Autoinflammatory disorders
| Disease . | Genetic defect . | Inheritance . | OMIM . | T cells . | B cells . | Functional defect . | Associated features . |
|---|---|---|---|---|---|---|---|
| 1. Type 1 interferonopathies | |||||||
| AD STING-associated vasculopathy, infantile-onset (SAVI) | TMEM173** (STING) | AD | 612374 | Not assessed | Not assessed | STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN | Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL |
| AR STING-associated vasculopathy, infantile-onset (SAVI) | AR GOF | 615934 | Not assessed | Not assessed | STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN | FTT, early-onset rash, fever, dyspnea, interstitial lung disease/pneumonitis, polyarthritis, autoAbs, increased inflammatory markers, IFN gene signature. Phenocopy of SAVI due to AD GOF TMEM173 | |
| ADA2 deficiency | ADA2 | AR | 607575 | Not assessed | Not assessed | ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors | Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever; some patients develop hypogammaglobulinemia |
| TREX1 deficiency, Aicardi–Goutières syndrome 1 (AGS1) | TREX1 | AR | 606609 | Not assessed | Not assessed | Intracellular accumulation of abnormal ssDNA species leading to increased type I IFN production | Classical AGS, SLE, FCL |
| AD | |||||||
| RNASEH2B deficiency, AGS2 | RNASEH2B | AR | 610326 | Not assessed | Not assessed | Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production | Classical AGS, SP |
| RNASEH2C deficiency, AGS3 | RNASEH2C | AR | 610330 | Not assessed | Not assessed | Classical AGS | |
| RNASEH2A deficiency, AGS4 | RNASEH2A | AR | 606034 | Not assessed | Not assessed | Classical AGS | |
| SAMHD1 deficiency, AGS5 | SAMHD1 | AR | 606754 | Not assessed | Not assessed | Controls dNTPs in the cytosol, failure of which leads to increased type I IFN production | Classical AGS, FCL |
| ADAR1 deficiency, AGS6 | ADAR1 | AR | 615010 | Not assessed | Not assessed | Catalyzes the deamination of adenosine to inosine in dsRNA substrates, failure of which leads to increased type I IFN production | Classical AGS, BSN, SP |
| AD (G1007R) | NA | ||||||
| Aicardi–Goutières syndrome 7 (AGS7) | IFIH1 | AD GOF | 615846 | Not assessed | Not assessed | IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule | Classical AGS, SLE, SP, SMS |
| DNase II deficiency | DNASE2 | AR | 619858 | Not assessed | Not assessed | DNase II degrades and eliminates DNA. Loss of DNase II activity induces type I interferon signaling | AGS |
| LSM11 deficiency | LSM11 | AR | 619486 | Not assessed | Not assessed | Increased IFN signaling in fibroblasts | AGS, type 1 IFN-opathy |
| RNU7-1 deficiency | RNU7-1 | AR | 619487 | Not assessed | Not assessed | Increased IFN signaling in fibroblasts | AGS, type 1 IFN-opathy |
| ARF1 deficiency | ARF1 | AD | 103180 | Not assessed | Not assessed | Increased type I IFN signaling in cell lines and patient cells | AGS, type 1 IFN-opathy |
| Pediatric SLE due to DNASE1L3 deficiency | DNASE1L3 | AR | 614420 | DNASE1L3 is an endonuclease that degrades extracellular DNA. DNASE1L3 deficiency decreases clearance of apoptotic cells | Very early-onset SLE, reduced complement levels, autoantibodies (dsDNA, ANCA), lupus nephritis, hypocomplementemic urticarial vasculitis syndrome | ||
| Spondyloenchondrodysplasia with immune dysregulation (SPENCD) | ACP5 | AR | 171640 | Not assessed | Not assessed | Upregulation of IFN through mechanism possibly relating to pDCS | Short stature, SP, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections |
| USP18 deficiency | USP18 | AR | 607057 | Not assessed | Not assessed | Defective negative regulation of ISG15 leading to increased IFN | TORCH-like syndrome, autoinflammation, and mycobacterial disease |
| OAS1 GOF | OAS1 | AD GOF | 618042 | Low | Increased interferon from recognition of RNA | Pulmonary alveolar proteinosis, skin rash | |
| CDC42 deficiency | CDC42 | AD | 616737 | Normal/decreased | Normal/decreased | ↑serum levels of IL-1, IL-18, IFN-α↑, ferritin, sCD25, CRP, etc. Mutation affects actin function, ↓ NK cell cytotoxicity | Neonatal onset: pancytopenia, fever, rash, hepatosplenomegaly, multisystemic inflammation, myelofibrosis/proliferation, HLH, enterocolitis; recurrent GIT/URT infections; neurodevelopmental delay, FTT |
| STAT2 loss of negative regulation | STAT2 | AR | 616636 | Increased | Normal | Patient cells hypersensitive to IFN-α, GOF for induction of the late (not early) response to type 1 IFNs due to impaired interaction of mutant STAT2 with USP18, a negative regulator of type 1 IFN responses | Severe fatal early-onset autoinflammation, ↑serum IFN-α, IL-6, TNF-α, phenocopy of USP18 deficiency |
| ATAD3A deficiency | ATAD3A | AD/AR | 617183 | Not assessed | Not assessed | Elevated ISG expression, increased serum type 1 IFNs | Predominantly neurological defects (development delay, spasticity) |
