Primary immunodeficiencies: 2009 update

Abstract

More than 50 years after Ogdeon Bruton’s discovery of congenital agammaglobulinemia, human primary immunodeficiencies (PIDs) continue to unravel novel molecular and cellular mechanisms that govern development and function of the human immune system. This report provides the updated classification of PIDs, that has been compiled by the International Union of Immunological Societies (IUIS) Expert Committee of Primary Immunodeficiencies after its biannual meeting, in Dublin (Ireland) in June 2009. Since the appearance of the last classification in 2007, novel forms of PID have been discovered, and additional pathophysiology mechanisms that account for PID in humans have been unraveled. Careful analysis and prompt recognition of these disorders is essential to prompt effective forms of treatment and thus to improve survival and quality of life in patients affected with PIDs.

Since 1970, a Committee of experts in the field of Primary Immunodeficiencies (PID) has met every two years with the goal of classifying and defining these disorders. The most recent meeting, organized by the Experts Committee on Primary Immunodeficiencies of the International Union of Immunological Societies (IUIS), with support from the Jeffrey Modell Foundation and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, took place in Dublin, Ireland, in June 2009. In addition to members of the Experts Committee, the meeting gathered more than 30 speakers and over 200 participants from six continents. Recent discoveries on the molecular and cellular bases of PID and advances in the diagnosis and treatment of these disorders were discussed. At the end of the meeting, the IUIS Experts Committee on Primary Immunodeficiencies met to update the classification of PIDs, presented in Table 1–Table 8.

TABLE I.

Combined T and B cell immunodeficiencies

Disease	Circulating T cells	Circulating B cells	Serum Ig	Associated Features/atypical presentation	Inheritance	Molecular defect/presumed pathogenesis	Relative frequency among PIDs**
1. T−B+ SCID*
(a) γc deficiency	Markedly decreased	Normal or increased	Decreased	Markedly decreased NK cells Leaky cases may present with low to normal T and/or NK cells	XL	Defect in γ chain of receptors for IL-2, -4, -7, -9, -15, -21	Rare
(b) JAK3 deficiency	Markedly decreased	Normal or increased	Decreased	Markedly decreased NK cells Leaky cases may present with variable T and/or NK cells	AR	Defect in Janus activating kinase 3	Very rare
(c) IL7Rα deficiency	Markedly decreased	Normal or increased	Decreased	Normal NK cells	AR	Defect in IL-7 receptor α chain	Very rare
(d) CD45 deficiency	Markedly decreased	Normal	Decreased	Normal γ/δ T cells	AR	Defect in CD45	Extremely rare
(e) CD3δ/CD3ε /CD3ζ deficiency	Markedly Decreased	Normal	Decreased	Normal NK cells No γ/δ T cells	AR	Defect in CD3δ CD3ε or CD3ζ chains of T cell antigen receptor complex	Very rare
(f) Coronin-1A deficiency	Markedly decreased	Normal	Decreased	Detectable thymus	AR	Defective thymic egress of T cells and T cell locomotion	Extremely rare
2. T−B− SCID*
(a) RAG 1/2 deficiency	Markedly decreased	Markedly decreased	Decreased	Defective VDJ recombination May present with Omenn syndrome	AR	Defect of recombinase activating gene (RAG) 1 or 2	Rare
(b) DCLRE1C (Artemis) deficiency	Markedly decreased	Markedly decreased	Decreased	Defective VDJ recombination, radiation sensitivity May present with Omenn syndrome	AR	Defect in Artemis DNA recombinase-repair protein	Very rare
(c) DNA PKcs deficiency	Markedly decreased	Markedly decreased	Decreased	[widely studied scid mouse defect]	AR	Defect in DNAPKcs Recombinase repair protein	Extremely rare
(d) Adenosine deaminase (ADA) deficiency	Absent from birth (null mutations) or progressive decrease	Absent from birth or progressive decrease	Progressive decrease	Costochondral junction flaring, neurological features, hearing impairment, lung and liver manifestations. Cases with partial ADA activity may have a delayed or milder presentation	AR	Absent ADA, elevated lymphotoxic metabolites (dATP, S-adenosyl homocysteine)	Rare
(e) Reticular dysgenesis	Markedly decreased	Decreased or normal	Decreased	Granulocytopenia, deafness	AR	Defective maturation of T, B and myeloid cells (stem cell defect) Defect in mitochondrial adenylate kinase 2.	Extremely rare
3. Omenn syndrome***	Present; restricted heterogeneity	Normal or decreased	Decreased, except increased IgE	Erythroderma, eosinophilia, adenopathy, hepatosplenomegaly	AR	Hypomorphic mutations in RAG1/2, Artemis, IL-7Rα, RMRP, ADA, DNA Ligase IV, γc	Rare
4. DNA ligase IV deficiency	Decreased	Decreased	Decreased	Microcephaly, facial dysmorphisms, radiation sensitivity May present with Omenn syndrome or with a delayed clinical onset.	AR	DNA ligase IV defect, impaired nonhomologous end joining (NHEJ)	Very rare
5. Cernunnos deficiency	Decreased	Decreased	Decreased	Microcephaly, in utero growth retardation, radiation sensitivity	AR	Cernunnos defect, impaired NHEJ	Very rare
6. CD40 ligand deficiency	Normal	IgM+ and IgD+ B cells present, other isotypes absent	IgM increased or normal, other isotypes decreased	Neutropenia, thrombocytopenia; hemolytic anemia, biliary tract and liver disease, opportunistic infections	XL	Defects in CD40 ligand (CD40L) causedefective isotype switching and impaired dendritic cell signaling	Rare
7. CD40 deficiency	Normal	IgM+ and IgD+ B cells present, other isotypes absent	IgM increased or normal, other isotypes decreased	Neutropenia, gastrointestinal and liver/biliary tract disease, opportunistic infections	AR	Defects in CD40 cause defective isotype switching and impaired dendritic cell signaling	Extremely rare
8. Purine nucleoside phosphorylase deficiency (PNP)	Progressive decrease	Normal	Normal or decreased	Autoimmune haemolytic anaemia, neurological impairment	AR	Absent PNP, T-cell and neurologic defects from elevated toxic metabolites (e.g. dGTP)	Very rare
9. CD3γ deficiency	Normal, but reduced TCR expression	Normal	Normal		AR	Defect in CD3 γ	Extremely rare
10. CD8 deficiency	Absent CD8, normal CD4 cells	Normal	Normal		AR	Defects of CD8 α chain	Extremely rare
11. ZAP-70 deficiency	Decreased CD8, normal CD4 cells	Normal	Normal		AR	Defects in ZAP-70 signaling kinase	Very rare
12. Ca++ channel deficiency	Normal counts, defective TCR mediated activation	Normal counts	Normal	Autoimmunity, anhydrotic ectodermic dysplasia, non- progressive myopathy	AR AR	Defect in Orai-1, a Ca++ channel component Defect in Stim-I, a Ca++ sensor	Extremely rare
13. MHC class I deficiency	Decreased CD8, normal CD4	Normal	Normal	Vasculitis	AR	Mutations in TAP1, TAP2 or TAPBP (tapasin) genes giving MHC class I deficiency	Very rare
14. MHC class II deficiency	Normal number, decreased CD4 cells	Normal	Normal or decreased		AR	Mutation in transcription factors for MHC class II proteins (C2TA, RFX5, RFXAP, RFXANK genes)	Rare
15. Winged helix deficiency (Nude)	Markedly decreased	Normal	Decreased	Alopecia, abnormal thymic epithelium, impaired T cell maturation [widely studied nude mouse defect]	AR	Defects in forkhead box N1 transcription factor encoded by FOXN1, the gene mutated in nude mice	Extremely rare
16. CD25 deficiency	Normal to modestly decreased	Normal	Normal	Lymphoproliferation (lymphadenopathy, hepatosplenomegaly), autoimmunity (may resemble IPEX syndrome), impaired T-cell proliferation	AR	Defects in IL-2Rα chain	Extremely rare
17. STAT5b deficiency	Modestly decreased	Normal	Normal	Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstital pneumonitis, autoimmunity	AR	Defects of STAT5b, impaired development and function of γδT cells, Treg and NK cells, impaired T-cell proliferation	Extremely rare
18. Itk deficiency	Modestly decreased	Normal	Normal or decreased		AR	EBV associated lymphoproliferation	Extremely rare
19. DOCK8 deficiency	Decreased	Decreased	Low IgM, increased IgE	Recurrent respiratory infections. Extensive cutaneous viral and bacterial (staph.) infections, susceptibility to cancer, hypereosinophilia, severe atopy, low NK cells	AR	Defect in DOCK8	Very rare

