MSMD, Mendelian susceptibility to mycobacterial disease; N, neutrophils; NCF1, neutrophil cytosolic factor 1; NCF2, neutrophil cytosolic factor 2; NCF4, neutrophil cytosolic factor 4; NK, natural killer cells; ROBLD3: roadblock domain containing 3; SBDS, Shwachman–Bodian–Diamond syndrome; STAT, signal transducer and activator of transcription.

aTen or fewer unrelated cases reported in the literature.

Table ​Table55 includes seven newly described genetic defects of phagocyte number and/or function including Barth syndrome, Cohen syndrome, and poikiloderma with neutropenia. In these three clinically well-known diseases, the genetic defects have been elucidated, although their molecular pathogenesis remains ill-defined. A new cause of autosomal recessive chronic granulomatous disease, namely a deficiency of the cytosolic activating protein p40 phox, has now been found in two CGD patients and is included under defects of respiratory burst. Under the heading of Mendelian susceptibility of mycobacterial disease (MSMD), two new entities were added: (a) a subgroup of X-linked gp91 phox deficiency with isolated susceptibility to mycobacteria and a defect of the respiratory burst in macrophages only; (b) an autosomal dominant form of IRF8-deficiency, resulting from a lack of CD1c+ myeloid dendritic cells that would normally secrete IL-12. The clinical phenotype of MSMD may vary, depending on the nature of the genetic defect. Finally, GATA2 deficiency was recently identified as the cause of the Mono MAC syndrome, with multilineage cytopenias (of monocytes, peripheral dendritic cells, NK- and B-lymphocytes) resulting in opportunistic infections (including mycobacteria), alveolar proteinosis, and malignancy.

Table 6

Defects in innate immunity.

