Table 6.
Defects in innate immunity.
| Disease | Genetic defect/presumed pathogenesis | Inheritance | Affected cell | Functional defect | Associated features | OMIM 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 activation | XL | Lymphocytes + monocytes | NF-κB signaling pathway | Various infections (bacteria, Mycobacteria, viruses, and fungi) | 300248 |
| Colitis | ||||||
| EDA (not in all patients) | ||||||
| Hypogammaglobulinemia to specific antibody polysaccharides deficiency | ||||||
| (b) EDA-ID, autosomal-dominanta | Gain-of-function mutations of IKBA, resulting in impaired activation of NF-κB | AD | Lymphocytes + monocytes | NF-κB signaling pathway | Various infections (bacteria, viruses, and fungi) | 612132 |
| EDA | ||||||
| T cell defect | ||||||
| 2. TIR signaling pathway deficiency | ||||||
| (a) IRAK-4 deficiency | Mutations of IRAK-4, a component of TLR- and IL-1R-signaling pathway | AR | Lymphocytes + granulocytes + monocytes | TIR–IRAK signaling pathway | Bacterial infections (pyogenes) | 607676 |
| (b) MyD88 deficiency | Mutations of MYD88, a component of the TLR and IL-1R signaling pathway | AR | Lymphocytes + granulocytes + monocytes | TIR–MyD88 signaling pathway | Bacterial infections (pyogenes) | 612260 |
| 3. HOIL1 deficiencya | Mutation of HOIL1, a component of LUBAC | AR | Lymphocytes + granulocytes + monocytes | NF-κB signaling pathway | Bacterial infections (pyogenes) | Not assigned |
| Autoinflammation | ||||||
| Amylopectinosis | ||||||
| 4. WHIM (Warts, hypogammaglobulinemia, infections, myelokathexis) syndrome | Gain-of-function mutations of CXCR4, the receptor for CXCL12 | AD | Granulocytes + lymphocytes | Increased response of the CXCR4 chemokine receptor to its ligand CXCL12 (SDF-1) | Warts/human papilloma virus (HPV) infection | 193670 |
| Neutropenia | ||||||
| Reduced B cell number | ||||||
| Hypogammaglobulinemia | ||||||
| 5. Epidermodysplasia verruciformis | ||||||
| EVER1 deficiency | Mutations of EVER1 | AR | Keratinocytes and leukocytes | EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes | HPV (group B1) infections and cancer of the skin (typical EV) | 226400 |
| EVER2 deficiency | Mutations of EVER2 | AR | Keratinocytes and leukocytes | EVER proteins may be involved in the regulation of cellular zinc homeostasis in lymphocytes | HPV (group B1) infections and cancer of the skin (typical EV) | 226400 |
| 6. Predisposition to severe viral infection | ||||||
| (a) STAT2 deficiencya | Mutations of STAT2 | AR | T and NK cells | STAT2-dependent | Severe viral infections (disseminated vaccine-strain measles) | Not assigned |
| IFN-α and -β response | ||||||
| (b) MCM4 deficiencya | Mutations in MCM4 | AR | NK cells | DNA repair disorder | Viral infections (EBV, HSV, VZV) | 609981 |
| Adrenal failure | ||||||
| Short stature | ||||||
| 7. Herpes simplex encephalitis (HSE) | ||||||
| (a) TLR3 deficiencya | (b) Mutations of TLR3 | AD | Central nervous system (CNS) resident cells and fibroblasts | TLR3-dependent | Herpes simplex virus 1 encephalitis (incomplete clinical penetrance for all etiologies listed here) | 613002 |
| AR | IFN-α, -β, and -λ induction | |||||
| (b) UNC93B1 deficiencya | (a) Mutations of UNC93B1 | AR | CNS resident cells and fibroblasts | UNC-93B-dependent | Herpes simplex virus 1 encephalitis | 610551 |
| IFN-α, -β, and -λ induction | ||||||
| (c) TRAF3 deficiencya | (c) Mutations of TRAF3 | AD | CNS resident cells and fibroblasts | TRAF3-dependent | Herpes simplex virus 1 encephalitis | 614849 |
| IFN-α, -β, and -λ induction | ||||||
| (d) TRIF deficiencya | (c) Mutations of TRIF | AD | CNS resident cells and fibroblasts | TRIF-dependent | Herpes simplex virus 1 encephalitis | 614850 |
| AR | IFN-α, -β, and -λ induction | |||||
| (e) TBK1 deficiencya | (c) Mutations of TBK1 | AD | CNS resident cells and fibroblasts | TBK1-dependent | Herpes simplex virus 1 encephalitis | Not assigned |
| IFN-α, -β, and -λ induction | ||||||
| 8. Predisposition to invasive fungal diseasesa | ||||||
| CARD9 deficiency | Mutations of CARD9 | AR | Mononuclear phagocytes | CARD9 signaling pathway | Invasive candidiasis infection Deep dermatophytoses | 212050 |
| 9. Chronic mucocutaneous candidiasis (CMC) | ||||||
| (a) IL-17RA deficiencya | (a) Mutations in IL-17RA | AR | Epithelial cells, fibroblasts, mononuclear phagocytes | IL-17RA signaling pathway | CMC Folliculitis | 605461 |
| (b) IL-17F deficiencya | (b) Mutations in IL-17F | AD | T cells | IL-17F-containing dimers | CMC Folliculitis | 606496 |
| (c) STAT1 gain-of-function | (c) Gain-of-function mutations in STAT1 | AD | T cells | Gain-of-function STAT1 mutations that impair the development of IL-17-producing T cells | CMC | 614162 |
| Various fungal, bacterial, and viral (HSV) infections | ||||||
| Autoimmunity (thyroiditis, diabetes, cytopenia) | ||||||
| Enteropathy | ||||||
| (d) ACT1 deficiencya | (c) Mutations in ACT1 | AR | T cells, fibroblasts | Fibroblasts fail to respond to IL-17A and IL-17F, and their T cells to IL-17E | CMC | 615527 |
| Blepharitis, folliculitis, and macroglossia | ||||||
| 10. Trypanosomiasisa | Mutations in APOL-I | AD | APOL-I | Trypanosomiasis | 603743 | |
| 11. Isolated congenital asplenia (ICA) | Mutations in RPSA | AD | Spleen | RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome | Bacteremia (encapsulated bacteria) No spleen | 271400 |
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 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.