Abbreviations: SCID, severe combined immune deficiencies; XL, X-linked inheritance; AR, autosomal recessive inheritance; NK, natural killer cells.

^*Atypical cases of SCID may present with T cells because of hypomorphic mutations or somatic mutations in T cell precursors.

^**Frequency : may vary from region to region or even among communities i.e. Mennonite, Innuit etc.

^***Some cases of Omenn syndrome remain genetically undefined

^****Some metabolic disorders such methylmalonic aciduria may present with profound lymphopenia in addition to their typical presenting features.

Table VIII.

Complement deficiencies

Disease	Functional Defect	Associated Features	Inheritance	Gene Defects	Relative frequency among PIDs
C1q deficiency	-Absent C hemolytic activity, Defective MAC * -Faulty dissolution of immune complexes -Faulty clearance of apoptotic cells	SLE–like syndrome, rheumatoid disease, infections	AR	C1q	Very rare
C1r deficiency*	-Absent C hemolytic activity, Defective MAC -Faulty dissolution of immune complexes	SLE–like syndrome, rheumatoid disease, infections	AR	C1r*	Very rare
C1s deficiency	-Absent C hemolytic activity	SLE-like syndrome; multiple autoimmune diseases	AR	C1s*	Extremely rare
C4 deficiency	-Absent C hemolytic activity, Defective MAC -Faulty dissolution of immune complexes -Defective humoral immune response	SLE–like syndrome, rheumatoid disease, infections	AR	C4A and C4B§	Very rare
C2 deficiency**	-Absent C hemolytic activity, Defective MAC -Faulty dissolution of immune complexes	SLE–like syndrome, vasculitis, polymyositis, pyogenic infections	AR	C2**	Rare
C3 deficiency	-Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity -Defective humoral immune response	Recurrent pyogenic infections	AR	C3	Very rare
C5 deficiency	-Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity	Neisserial infections, SLE	AR	C5	Very rare
C6 deficiency	-Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity	Neisserial infections, SLE	AR	C6	Rare
C7 deficiency	-Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity	Neisserial infections, SLE, vasculitis	AR	C7	Rare
C8a deficiency***	-Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity	Neisserial infections, SLE	AR	C8α	Very rare
C8b deficiency	-Absent C hemolytic activity, Defective MAC -Defective Bactericidal activity	Neisserial infections, SLE	AR	C8β	Very rare
C9 deficiency	-Reduced C hemolytic activity, Defective MAC -Defective Bactericidal activity	Neisserial infections****	AR	C9	Rare
C1 inhibitor deficiency	-Spontaneous activation of the complement pathway with consumption of C4/C2 -Spontaneous activation of the contact system with generation of bradykinin from high molecular weight kininogen	Hereditary angioedema	AD	C1 inhibitor	Relative common
Factor I deficiency	-Spontaneous activation of the alternative complement pathway with consumption of C3	Recurrent pyogenic infections, glomerulonephritis, hemolytic-uremic syndrome	AR	Factor I	Very rare
Factor H deficiency	-Spontaneous activation of the alternative complement pathway with consumption of C3	Hemolytic-uremic syndrome, membranoproliferative glomerulonephritis	AR	Factor H	Rare
Factor D deficiency	-Absent hemolytic activity by the alternate pathway	Neisserial infection	AR	Factor D	Very rare
Properdin deficiency	-Absent hemolytic activity by the alternate pathway	Neisserial infection	XL	Properdin	Rare
MBP deficiency *****	-Defective mannose recognition -Defective hemolytic activity by the lectin pathway.	Pyogenic infections with very low penetrance mostly asymptamatic	AR	MBP *****	Relative common
MASP2 deficiency	-Absent hemolytic activity by the lectin pathway	SLE syndrome, pyogenic infection	AR	MASP2	Extremely rare
Complement Receptor 3 (CR3) deficiency	-see LAD1 in Table V, above		AR	INTGB2	Rare
Membrane Cofactor Protein (CD46) deficiency	-Inhibitor of complement alternate pathway, decreased C3b binding	Glomerulonephritis, atypical hemolytic uremic syndrome	AD	MCP	Very rare
Membrane Attack Complex Inhibitor (CD59) deficiency	-Erythrocytes highly susceptible to complement- mediated lysis	Hemolytic anemia, thrombosis	AR	CD59	Extremely rare
Paroxysmal nocturnal hemoglobinuria	-Complement-mediated hemolysis	Recurrent hemolysis	Acquired X- linked mutation	PIGA	Relative common
Immunodeficiency associated with Ficolin 3 deficiency	Absence of complement activation by the Ficolin 3 pathway	Recurrent severe pyogenic infections mainly in the lungs	AR	FCN3	Extremely rare