DiseaseGenetic defect/presumed pathogenesisInheritanceAffected cellFunctional defectAssociated featuresOMIM number
1. Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)
(a) EDA-ID, X-linked (NEMO deficiency)Mutations of NEMO (IKBKG), a modulator of NF-κB activationXLLymphocytes + monocytesNF-κB signaling pathwayVarious infections (bacteria, Mycobacteria, viruses, and fungi)300248
Colitis
EDA (not in all patients)
Hypogammaglobulinemia to specific antibody polysaccharides deficiency
(b) EDA-ID, autosomal-dominantaGain-of-function mutations of IKBA, resulting in impaired activation of NF-κBADLymphocytes + monocytesNF-κB signaling pathwayVarious infections (bacteria, viruses, and fungi)612132
EDA
T cell defect
2. TIR signaling pathway deficiency
(a) IRAK-4 deficiencyMutations of IRAK-4, a component of TLR- and IL-1R-signaling pathwayARLymphocytes + granulocytes + monocytesTIR–IRAK signaling pathwayBacterial infections (pyogenes)607676
(b) MyD88 deficiencyMutations of MYD88, a component of the TLR and IL-1R signaling pathwayARLymphocytes + granulocytes + monocytesTIR–MyD88 signaling pathwayBacterial infections (pyogenes)612260
3. HOIL1 deficiencyaMutation of HOIL1, a component of LUBACARLymphocytes + granulocytes + monocytesNF-κB signaling pathwayBacterial infections (pyogenes)Not assigned
Autoinflammation
Amylopectinosis
4. WHIM (Warts, hypogammaglobulinemia, infections, myelokathexis) syndromeGain-of-function mutations of CXCR4, the receptor for CXCL12ADGranulocytes + lymphocytesIncreased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1)Warts/human papilloma virus (HPV) infection193670
Neutropenia
Reduced B cell number
Hypogammaglobulinemia
5. Epidermodysplasia verruciformis
EVER1 deficiencyMutations of EVER1ARKeratinocytes and leukocytesEVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytesHPV (group B1) infections and cancer of the skin (typical EV)226400
EVER2 deficiencyMutations of EVER2ARKeratinocytes and leukocytesEVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytesHPV (group B1) infections and cancer of the skin (typical EV)226400
6. Predisposition to severe viral infection
(a) STAT2 deficiencyaMutations of STAT2ART and NK cellsSTAT2-dependentSevere viral infections (disseminated vaccine-strain measles)Not assigned
IFN-α and -β response
(b) MCM4 deficiencyaMutations in MCM4ARNK cellsDNA repair disorderViral infections (EBV, HSV, VZV)609981
Adrenal failure
Short stature
7. Herpes simplex encephalitis (HSE)
(a) TLR3 deficiencya(b) Mutations of TLR3ADCentral nervous system (CNS) resident cells and fibroblastsTLR3-dependentHerpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here)613002
ARIFN-α, -β, and -λ induction
(b) UNC93B1 deficiencya(a) Mutations of UNC93B1ARCNS resident cells and fibroblastsUNC-93B-dependentHerpes simplex virus 1 encephalitis610551
IFN-α, -β, and -λ induction
(c) TRAF3 deficiencya(c) Mutations of TRAF3ADCNS resident cells and fibroblastsTRAF3-dependentHerpes simplex virus 1 encephalitis614849
IFN-α, -β, and -λ induction
(d) TRIF deficiencya(c) Mutations of TRIFADCNS resident cells and fibroblastsTRIF-dependentHerpes simplex virus 1 encephalitis614850
ARIFN-α, -β, and -λ induction
(e) TBK1 deficiencya(c) Mutations of TBK1ADCNS resident cells and fibroblastsTBK1-dependentHerpes simplex virus 1 encephalitisNot assigned
IFN-α, -β, and -λ induction
8. Predisposition to invasive fungal diseasesa
CARD9 deficiencyMutations of CARD9ARMononuclear phagocytesCARD9 signaling pathwayInvasive candidiasis infection Deep dermatophytoses212050
9. Chronic mucocutaneous candidiasis (CMC)
(a) IL-17RA deficiencya(a) Mutations in IL-17RAAREpithelial cells, fibroblasts, mononuclear phagocytesIL-17RA signaling pathwayCMC Folliculitis605461
(b) IL-17F deficiencya(b) Mutations in IL-17FADT cellsIL-17F-containing dimersCMC Folliculitis606496
(c) STAT1 gain-of-function(c) Gain-of-function mutations in STAT1ADT cellsGain-of-function STAT1 mutations that impair the development of IL-17-producing T cellsCMC614162
Various fungal, bacterial, and viral (HSV) infections
Autoimmunity (thyroiditis, diabetes, cytopenia)
Enteropathy
(d) ACT1 deficiencya(c) Mutations in ACT1ART cells, fibroblastsFibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17ECMC615527
Blepharitis, folliculitis, and macroglossia
10. TrypanosomiasisaMutations in APOL-IADAPOL-ITrypanosomiasis603743
11. Isolated congenital asplenia (ICA)Mutations in RPSAADSpleenRPSA encodes ribosomal protein SA, a component of the small subunit of the ribosomeBacteremia (encapsulated bacteria) No spleen271400

XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; NF-κB, nuclear factor kappa B; TIR, Toll and interleukin 1 receptor; IFN, interferon; HVP, human papilloma virus; TLR, Toll-like receptor; IL, interleukin.

aTen or fewer unrelated cases reported in the literature.

Eight new disorders have been added to Table ​Table6.6. Three new entries have been added in the table. One is a new PID with the association of recurrent bacterial infections, autoinflammation, and amylopectinosis caused by AR HOIL1 mutations found in two kindreds. The second is severe viral infection, for which three genetic etiologies have been discovered. AR-STAT2 deficiency and AR-CD16 deficiency have been found in one kindred each. AR MCM4 deficiency has been found in several Irish kindreds. The third is isolated congenital asplenia identified in 18 patients from 8 kindreds.

XR-EDA-ID is highly heterogeneous clinically, both in terms of developmental features (some patients display osteopetrosis and lymphedema, in addition to EDA, while others do not display any developmental features) and infectious diseases (some display multiple infections, viral, fungal, and bacterial, while others display a single type of infection). The various OMIM entries correspond to these distinct clinical diseases.

Table 7

Autoinflammatory disorders.