^*The C1r and C1s genes are located within 9.5 kb of each other. In many cases of C1r deficiency, C1s is also deficient.

^§Gene duplication has resulted in two active C4A genes located within 10 kb. C4 deficiency requires abnormalities in both genes, usually the result of deletions.

^**Type 1 C2 deficiency is in linkage disequilibrium with HLA-A25, B18 and -DR2 and complotype, SO42 (slow variant of Factor B, absent C2, type 4 C4A, type 2 C4B) and is common in Caucasians (about 1 per 10,000). It results from a 28-bp deletion resulting in a premature stop codon in the C2 gene; C2 mRNA is not produced. Type 2 C2 deficiency is very rare and involves amino acid substitutions which result in C2 secretory block.

^***C8alpha deficiency is always associated with C8gamma deficiency. The gene encoding C8gamma maps to chromosome 9 and is normal. C8gamma is covalently bound to C8alpha.

^****Association is weaker than with C5, C6, C7 and C8 deficiencies. C9 deficiency occurs in about 1 per 1,000 Japanese.

^*****Population studies reveal no detectable increase in infections in MBP deficient adults.

Abbreviations: MAC= Membrane attack complex SLE: systemic lupus erythematosus; MBP: Mannose binding Protein; MASP-2: MBP associated serine protease 2.

The general outline of the classification has remained substantially unchanged. Novel PIDs, whose molecular basis has been identified and reported in the last two years, have been added to the list. In Table I (Combined T and B cell immunodeficiencies), coronin-1A deficiency (resulting in impaired thymic egress) has been added to the genetic defects causing T⁻ B⁺ SCID. The first case of DNA-PKcs deficiency has also been reported, and adds to the list of defects of non-homologous end-joining resulting in T⁻ B⁻ SCID. Among calcium flux defects, defects of Stim-1, a Ca⁺⁺ sensor, have been reported in children with immunodeficiency, myopathy and autoimmunity. Mutations of the gene encoding the dedicator of cytokinesis 8 (DOCK8) protein have been shown to cause an autosomal recessive combined immunodeficiency with hyper-IgE, also characterized by extensive cutaneous viral infections, severe atopy and increased risk of cancer. In the same Table, mutations of the adenylate kinase 2 (AK2) gene have been shown to cause reticular dysgenesis, and mutations in DNA ligase IV, ADA and γc have been added to the list of genetic defects that may cause Omenn syndrome.

In Table II (Predominantly antibody deficiencies), mutations in TACI and in BAFF-receptor (BAFF-R) have been added to the list of gene defects that may cause hypogammaglobulinemia. However, it should be noted that only few TACI mutations appear to be disease-causing. Furthermore, variability of clinical expression has been associated with the rare BAFF-R deficiency. Table III lists other well-defined immunodeficiency syndromes. PMS2 deficiency and ICF syndrome (immunodeficiency with centromeric instability and facial anomalies) have been added to the list of DNA repair defects, whereas Comel-Netherton syndrome is now included among the immune-osseous dysplasias, and hyper-IgE syndrome due to DOCK8 mutation has also been added. ITK deficiency has been included among the molecular causes of lymphoproliferative syndrome in Table IV (Diseases of immune dysregulation). In the same Table, CD25 deficiency has been listed, to reflect the occurrence of autoimmuninty in this rare disorder. Progress in the molecular characterization of congenital neutropenia and other innate immunity defects has resulted in the inclusion of G6PT1 and G6PC3 defects in Table V (Congenital defects of phagocyte number, function, or both), and of MyD88 deficiency (causing recurrent pyogenic bacterial infections) in Table VI (Defects of innate immunity), respectively. These two Tables also include two novel genetic defects that result in clinical phenotypes distinct from the classical definition of PIDs. In particular, mutations of the CSFR2A gene, encoding for granulocyte macrophage-colony stimulating factor receptor α (GM-CSF Rα), have been shown to cause primary alveolar proteinosis due to defective surfactant catabolism by alveolar macrophages (see: Table V). Mutations in APOL-I are associated with trypanosomiasis, as reported in Table VI. It can be anticipated that a growing number of defects in immune-related genes will be shown to be responsible for non-classical forms of PIDs in the future. Along the same line, the spectrum of genetically defined autoinflammatory disorders (Table VIII) has expanded to include NLRP12 mutations (responsible for familial cold autoinflammatory syndrome) and IL1RN defects (causing deficiency of the Interleukin-1 receptor antagonist). Again, it is expected that a growing number of genetic defects will be identified in other inflammatory conditions. Finally, defects of Ficolin 3 (that plays an important role in complement activation) have been shown to cause recurrent pyogenic infections in the lung (Table VIII).

Table II.

Predominantly Antibody Deficiencies

Disease	Serum Ig	Associated Features	Inheritance	Genetic Defects/presumed pathogenesis	Relative frequency among PIDs
1. Severe reduction in all serum immunoglobulin isotypes with profoundly decreased or absent B cells
a)   Btk deficiency	All isotypes decreased	Severe bacterial infections; normal numbers of pro-B cells	XL	Mutations in BTK	rare
b)   μ heavy chain deficiency	All isotypes decreased	Severe bacterial infections; normal numbers of pro-B cells	AR	Mutations in μ heavy chain	very rare
c)   λ 5 deficiency	All isotypes decreased	Severe bacterial infections; normal numbers of pro-B cells	AR	Mutations in λ5	extremely rare
d)   Igα deficiency	All isotypes decreased	Severe bacterial infections; normal numbers of pro-B cells	AR	Mutations in Igα	extremely rare
e)   Ig β deficiency	All isotypes decreased	Severe bacterial infections normal numbers of pro-B cells	AR	Mutations in Igβ	extremely rare
f)   BLNK deficiency	All isotypes decreased	Severe bacterial infections normal numbers of pro-B cells	AR	Mutations in BLNK	extremely rare
g)   Thymoma with immunodeficiency	All isotypes decreased	Bacterial and opportunistic infections; autoimmunity	None	Unknown	rare
2. Severe reduction in at least 2 serum immunoglobulin isotypes with normal or low numbers of B cells
a)   Common variable immunodeficiency disorders*	Low IgG and IgA and/or IgM	Clinical phenotypes vary: most have recurrent bacterial infections, some have autoimmune, lymphoproliferative and/or granulomatous disease	Variable	Unknown	relatively common
b)   ICOS deficiency	Low IgG and IgA and/or IgM	-	AR	Mutations in ICOS	extremely rare
c)   CD19 deficiency	Low IgG, and IgA and/or IgM	-	AR	Mutations in CD19	extremely rare
d)   TACI deficiency**	Low IgG and IgA and/or IgM	-	AD or AR or complex	Mutations in TNFRSF13B (TACI)	very common
e)   BAFF receptor deficiency**	Low IgG and IgM	Variable clinical expression	AR	Mutations in TNFRSF13C (BAFF-R)	extremely rare
3. Severe reduction in serum IgG and IgA with normal/elevated IgM and normal numbers of B cells
a)   CD40L deficiency***	IgG and IgA decreased; IgM may be normal or increased; B cell numbers may be normal or increased	Opportunistic infections, neutropenia, autoimmune disease	XL	Mutations in CD40L (also called TNFSF5 or CD154)	rare
b)   CD40 deficiency***	Low IgG and IgA; normal or raised IgM	Opportunistic infections, neutropenia, autoimmune disease	AR	Mutations in CD40 (also called TNFRSF5)	extremely rare
c)   AID deficiency*****	IgG and IgA decreased; IgM increased	Enlarged lymph nodes and germinal centers	AR	Mutations in AICDA gene	very rare
d)   UNG deficiency****	IgG and IgA decreased; IgM increased	Enlarged lymph nodes and germinal centers	AR	Mutation in UNG	extremely rare
4. Isotype or light chain deficiencies with normal numbers of B cells
a)   Ig heavy chain mutations and deletions	One or more IgG and/or IgA subclasses as well as IgE may be absent	May be asymptomatic	AR	Mutation or chromosomal deletion at 14q32	Relatively common
b)   κ chain deficiency	All immunoglobulins have lambda light chain	Asymptomatic	AR	Mutation in Kappa constant gene	Extremely rare
c)   Isolated IgG subclass deficiency	Reduction in one or more IgG subclass	Usually asymptomatic; may have recurrent viral/ bacterial infections	Variable	Unknown	Relatively common
d)   IgA with IgG subclass deficiency	Reduced IgA with decrease in one or more IgG subclass;	Recurrent bacterial infections in majority	Variable	Unknown	Relatively common
e)   Selective IgA deficiency	IgA decreased/ absent	Usually asymptomatic; may have recurrent infections with poor antibody responses to carbohydrate antigens; may have allergies or autoimmune disease. A few cases progress to CVID, others coexist with CVID in the same family.	Variable	Unknown	Most common
5. Specific antibody deficiency with normal Ig concentrations and normal numbers of B cells	Normal	Inability to make antibodies to specific antigens	Variable	Unknown	Relatively common
6. Transient hypogammaglobulinemia of infancy with normal numbers of B cells	IgG and IgA decreased	Recurrent moderate bacterial infections	Variable	Unknown	common

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

^*Common variable immunodeficiency disorders: there are several different clinical phenotypes, probably representing distinguishable diseases with differing immunopathogeneses

^**Alterations in TNFRSF13B (TACI) and TNFRSF13C (BAFF-R) sequence may represent disease modifying mutations rather than disease causing mutations

^***CD40L and CD40 deficiency are also included in Table I

^*****Deficiency of activation induced cytidine deaminse (AID) or uracil-DNA glycosylase (UNG) present as forms of the hyper-IgM syndrome but differ from CD40L and CD40 deficiencies in that the patients have large lymph nodes with germinal centers and are not susceptible to opportunistic infections.

Table III.

Other well-defined immunodeficiency syndromes.