DiseaseGenetic defect/presumed pathogenesisInheritanceAffected cellsFunctional defectsAssociated featuresOMIM number
1. Defects effecting the inflammasome
(a) Familial Mediterranean feverMutations of MEFV (lead to gain of pyrin function, resulting in inappropriate IL-1β release)ARMature granulocytes, cytokine-activated monocytesDecreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury; macrophage apoptosis decreasedRecurrent fever, serositis, and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease249100
(b) Mevalonate kinase deficiency (hyper IgD syndrome)Mutations of MVK (lead to a block in the mevalonate pathway). Interleukin-1beta mediates the inflammatory phenotypeARAffecting cholesterol synthesis; pathogenesis of disease is unclearPeriodic fever and leukocytosis with high IgD levels260920
(c) Muckle–Wells syndromeMutations of CIAS1 (also called PYPAF1 or NALP3) lead to constitutive activation of the NLRP3 inflammasomeADPMNs monocytesDefect in cryopyrin, involved in leukocyte apoptosis and NF-κB signaling and IL-1 processingUrticaria, SNHL, amyloidosis191900
(d) Familial cold autoinflammatory syndromeMutations of CIAS1 (see above) Mutations of NLRP12ADPMNs, monocytesSame as aboveNon-pruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure120100
5. Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)Mutations of CIAS1 (see above)ADPMNs, chondrocytesSame as aboveNeonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation607115
2. Non inflammasome-related conditions
(a) TNF receptor-associated periodic syndrome (TRAPS)Mutations of TNFRSF1 (resulting in increased TNF inflammatory signaling)ADPMNs, monocytesMutations of 55-kDa TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNFRecurrent fever, serositis, rash, and ocular or joint inflammation142680
(b) Early-onset inflammatory bowel diseaseMutations in IL-10 (results in increase many proinflammatory cytokines)ARMonocyte/macrophage, activated T cellsIL-10 deficiency leads to increase of TNFγ and other proinflammatory cytokinesEarly-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis124092
(b) Early-onset inflammatory bowel diseaseMutations in IL-10RA (see above)ARMonocyte/macrophage, activated T cellsMutation in IL-10 receptor alpha leads to increase of TNFγ and other proinflammatory cytokinesEarly-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis146933
(b) Early-onset inflammatory bowel diseaseMutations in IL-10RB (see above)ARMonocyte/macrophage, activated T cellsMutation in IL-10 receptor beta leads to increase of TNFγ and other proinflammatory cytokinesEarly-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis123889
(c) Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndromeMutations of PSTPIP1 (also called C2BP1) (affects both pyrin and protein tyrosine phosphatase to regulate innate and adaptive immune responses)ADHematopoietic tissues, upregulated in activated T cellsDisordered actin reorganization leading to compromised physiologic signaling during inflammatory responseDestructive arthritis, inflammatory skin rash, myositis604416
(d) Blau syndromeMutations of NOD2 (also called CARD15) (involved in various inflammatory processes)ADMonocytesMutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signalingUveitis, granulomatous synovitis, camptodactyly, rash, and cranial neuropathies, 30% develop Crohn’s disease186580
10. Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)aMutations of LPIN2 (increased expression of the proinflammatory genes)ARNeutrophils, bone marrow cellsUndefinedChronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders609628
11. DIRA (deficiency of the interleukin 1 receptor antagonist)aMutations of IL-1RN (see functional defect)ARPMNs, monocytesMutations in the IL-1 receptor antagonist allow unopposed action of Interleukin 1Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis612852
12. DITRA – deficiency of IL-36 receptor antagonistMutation in IL-36RN (see functional defect)ARKeratinocyte leukocytesMutations in IL-36RN leads to increase IL-8 productionPustular psoriasis614204
13. SLC29A3 mutationMutation in SLC29A3 (?)ARLeukocyte, bone cellsMacrophage activation?Hyperpigmentation hypertrichosis602782
14. CAMPS (CARD14 mediated psoriasis)Mutation in CARD14 (see functional defect)ADMainly in keratinocyteMutations in CARD14 activate the NF-κB pathway and production of IL-8Psoriasis173200
15. CherubismMutation in SH3BP2 (see functional defect)ADStroma cells, bone cellsHyperactivated macrophage and increased NF-κBBone degeneration in jaws11840
16. CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)Mutation in PSMB8 (see functional defect)ADKeratinocyte, B cell adipose cellsMutations cause increase IL-6 productionDystrophy, panniculitis256040
17. HOIL1 deficiencyMutation in HOIL1 (see functional defect)ARPMNs, fibroblastMutation in HOIL1 leads to IL-1β dysfunctionImmunodeficiency autoinflammation amylopectinosis610924
18. PLAID (PLCγ2 associated antibody deficiency and immune dysregulation)Mutation in PLCG2 (see functional defect)ADB cells, NK, mast cellsMutations cause activation of IL-1 pathwaysCold urticaria hypogammaglobulinemia614878

AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; PMN, polymorphonuclear cells; ASC, apoptosis-associated speck-like protein with a caspase recruitment domain; CARD, caspase recruitment domain; CD2BP1, CD2 binding protein 1; PSTPIP1, proline/serine/threonine phosphatase-interacting protein 1; SNHL, sensorineural hearing loss; CIAS1, cold-induced autoinflammatory syndrome 1.

aTen or fewer unrelated cases reported in the literature.

Autoinflammatory diseases are clinical disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition. While the genetic defect of one of the most common autoinflammatory conditions, PFAPA, is not known, recent studies suggest that it is associated with activation of IL-1 pathway and response to IL-1beta antagonists.

Muckle–Wells syndrome, familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), which is also called chronic infantile neurologic cutaneous and articular syndrome (CINCA) are caused by similar mutations in CIAS1 mutations. The disease phenotype in any individual appears to depend on modifying effects of other genes and environmental factors.

In this updated version, we have added a new category in Table ​Table99 in which “Phenocopies of PID” are listed. This has resulted from our understanding and study of conditions that present as inherited immunodeficiencies, but which are not due to germline mutations and instead arise from acquired mechanisms. Examples include somatic mutations in specific immune cell populations that give rise to the phenotype of autoimmune lymphoproliferative syndrome (ALPS), and also autoantibodies against specific cytokines or immunological factors, with depletion of these factors leading to immunodeficiency. It is likely that increasing numbers of PID phenocopies will be identified in the future, and this may be the start of a much longer table.

Table 9

Phenocopies of PID.

DiseaseGenetic defect/presumed pathogenesisCirculating T cellsCirculating B cellsSerum IgAssociated features/similar PID
Associated with somatic mutations
(a) Autoimmune lymphoproliferative syndrome (ALPS–SFAS)Somatic mutation in TNFRSF6Increased CD4−CD8−double negative (DN) T alpha/beta cellsNormal, but increased number of CD5+ B cellsNormal or increasedSplenomegaly, lymphadenopathy, autoimmune cytopenias
Defective lymphocyte apoptosis/ALPS–FAS (=ALPS type Im)
(b) RAS-associated autoimmune leukoproliferative disease (RALD)Somatic mutation in KRAS (gain-of-function)NormalB cell lymphocytosisNormal or increasedSplenomegaly, lymphadenopathy, autoimmune cytopenias, granulocytosis, monocytosis/ALPS-like
(c) RAS-associated autoimmune leukoproliferative disease (RALD)Somatic mutation in NRAS (gain-of-function)Increased CD4−CD8−double negative (DN) T alpha/beta cellsLymphocytosisSplenomegaly, lymphadenopathy, autoantibodies/ALPS-like
Associated with autoantibodies
(a) Chronic mucocutaneous candidiasis (isolated or with APECED syndrome)Germline mutation in AIREAutoAb to IL-17 and/or IL-22NormalNormalNormalEndocrinopathy, chronic mucocutaneous candidiasis/CMC
(b) Adult-onset immunodeficiencyAutoAb to IFN gammaDecreased naive T cellsNormalNormalMycobacterial, fungal, Salmonella VZV infections/MSMD, or CID
(c) Recurrent skin infectionAutoAb to IL-6NormalNormalNormalStaphylococcal infections/STAT3 deficiency
(d) Pulmonary alveolar proteinosisAutoAb to GM-CSFNormalNormalNormalPulmonary alveolar proteinosis, cryptococcal meningitis/CSF2RA deficiency
(e) Acquired angioedemaAutoAb to CI inhibitorNormalNormalNormalAngioedema/C1 INH deficiency (hereditary angioedema)