Disease	Circulating T cells	Circulating B cells	Serum Ig	Associated features	Inheritance	Genetic defects/Presumed Pathogenesis	Relative frequency among PIDs
1. Wiskott-Aldrich syndrome (WAS)	Progressive decrease, Abnormal lymphocyte responses to anti-CD3	Normal	Decreased IgM: antibody to polysaccharides particularly decreased; often increased IgA and IgE	Thrombocytopenia with small platelets; eczema; lymphomas; 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 WASP	XL	Mutations in WASP; cytoskeletal defect affecting haematopoietic stem cell derivatives	Rare
2. DNA repair defects (other than those in Table 1)
(a) Ataxia-telangiectasia	Progressive decrease	Normal	Often decreased IgA, IgE and IgG subclasses; increased IgM monomers; antibodies variably decreased	Ataxia; telangiectasia; pulmonary infections; lympho-reticular and other malignancies; increased alpha fetoprotein and X-ray sensitivity; chromosomal instability	AR	Mutations in ATM; disorder of cell cycle check-point and DNA double-strand break repair	Relatively common
(b) Ataxia-telangiectasia like disease (ATLD)	Progressive decrease	Normal	Antibodies variably decreased	Moderate ataxia; pulmonary infections; severely increased radiosensitivity	AR	Hypomorphic mutations in MRE11; disorder of cell cycle checkpoint and DNA double- strand break repair	Very rare
(c) Nijmegen breakage syndrome	Progressive decrease	Variably reduced	Often decreased IgA, IgE and IgG subclasses; increased IgM; antibodies variably decreased	Microcephaly; bird-like face; lymphomas; solid tumors; ionizing radiation sensitivity; chromosomal instability	AR	Hypomorphic mutations in NBS1 (Nibrin); disorder of cell cycle checkpoint and DNA double- strand break repair	Rare
(d) Bloom Syndrome	Normal	Normal	Reduced	Short stature; bird like face; sun- sensitive erythema; marrow failure; leukemia; lymphoma; chromosomal instability	AR	Mutations in BLM; RecQ like helicase	Rare
(e) Immunodeficiency with centromeric instability and facial anormalies (ICF)	Decreased or normal	Decreased or normal	Hypogammaglobulinemia; variable antibody deficiency	Facial dysmorphic features; macroglossia; bacterial/opportunistic infections; malabsorption; multiradial configurations of chromosomes 1, 9, 16; no DNA breaks	AR	Mutations in DNA methyltransferase DNMT3B, resulting in defective DNA methylation	Very rare
(f) PMS2 Deficiency (Class Switch recombination [CSR] deficiency due to defective mismatch repair)	Normal	Switched and non- switched B cells are reduced	Low IgG and IgA, elevated IgM, abnormal antibody responses	Recurrent infections; café-au-lait spots; lymphoma, colorectal carcinoma, brain tumor	AR	Mutations in PMS2, resulting in defective CSR- induced DNA double strand breaks in Ig switch regions	Very rare
3. Thymic defects
DiGeorge anomaly (Chromosome 22q11.2 deletion syndrome	Decreased or Normal	Normal	Normal or decreased	Conotruncal malformation; abnormal facies; large deletion (3Mb) in 22q11.2 (or rarely a deletion in 10p)	De novo defect or AD	Contiguous gene defect in 90% affecting thymic development; mutation in TBX1	Common
4. Immune-osseous dysplasias
(a) Cartilage hair hypoplasia	Decreased or Normal; impaired lymphocyte proliferation*	Normal	Normal or reduced. Antibodies variably decreased	Short-limbed dwarfism with metaphyseal dysostosis, sparse hair, bone marrow failure, autoimmunity, susceptibility to lymphoma and other cancers, impaired spermatogenesis, neuronal dysplasia of the intestine	AR	Mutations in RMRP (RNase MRP RNA) Involved in processing of mitochondrial RNA and cell cycle control	Rare
(b) Schimke syndrome	Decreased	Normal	Normal	Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy; bacterial, viral, fungal infections; may present as SCID; bone marrow failure	AR	Mutations in SMARCAL1 Involved in chromatin remodeling	Very rare
5. Comel-Netherton Syndrome	Normal	Switched and non- switched B cells are reduced	Elevated IgE and IgA Antibody variably decreased	Congenital ichthyosis, bamboo hair, atopic diathesis, increased bacterial infections, failure to thrive	AR	Mutations in SPINK5 resulting in lack of the serine protease inhibitor LEKTI, expressed in epithelial cells	Rare
6. Hyper-IgE syndromes (HIES)
(a) AD-HIES (Job Syndrome)	Normal Th-17 cells decreased	Normal	Elevated IgE; specific antibody production decreased	Distinctive facial features (broad nasal bridge), eczema, osteoporosis and fractures, scoliosis, failure/delay of shedding primary teeth, hyperextensible joints, bacterial infections (skin and pulmonary abscesses/pneumatoceles) due to Staphylococcus aureus, candidiasis	AD Often de novo defect	Dominant-negative heterozygous mutations in STAT 3	Rare
(b) AR-HIES				No skeletal and connective tissue abnormalities;	AR
	Normal	Normal	Elevated IgE	i)  susceptibility to   intracellular bacteria   (Mycobacteria,   Salmonella), fungi and   viruses		Mutation in TYK2	Extremely rare
	Reduced	Reduced	Elevated IgE, low IgM	ii)  recurrent respiratory   infections; extensive   cutaneous viral and   staphylococcal   infections, increased     risk of cancer, severe   atopy with anaphylaxis		Mutation in DOCK8	Very rare
	Normal	Normal	Elevated IgE	iii)  CNS hemorrhage,   fungal and viral   infections		Unknown	Extremely rare
7. Chronic mucocutaneous candidiasis	Normal	Normal	Normal	Chronic mucocutaneous candidiasis, impaired delayed-type hypersensitivity to candida antigens, autoimmunity, no ectodermal dysplasia	AD, AR, sporadic	Unknown	Very rare
8. Hepatic venoocculusive disease with immunodeficiency (VODI)	Normal (Decreased memory T cells)	Normal (Decreased memory B cells)	Decreased IgG, IgA, IgM	Hepatic veno-occulusive disease; Pneumocystis jiroveci pneumonia; thrombocytopenia; hepatosplenomegaly	AR	Mutations in SP110	Extremely rare
9. XL-Dyskeratosis congenita (Hoyeraal-Hreidarsson Syndrome)	Progressive decrease	Progressive decrease	Variable	Intrauterine growth retardation, microcephaly, nail dystrophy, recurrent infections, digestive tract involvement, pancytopenia, reduced number and function of NK cells	XL	Mutations in Dyskerin (DKC1)	Very rare

^*Patients with cartilage-hair hypoplasia can present also with typical SCID or with Omenn syndrome

TABLE IV.