As with all complex diseases, any classification cannot be strictly adhered to. Certain conditions fall into more than one category and so appear in more than one table. For example, CD40L ligand deficiency is reported in both Tables ​Tables11 and ​and33 as it was initially identified as a defect of B cell isotype switching but is now known to be a defect of co-stimulatory T cell help and function. Similarly, XLP1 due to defects in SH2D1A is listed in Table ​Table11 – combined immunodeficiencies, due to defects of T cell cytotoxicity, T cell help, and B cell maturation, but also in Table ​Table44 – diseases of immune dysregulation, due to the susceptibility to hemophagocytosis. There is a growing appreciation that there can be wide phenotypic viability within a specific genotype that is a product of varied specific mutations between different patients as well as other host and/or environmental factors. The complexities of these conditions in terms of clinical and immunological presentation and heterogeneity cannot be easily captured in the limited space of a table format. For this reason, the furthest left column contains the Online Mendelian Inheritance in Man (OMIM) reference for each condition to allow access to greater detail and updated information.

Table 4

Diseases of immune dysregulation.

DiseaseGenetic defect/presumed pathogenesisInheritanceCirculating T cellsCirculating B cellsFunctional defectAssociated featuresOMIM number
1. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes
1.1 FHL syndromes without hypopigmentation
(a) Perforin deficiency (FHL2)Mutations in PRF1; perforin is a major cytolytic proteinARIncreased activated T cellsNormalDecreased to absent NK and CTL activities (cytotoxicity)Fever, hepatosplenomegaly (HSMG), hemophagocytic lymphohistiocytosis (HLH), cytopenias603553
(b) UNC13D/Munc13-4 deficiency (FHL3)Mutations in UNC13D a; required to prime vesicles for fusionARIncreased activated T cellsNormalDecreased to absent NK and CTL activities (cytotoxicity and/or degranulation)Fever, HSMG, HLH, cytopenias608898
(c) Syntaxin 11 deficiency (FHL4)Mutations in STX11, required for secretory vesicle fusion with the cell membraneARIncreased activated T cellsNormalDecreased NK activity (cytotoxicity and/or degranulation)Fever, HSMG, HLH, cytopenias603552
(d) STXBP2/Munc18-2 deficiency (FHL5)Mutations in STXBP2, required for secretory vesicle fusion with the cell membraneARIncreased activated T cellsNormalDecreased NK and CTL activities (cytotoxicity and/or degranulation)Fever, HSMG, HLH, cytopenias613101
1.2. FHL syndromes with hypopigmentation
(a) Chediak–Higashi syndromeMutations in LYST Impaired lysosomal traffickingARIncreased activated T cellsNormalDecreased NK and CTL activities (cytotoxicity and/or degranulation)Partial albinism
Recurrent infections, fever
HSMG, HLH
Giant lysosomes, neutropenia, cytopenias
Bleeding tendency
Progressive neurological dysfunction		214500
(b) Griscelli syndrome, type 2Mutations in RAB27A encoding a GTPase that promotes docking of secretory vesicles to the cell membraneARNormalNormalDecreased NK and CTL activities (cytotoxicity and/or degranulation)Partial albinism, fever, HSMG, HLH, cytopenias607624
(c) Hermansky–Pudlak syndrome, type 2Mutations in AP3B1 gene, encoding for the b subunit of the AP-3 complexARNormalNormalDecreased NK and CTL activities (cytotoxicity and/or degranulation)Partial albinism
Recurrent infections
Pulmonary fibrosis
Increased bleeding
Neutropenia
HLH		608233
2. Lymphoproliferative syndromes
(a) SH2D1A deficiency (XLP1)Mutations in SH2D1A encoding an adaptor protein regulating intracellular signalingXLNormal or increased activated T cellsReduced memory B cellsPartially defective NK cell and CTL cytotoxic activityClinical and immunological features triggered by EBV infection: HLH
Lymphoproliferation, aplastic anemia, lymphoma
Hypogammaglobulinemia
Absent iNKT cells		308240
(b) XIAP deficiency (XLP2)Mutations in XIAP/BIRC4 encoding an inhibitor of apoptosisXLNormal or increased activated T cells; low/normal iNK T cellsNormal or reduced memory B cellsIncreased T cells susceptibility to apoptosis to CD95 and enhanced activation-induced cell death (AICD)EBV infection, splenomegaly, lymphoproliferation HLH, colitis, IBD, hepatitis Low iNKT cells300635
(c) ITK deficiencyaMutations in ITK encoding IL-2 inducible T cell kinase required for TCR-mediated activationARProgressive decreaseNormalDecreased T cell activationsEBV-associated B cell lymphoproliferation, lymphoma
Normal or decreased IgG		613011
(d) CD27 deficiencyaMutations in CD27, encoding TNF-R member superfamily required for generation and long-term maintenance of T cell immunityARNormalNo memory B cellsLow T and NK cells functionsClinical and immunological features triggered by EBV infection: HLH
Aplastic anemia, lymphoma, hypogammaglobulinemia
Low iNKT cells		615122
3. Genetic defects of regulatory T cells
(a) IPEX, immune dysregulation, polyendocrinopathy, enteropathy X-linkedMutations in FOXP3, encoding a T cell transcription factorXLNormalNormalLack of (and/or impaired function of) CD4+ CD25+ FOXP3+ regulatory T cells (Tregs)Autoimmune enteropathy
Early-onset diabetes
Thyroiditis, hemolytic anemia, thrombocytopenia, eczema
Elevated IgE, IgA		304790
(b) CD25 deficiencyaMutations in IL-2RA, encoding IL-2Rα chainARNormal to decreasedNormalNo CD4+ C25+ cells with impaired function of Tregs cellsLymphoproliferation, autoimmunity. Impaired T cell proliferation606367
(c) STAT5b deficiencyaMutations in STAT5B, signal transducer, and transcription factor, essential for normal signaling from IL-2 and 15, key growth factors for T and NK cellsARModestly decreasedNormalImpaired development and function of γδT cells, Tregs, and NK cells Low T cell proliferationGrowth-hormone insensitive dwarfism245590
Dysmorphic features
Eczema
Lymphocytic interstitial pneumonitis, autoimmunity
4. Autoimmunity without lymphoproliferation
(a) APECED (APS-1), autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophyMutations in AIRE, encoding a transcription regulator needed to establish thymic self-toleranceARNormalNormalAIRE-1 serves as checkpoint in the thymus for negative selection of autoreactive T cells and for generation of TregsAutoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction, and other endocrine abnormalities240300
Chronic mucocutaneous candidiasis
Dental enamel hypoplasia
Alopecia areata
Enteropathy, pernicious anemia
(b) ITCH deficiencyaMutations in ITCH, an E3 ubiquitin ligase catalyzes the transfer of ubiquitin to a signaling protein in the cell including phospholipase Cγ1 (PLCγ1)ARNot assessedNot assessedItch deficiency may cause immune dysregulation by affecting both anergy induction in autoreactive effector T cells and generation of TregsEarly-onset chronic lung disease (interstitial pneumonitis)613385
Autoimmune disorder (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis)
Failure to thrive, developmental delay, dysmorphic facial features
5. Autoimmune lymphoproliferative syndrome (ALPS)
(a) ALPS–FASGerminal mutations in TNFRSF6, encoding CD95/Fas cell surface apoptosis receptorbADIncreased CD4−CD8− TCRα/β double negative (DN) T cellsNormal, low memory B cellsApoptosis defect FAS mediatedSplenomegaly, adenopathies, autoimmune cytopenias601859
ARcIncreased lymphoma risk
IgG and A normal or increased
Elevated FasL and IL-10, vitamin B12
(b) ALPS– FASLGMutations in TNFSF6, Fas ligand for CD95 apoptosisARIncreased DN T cellsNormalApoptosis defect FAS mediatedSplenomegaly, adenopathies, autoimmune cytopenias, SLE134638
Soluble FasL is not elevated
(c) ALPS–caspase 10aMutations in CASP10, intracellular apoptosis pathwayADIncreased DN T cellsNormalDefective lymphocyte apoptosisAdenopathies, splenomegaly, autoimmunity603909
(d) ALPS–caspase 8aMutations in CASP8, intracellular apoptosis, and activation pathwaysARSlightly increased DN T cellsNormalDefective lymphocyte apoptosis and activationAdenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia607271
(e) FADD deficiencyaMutations in FADD encoding an adaptor molecule interacting with FAS, and promoting apoptosisARIncreased DN T cellsNormalDefective lymphocyte apoptosisFunctional hyposplenism, bacterial and viral infections613759
Recurrent episodes of encephalopathy and liver dysfunction
(f) CARD11 gain-of-function (GOF) mutationsaGOF mutations in CARD11, encoding a protein required for antigen receptor–induced NF-κB activation in B and T lymphocytesADNormalIncreased M+D+CD19+ CD20+ B cellsConstitutive activation of NF-κB in B & TLymphoproliferation606445