Diseases of immune Dysregulaton

Disease	Circulating T Cells	Circulating B cells	Serum Ig	Associated Features	Inheri- tance	Genetic defects, Presumed Pathogenesis	Relative frequency among PIDs
1. Immuno-deficiency with/ hypopigmentation
(a) Chediak-Higashi syndrome	Normal	Normal	Normal	Partial albinism, giant lysosomes, low NK and CTL activities, heightened acute-phase reaction, late-onset primary encephalopathy	AR	Defects in LYST, impaired lysosomal trafficking	Rare
(b) Griscelli Syndrome, type 2	Normal	Normal	Normal	Partial albinism, low NK and CTL activities, heightened acute phase reaction, encephalopathy in some patients	AR	Defects in RAB27A encoding a GTPase in secretory vescicles	Rare
(c) Hermansky-Pudlak syndrome, type 2	Normal	Normal	Normal	Partial albinism, neutropenia, low NK and CTL activity, increased bleeding	AR	Mutations of AP3B1 gene, encoding for the β subunit of the AP-3 complex	Extremely rare
2. Familial hemophagocytic lymphohistiocytosis (FHL) syndromes
(a) Perforin deficiency	Normal	Normal	Normal	Severe inflammation, fever, decreased NK and CTL activities	AR	Defects in PRF1; perforin, a major cytolytic protein	Rare
(b) Munc 13-D deficiency	Normal	Normal	Normal	Severe inflammation, fever, decreased NK and CTL activities	AR	Defects in MUNC13D required to prime vescicles for fusion	Rare
(c) Syntaxin 11 deficiency	Normal	Normal	Normal	Severe inflammation, fever, decreased NK activity	AR	Defects in STX11, involved in vescicle trafficking and fusion	Very rare
3. Lymphoproliferative syndromes
(a) XLP1, SH2D1A deficiency	Normal	Normal or reduced	Normal or low immuno- globulins	Clinical and immunologic abnormalities triggered by EBV infection, including hepatitis, aplastic anaemia, lymphoma	XL	Defects in SH2D1A encoding an adaptor protein regulating intracellular signals	Rare
(b) XLP2, XIAP deficiency	Normal	Normal or reduced	Normal or low immuno- globulins	Clinical and immunologic abnormalities triggered by EBV infection, including splenomegaly, hepatitis, hemophagocytic syndrome, lymphoma	XL	Defects in XIAP encoding an inhibitor of apoptosis	Very rare
(c) ITK deficiency	Modestly decreased	Normal	Normal or decreased	EBV-associated lymphoproliferation	AR	Mutations in ITK	Extremely rare
4. Syndromes with autoimmunity
(a) Autoimmune lymphoproliferative syndrome (ALPS)
(i) CD95 (Fas) defects, ALPS type 1a	Increased CD4− CD8− double negative (DN) T cells	Normal	Normal or increased	Splenomegaly, adenopathy, autoimmune blood cytopenias, defective lymphocyte apoptosis increased lymphoma risk	AD (rare severe AR cases)	Defects in TNFRSF6, cell surface apoptosis receptor; in addition to germline mutations, somatic mutations cause a similar phenotype	Rare
(ii) CD95L (Fas ligand) defects, ALPS type 1b	Increased DN T cells	Normal	Normal	Splenomegaly, adenopathy, autoimmune blood cytopenias, defective lymphocyte apoptosis, SLE	AD AR	Defects in TNFSF6, ligand for CD95 apoptosis receptor	Extremely rare
(iii) Caspase 10 defects, ALPS type 2a	Increased DN T cells	Normal	Normal	Adenopathy, splenomegaly, autoimmune disease, defective lymphocyte apoptosis	AD	Defects in CASP10, intracellular apoptosis pathway	Extremely rare
(iv) Caspase 8 defects, ALPS type 2b	Slightly increased DN T cells	Normal	Normal or decreased	Adenopathy, splenomegaly, recurrent bacterial and viral infections, defective lymphocyte apoptosis and activation;	AD	Defects in CASP8, intracellular apoptosis and activation pathways	Extremely rare
(v) Activating N-Ras defect, N- Ras ALPS	Increased DN T cells	Elevation of CD5 B cells	Normal	Adenopathy, splenomegaly, leukemia, lymphoma, defective lymphocyte apoptosis following IL-2 withdrawal	AD	Defect in NRAS encoding a GTP binding protein with diverse signaling functions, activating mutations impair mitochondrial apoptosis	Extremely rare
(b) APECED, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy	Normal	Normal	Normal	Autoimmune disease, particularly of parathyroid, adrenal and other endocrine organs plus candidiasis, dental enamel hypoplasia and other abnormalities	AR	Defects in AIRE, encoding a transcription regulator needed to establish thymic self-tolerance	Rare
(c) IPEX, immune dysregulation, polyendocrinopathy, enteropathy (X-linked)	Lack of CD4+ CD25+ FOXP3+ regulatory T cells	Normal	Elevated IgA, IgE	Autoimmune diarrhea, early onset diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, eczema	XL	Defects in FOXP3, encoding a T cell transcription factor	Rare
(d) CD25 deficiency	Normal to modestly decreased	Normal	Normal	Lymphorpoliferation, autoimmunity, impaired T cell proliferation	AR	Defects in IL-2Rα chain	Extremely rare

AR: autosomal recessive; XL: X-linked; AD: autosomal dominant; DN: double-negative; SLE; systemic lupus erythematosus

TABLE V.

Congenital defects of phagocyte number, function, or both

	Disease	Affected cells	Affected functon	Associated features	Inheritance	Gene defect – presumed pathogenesis	Relative frequency among PIDs
1.–2.	Severe congenital neutropenias	N	Myeloid differentiation	Subgroup with myelodysplasia	AD	ELA2: mistrafficking of elastase	Rare
		N	Myeloid differentiation	B/T lymphopenia	AD	GFI1: repression of elastase	Extremely rare
3.	Kostmann Disease	N	Myeloid differentiation	Cognitive and neurological defects*	AR	HAX1:control of apoptosis	Rare
4	Neutropenia with cardiac and urogenital malformations	N + F	Myeloid differentiation	Structural heart defects, urogenital abnormalities, and venous angiectasias of trunks and limbs	AR	G6PC3: abolished enzymatic activity of glucose-6-phosphatase and enhanced apoptosis of N and F	Very rare
5	Glycogen storage disease type 1b	N + M	Killing, chemotaxis, O2− production	Fasting hypoglycemia, lactic acidosis, hyperlipidemia, hepatomegaly, neutropenia	AR	G6PT1: Glucose-6-phosphate transporter 1	Very rare
6.	Cyclic neutropenia	N	?	Oscillations of other leukocytes and platelets	AD	ELA2: mistrafficking of elastase	Very rare
7.	X-linked neutropenia/ myelodysplasia	N + M	?	Monocytopenia	XL	WASP: Regulator of actin cytoskeleton (loss of autoinhibition)	Extremely rare
8.	P14 deficiency	N+L Mel	Endosome biogenesis	Neutropenia Hypogammaglobulinemia ↓CD8 cytotoxicity Partial albinism Growth failure	AR	MAPBPIP: Endosomal adaptor protein 14	Extremely rare
9.	Leukocyte adhesion deficiency type 1	N + M + L + NK	Adherence Chemotaxis Endocytosis T/NK cytotoxicity	Delayed cord separation, skin ulcers Periodontitis Leukocytosis	AR	INTGB2: Adhesion protein	Very rare
10.	Leukocyte adhesion deficiency type 2	N + M	Rolling Chemotaxis	Mild LAD type 1 features plus hh-blood group plus mental and growth retardation	AR	FUCT1: GDP-Fucose transporter	Extremely rare
11.	Leukocyte adhesion deficiency type 3	N + M + L + NK	Adherence	LAD type 1 plus bleeding tendency	AR	KINDLIN3: Rap1-activation of β1–3 integrins	Extremely rare
12.	Rac 2 deficiency	N	Adherence Chemotaxis O2− production	Poor wound healing, leukocytosis	AD	RAC2: Regulation of actin cytoskeleton	Extremely rare: Regulation of actin cytoskeleton
13.	β-actin deficiency	N + M	Motility	Mental retardation, short stature	AD	ACTB: Cytoplasmic Actin	Extremely rare
14.	Localized juvenile Periodontitis	N	Formylpeptide induced chemotaxis	Periodontitis only	AR	FPR1: Chemokine receptor	Very rare
15.	Papillon-Lefèvre Syndrome	N + M	Chemotaxis	Periodontitis, palmoplantar hyperkeratosis**	AR	CTSC: Cathepsin C activation of serine proteases	Very rare
16.	Specific granule deficiency	N	Chemotaxis	N with bilobed nuclei	AR	C/EBPE: myeloid transcription factor	Extremely rare
17.	Shwachman-Diamond Syndrome	N	Chemotaxis	Pancytopenia, exocrine pancreatic insufficiency, chondrodysplasia	AR	SBDS	Rare
18.	X-linked chronic granulomatous disease (CGD)	N + M	Killing (faulty O2− production)	McLeod phenotype in a subgroup of patients	XL	CYBB: Electron transport protein (gp91phox)	Relatively common
19.– 21.	Autosomal CGD’s	N + M	Killing (faulty O2− production)		AR	CYBA: Electron transport protein (p22phox) NCF1: Adapter protein (p47phox) NCF2: Activating protein (p67phox)	Relatively comùmo,n
22.	IL-12 and IL-23 receptor β1 chain deficiency	L + NK	IFN-γ secretion	Susceptibility to Mycobacteria and Salmonella	AR	IL12RB1: IL-12 and IL-23 receptor β1 chain	Rare
23.	IL-12p40 deficiency	M	IFN-γ secretion	Susceptibility to Mycobacteria and Salmonella	AR	IL12B: subunit of IL12/IL23	Very rare
24.	IFN-γ receptor 1 deficiency	M + L	IFN-γ binding and signaling	Susceptibility to Mycobacteria and Salmonella	AR, AD	IFNGR1: IFN-γR ligand binding chain	Rare
25.	IFN-γ receptor 2 deficiency	M + L	IFN-γ signaling	Susceptibility to Mycobacteria and Salmonella	AR	IFNGR2: IFN-γR accessory chain	Very rare
26.	STAT1 deficiency (2 forms)	M + L	IFN α/β, IFN-γ, IFN-λ and IL-27 signaling	Susceptibility to Mycobacteria, Salmonella and viruses	AR	STAT1	Extremely rare
			IFN-γ signalling	Susceptibility to Mycobacteria and Salmonella	AD	STAT1	Extremely rare
27.	AD hyper-IgE syndrome	L+M+N+ epithelial	IL-6/10/22/23 signalling	Distinctive facial features (broad nasal bridge); eczema; osteoporosis and fractures; scoliosis; failure/delay of shedding primary teeth; hyperextensible joints; bacterial infections (skin and pulmonary abscesses/pneumatoceles) due to Staphylococcus aureus; candidiasis	AD	STAT3	Rare
28.	AR hyper-IgE (TYK2 deficiency)	L+M+N+ others	IL-6/10/12/23/IFN- α/IFN-β signalling	Susceptibility to intracellular bacteria (Mycobacteria, Salmonella), staphylococcus and viruses.	AR	TYK2	Extremely rare

AD, autosomal dominant; XL, X-linked inheritance; AR, autosomal recessive inheritance; N, neutrophils; M, monocytes-macrophages; L, lymphocytes; NK, natural killer cells; Mel, melanocytes; F, fibroblasts; STAT1, signal transducer and activator of transcription 1;

^*cognitive ane neurological defects are observed in a fraction of patients;

^**periodontitis may be isolated.

Table VI.