Bacterial and viral infections
EBV chronic infection
Autoimmune cytopenia
Hypogammaglobulinemia
(g) PRKCδ deficiencyaMutations in PRKCD, encoding a member of the protein kinase C family critical for regulation of cell survival, proliferation, and apoptosisARNormalLow memory B cells and elevation of CD5 B cellsApoptotic defect in B cellsRecurrent infections; EBV chronic infection615559
Lymphoproliferation
SLE-like autoimmunity (nephrotic and antiphospholipid syndromes)
HypoIgG
6. Immune dysregulation with colitis
(a) IL-10 deficiencyaMutations in IL-10, encoding IL-10ARNormalNormalNo functional IL-10 secretionInflammatory bowel disease (IBD) folliculitisNot assigned
Recurrent respiratory diseases
Arthritis
(b) IL-10Rα deficiencyMutations in IL-10RA, encoding IL-10R1ARNormalNormalLeukocytes, no response to IL-10IBD, folliculitis613148
Recurrent respiratory diseases
Arthritis, lymphoma
(c) IL-10Rβ deficiencyMutations in IL-10RB, encoding IL-10R2ARNormalNormalLeukocytes, no response to IL-10, IL-22, IL-26, IL-28A, IL-28B, and IL-29IBD, folliculitis612567
Recurrent respiratory diseases
Arthritis, lymphoma
7. Type 1 interferonopathies
(a) TREX1 deficiency, Aicardi–Goutieres syndrome 1 (AGS1)Mutations in TREX1, encoding nuclease involves in clearing cellular nucleic debrisARNot assessedNot assessedIntracellular accumulation of abnormal single-stranded (ss) DNA species leading to increased CSF alpha-IFN productionProgressive encephalopathy intracranial calcifications606609
ADeCerebral atrophy, leukodystrophy
HSMG, thrombocytopenia
Elevated hepatic transaminases
Chronic cerebrospinal fluid (CSF) lymphocytosis
(b) RNASEH2B deficiency, AGS2Mutations in RNASEH2B, encoding nuclease subunit involves in clearing cellular nucleic debrisARNot assessedNot assessedIntracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN productionProgressive encephalopathy intracranial calcifications610326
Cerebral atrophy, leukodystrophy
HSMG, thrombocytopenia
Elevated hepatic transaminases
Chronic CSF lymphocytosis
(c) RNASEH2C deficiency, AGS3Mutations in RNASEH2C, encoding nuclease subunit involves in clearing cellular nucleic debrisARNot assessedNot assessedIntracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN productionProgressive encephalopathy intracranial calcifications610330
Cerebral atrophy, leukodystrophy
HSMG, thrombocytopenia
Elevated hepatic transaminases
Chronic CSF lymphocytosis
(d) RNASEH2A deficiency, AGS4aMutations in RNASEH2A, encoding nuclease subunit involves in clearing cellular nucleic debrisARNot assessedNot assessedIntracellular accumulation of abnormal ss-DNA species leading to increased CSF alpha-IFN productionProgressive encephalopathy intracranial calcifications606034
Cerebral atrophy, leukodystrophy
HSMG, thrombocytopenia
Elevated hepatic transaminases
Chronic CSF lymphocytosis
(e) SAMHD1 deficiency, AGS5Mutations in SAMHD1, encoding negative regulator of the immunostimulatory DNA responseARNot assessedNot assessedInduction of the cell intrinsic antiviral response, apoptosis, and mitochondrial DNA destruction leading to increased CSF alpha-IFN productionProgressive encephalopathy intracranial calcifications612952
Cerebral atrophy, leukodystrophy
HSMG, thrombocytopenia, anemia elevated lactates
Chronic CSF lymphocytosis
Skin vasculitis, mouth ulcers, arthropathy
(f) ADAR1 deficiency, AGS6Mutations in ADAR1, encoding an RNA-specific adenosine deaminaseARNot assessedNot assessedCatalyzes the deamination of adenosine to inosine in dsRNA substrates markedly elevated CSF IFN-alphaProgressive encephalopathy intracranial calcification Severe developmental delay, leukodystrophy615010
(g) Spondyloenchondro-dysplasia with immune dysregulation (SPENCD)Mutations in ACP5, encoding tartrate-resistant acid phosphatase (TRAP)ARNot assessedNot assessedUpregulation of IFN-alpha and type I IFN-stimulated genesRecurrent bacterial and viral infections, intracranial calcification607944
SLE-like autoimmunity (Sjögren’s syndrome, hypothyroidism, inflammatory myositis, Raynaud’s disease and vitiligo), hemolytic anemia, thrombocytopenia, skeletal dysplasia, short stature