Defects in Innate Immunity

Disease	Affected Cell	Functional Defect	Associated Features	Inheritance	Gene Defect/Presumed pathogenesis	Relative frequency among PIDs
Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)	Lymphocytes + Monocytes	NFκB signalling pathway	anhidrotic ectodermal dysplasia + specific antibody deficiency (lack of Ab response to polysaccharides) various infections (mycobacteria and pyogens)	XR	Mutations of NEMO (IKBKG), a modulator of NF-κB activation	Rare
Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)	Lymphocytes + Monocytes	NFκB signalling pathway	anhidrotic ectodermal dysplasia + T cell defect + various infections	AD	Gain-of-function mutation of IKBA, resulting in impaired activation of NF-κB	Extremely rare
Interleukin-1 Receptor Associated kinase 4 (IRAK4) deficiency	Lymphocytes + Monocytes	TIR-IRAK signalling patwhay	Bacterial infections (pyogens)	AR	Mutation of IRAK4, a component of TLR- and IL-1R- signaling pathway	Very rare
MyD88 deficiency	lymphocytes + Monocytes	TIR-MyD88 signalling pathway	Bacterial infections (pyogens)	AR	Mutation of MYD88, a component of the TLR and IL- 1R signaling pathway	Very rare
WHIM (Warts, Hypogammaglobulinemia infections,Myelokathexis) syndrome	Granulocytes + Lymphocytes	Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1)	Hypogammaglobulinemia, reduced B cell number, severe reduction of neutrophil count, warts/HPV infection	AD	Gain-of-function mutations of CXCR4, the receptor for CXCL12	Very rare
Epidermodysplasia verruciformis	Keratinocytes and leukocytes	?	Human Papilloma virus (group B1) infections and cancer of the skin	AR	Mutations of EVER1, EVER2	Extremely rare
Herpes simplex encephalitis (HSE)	Central nervous system resident cells, epithelial cells and leukocytes	UNC-93B–dependent IFN-α, -β, and –λ, induction	Herpes simplex virus 1 encephalitis and meningitis	AR	Mutations of UNC93B1	Extremely rare*
Herpes simplex encephalitis (HSE)	Central nervous system resident cells, epithelial cells, dendritic cells, cytotoxic lymphocytes	TLR3-dependent IFN-α, -β, and -λ, induction	Herpes simplex virus 1 encephalitis and meningitis	AD	Mutations of TLR3	Extremely rare*
Trypanosomiasis		APOL-I	Trypanosomiasis	AD	Mutation in APOL-I	Extremely rare*

NF-κB: nuclear factor Kappa B; TIR: Toll and Interleukin 1 Receptor; IFN: interferon; HPV: human papilloma virus; TLR: Toll-like receptor

^*Only a few patients have been genetically investigated, and they represented a small fraction of all patients tested, but the clinical phenotype being common, these genetic disorders may actually be more common.

While the revised classification of PIDs is meant to assist with the identification, diagnosis and management of patients with these conditions, it should not be used dogmatically. In particular, although the typical clinical and immunological phenotype is reported for each PID, it has been increasingly recognized that the phenotypic spectrum of these disorders is wider than originally thought. This variability reflects both the effect of different mutations within PID-causing genes, and the role of other genetic, epigenetic and environmental factors in modifying the phenotype. For example, germline hypomorphic mutations or somatic mutations in SCID-related genes may result in atypical/leaky SCID or Omenn syndrome, the latter associated with significant immunopathology. Furthermore, infections may also significantly modify the clinical and immunological phenotype, even in patients who initially present with typical SCID. Thus, the phenotype associated with single-gene defects listed in the revised classification should by no means be considered absolute.

Finally, a new column has been added to the revised classification, to illustrate the relative frequency of the various PID disorders. It should be noted that these frequency estimates are based on what has been reported in the literature, since, with few exceptions, no solid epidemiologic data exist that can be reliably used to define the incidence of PID disorders. Furthermore, the frequency of PIDs may vary in different countries. Certain populations (and especially, some restricted ethnic groups of geographical isolates) have a higher frequency of specific PID mutations, due to a founder effect and genetic drift. For example, DCLER1C (Artemis) and ZAP70 defects are significantly more common in Athabascan-speaking Native Americans and in members of the Mennonite Church, respectively, than in other populations. Similarly, MHC class II deficiency is more frequent in Northern Africa. Furthermore, the frequency of autosomal recessive immunodeficiencies is higher among populations with a high consanguinity rate.

Table VII.

Autoinflammatory Disorders

Disease	Affected cells	Functional defects	Associated Features	Inheritance	Gene defects	Relative frequency among PIDs
Familial Mediterranean Fever	Mature granulocytes, cytokine- activated monocytes.	Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury; macrophage apoptosis decreased.	Recurrent fever, serositis and inflammation responsive to colchicine. Predisoposes to vasculitis and inflammatory bowel disease.	AR	Mutations of MEFV	common
TNF receptor-associated periodic syndrome (TRAPS)	PMNs, monocytes	Mutations of 55-kD TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF	Recurrent fever, serositis, rash, and ocular or joint inflammation	AD	Mutations of TNFRSF1A	rare
Hyper IgD syndrome		Mevalonate kinase deficiency affecting cholesterol synthesis; pathogenesis of disease unclear	Periodic fever and leukocytosis with high IgD levels	AR	Mutations of MVK	rare
Muckle-Wells syndrome*	PMNs Monocytes	Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signalling and IL-1 processing	Urticaria, SNHL, amyloidosis. Responsive to IL-1R/antagonist	AD	Mutations of CIAS1 (also called PYPAF1 or NALP3)	rare
Familial cold autoinflammatory syndrome*	PMNs, monocytes	same as above	Non-pruritic urticaria, arthritis, chills, fever and leukocytosis after cold exposure. Responsive to IL-1R/antagonist (Anakinra)	AD	Mutations of CIAS1 Mutations of NLRP12	Very rare
Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)*	PMNs, chondrocytes	same as above	Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation responsive to IL-1R antagonist (Anakinra)	AD	Mutations of CIAS1	Very rare
Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome	hematopoietic tissues, upregulated in activated T-cells	Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response	Destructive arthritis, inflammatory skin rash, myositis	AD	Mutations of PSTPIP1 (also called C2BP1)	Very rare
Blau syndrome	Monocytes	Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signalling	Uveitis, granulomatous synovitis, camptodactyly, rash and cranial neuropathies, 30% develop Crohn’s disease	AD	Mutations of NOD2 (also called CARD15)	rare
Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)	Neutrophils, bone marrow cells	undefined	Chronic recurrent multifocal osteomyelitis, transfusion- dependent anemia, cutaneous inflammatory disorders	AR	Mutations of LPIN2	Very rare
DIRA(Deficiency of the Interleukin 1 Receptor Antagonist)	PMNs, Monocytes	Mutations in the IL1 receptor antagonist allows unopposed action of Interleukin 1	Neonatal onset of sterile multifocal osteomyelitis, periostitis and pustulosis.	AR	Mutations of IL1RN	Very rare

^*All three syndromes associated with similar CIAS1 mutations; disease phenotype in any individual appears to depend on modifying effects of other genes and environmental factors.

Abbreviations: PMN, polymorphonuclear cells; AD, autosomal dominant inheritance. ASC, apoptosis-asocated 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