XL, X-linked inheritance; AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; FHL, familial hemophagocytic lymphohistiocytosis; HLH, hemophagocytic lymphohistiocytosis; HSMG, hepatosplenomegaly; DN, double negative; SLE, systemic lupus erythematous; IBD, inflammatory bowel disease; CSF, chronic cerebrospinal fluid.

aTen or fewer unrelated cases reported in the literature.

bSomatic mutations of TNFRSF6 cause a similar phenotype (ALPS–sFAS), see Table ​Table9.9. Germinal mutation and somatic mutation of TNFRSF6 can be associated in some ALPS–FAS patients.

cAR ALPS–FAS patients have a most severe clinical phenotype.

dSomatic mutations in KRAS or NRAS can give this clinical phenotype associated autoimmune leukoproliferative disease (RALD) and are now included in Table ​Table99 entitled phenocopies of PID.

eDe novo dominant TREX1 mutations have been reported.

Fourteen new disorders have been added to Table ​Table4.4. Two new entries have been added in the table, including immune dysregulation with colitis and Type 1 interferonopathies. EBV-driven lymphoproliferation is also observed in MAGT1 deficiency (Table ​(Table11).

The rapid advances in gene identification technology, including the widespread use of whole exome and whole genome sequencing, has meant that the ability to identify gene defects in affected families and even single individuals with inherited diseases has grown enormously. In this report, over 30 new gene defects have been added that were identified since the previous classification in November, 2011. These defects can be found in all major groups of PIDs included in this report. In many cases, the mutations are not necessarily in genes formally implicated in immune cell function but are genes involved in essential cell processes. The more detailed analysis and functional consequences of such defects as illustrated by these PIDs will increase our understanding of the interplay between different cellular processes in the development and function of the immune system.

Among the newly identified, gene defects are many that are to date particular to a single pedigree or individual; such defects may prove exceedingly rare, or indeed may not necessarily be found to recur in other individuals. We have marked conditions for which there are 10 or fewer reported individuals with an asterisk, although historically, following the description of the first few cases, additional individuals with a similar PID phenotype and genotype have often been recognized. It is likely that we will uncover many more “personal” or very rare gene defects over time and that the spectrum of PIDs will become increasingly diverse and complex, due to contributions of both environmental exposures and genetic modifiers to each affected individual. The value of this report therefore to capture and catalog the full spectrum at any one time point becomes increasingly important.

The goal of the IUIS Expert Committee on PIDs is to increase awareness, facilitate recognition, and promote optimal treatment for patients with PIDs. In addition to the current report and previous “classification table” publications, the committee has also produced a “Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside,” which aims to lead physicians to particular groups of PIDs starting from clinical features and combining routine immunological investigations. Together, these contributions will hopefully allow a practical clinical framework for PID diagnosis. The committee also aims to establish a classification of PIDs based on other aspects and will work on publishing further guidelines in due course.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Articles from Frontiers in Immunology are provided here courtesy of Frontiers Media SA

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