| RELA haploinsufficiency | RELA | AD | 618287 | Normal/increased | Normal | Chronic mucocutaneous ulceration Impaired NF-κB activation; reduced production of inflammatory cytokines | |
| RELA interferonopathya | RELA | AD DN | 618287 | Leukocyte TLR7-dependent type I/III IFN production | Patients with RELA DN mutations shared clinical phenotypes with RELA haploinsufficiency, presenting chronic mucocutaneous ulcerations and autoimmune hematological disorders such as immune thrombocytopenia (ITP) and neutropenia. However, patients with RELA DN mutations additionally presented periodic fever, IBD juvenile idiopathic arthritis (JIA), and skin involvement | ||
| Disease . | Genetic defect . | Inheritance . | OMIM . | T cells . | B cells . | Functional defect . | Associated features . |
|---|---|---|---|---|---|---|---|
| 1. Type 1 interferonopathies | |||||||
| AD STING-associated vasculopathy, infantile-onset (SAVI) | TMEM173** (STING) | AD | 612374 | Not assessed | Not assessed | STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN | Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL |
| AR STING-associated vasculopathy, infantile-onset (SAVI) | AR GOF | 615934 | Not assessed | Not assessed | STING activates both the NF-κB and IRF3 transcription pathways to induce the expression of IFN | FTT, early-onset rash, fever, dyspnea, interstitial lung disease/pneumonitis, polyarthritis, autoAbs, increased inflammatory markers, IFN gene signature. Phenocopy of SAVI due to AD GOF TMEM173 | |
| ADA2 deficiency | ADA2 | AR | 607575 | Not assessed | Not assessed | ADAs deactivate extracellular adenosine and terminate signaling through adenosine receptors | Polyarteritis nodosa, childhood-onset, early-onset recurrent ischemic stroke and fever; some patients develop hypogammaglobulinemia |
| TREX1 deficiency, Aicardi–Goutières syndrome 1 (AGS1) | TREX1 | AR | 606609 | Not assessed | Not assessed | Intracellular accumulation of abnormal ssDNA species leading to increased type I IFN production | Classical AGS, SLE, FCL |
| AD | |||||||
| RNASEH2B deficiency, AGS2 | RNASEH2B | AR | 610326 | Not assessed | Not assessed | Intracellular accumulation of abnormal RNA-DNA hybrid species leading to increased type I IFN production | Classical AGS, SP |
| RNASEH2C deficiency, AGS3 | RNASEH2C | AR | 610330 | Not assessed | Not assessed | Classical AGS | |
| RNASEH2A deficiency, AGS4 | RNASEH2A | AR | 606034 | Not assessed | Not assessed | Classical AGS | |
| SAMHD1 deficiency, AGS5 | SAMHD1 | AR | 606754 | Not assessed | Not assessed | Controls dNTPs in the cytosol, failure of which leads to increased type I IFN production | Classical AGS, FCL |
| ADAR1 deficiency, AGS6 | ADAR1 | AR | 615010 | Not assessed | Not assessed | Catalyzes the deamination of adenosine to inosine in dsRNA substrates, failure of which leads to increased type I IFN production | Classical AGS, BSN, SP |
| AD (G1007R) | NA | ||||||
| Aicardi–Goutières syndrome 7 (AGS7) | IFIH1 | AD GOF | 615846 | Not assessed | Not assessed | IFIH1 gene encodes a cytoplasmic viral RNA receptor that activates type I interferon signaling through the MAVS adaptor molecule | Classical AGS, SLE, SP, SMS |
| DNase II deficiency | DNASE2 | AR | 619858 | Not assessed | Not assessed | DNase II degrades and eliminates DNA. Loss of DNase II activity induces type I interferon signaling | AGS |
| LSM11 deficiency | LSM11 | AR | 619486 | Not assessed | Not assessed | Increased IFN signaling in fibroblasts | AGS, type 1 IFN-opathy |
| RNU7-1 deficiency | RNU7-1 | AR | 619487 | Not assessed | Not assessed | Increased IFN signaling in fibroblasts | AGS, type 1 IFN-opathy |
| ARF1 deficiency | ARF1 | AD | 103180 | Not assessed | Not assessed | Increased type I IFN signaling in cell lines and patient cells | AGS, type 1 IFN-opathy |
| Pediatric SLE due to DNASE1L3 deficiency | DNASE1L3 | AR | 614420 | DNASE1L3 is an endonuclease that degrades extracellular DNA. DNASE1L3 deficiency decreases clearance of apoptotic cells | Very early-onset SLE, reduced complement levels, autoantibodies (dsDNA, ANCA), lupus nephritis, hypocomplementemic urticarial vasculitis syndrome | ||
| Spondyloenchondrodysplasia with immune dysregulation (SPENCD) | ACP5 | AR | 171640 | Not assessed | Not assessed | Upregulation of IFN through mechanism possibly relating to pDCS | Short stature, SP, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections |
| USP18 deficiency | USP18 | AR | 607057 | Not assessed | Not assessed | Defective negative regulation of ISG15 leading to increased IFN | TORCH-like syndrome, autoinflammation, and mycobacterial disease |
| OAS1 GOF | OAS1 | AD GOF | 618042 | Low | Increased interferon from recognition of RNA | Pulmonary alveolar proteinosis, skin rash | |
| CDC42 deficiency | CDC42 | AD | 616737 | Normal/decreased | Normal/decreased | ↑serum levels of IL-1, IL-18, IFN-α↑, ferritin, sCD25, CRP, etc. Mutation affects actin function, ↓ NK cell cytotoxicity | Neonatal onset: pancytopenia, fever, rash, hepatosplenomegaly, multisystemic inflammation, myelofibrosis/proliferation, HLH, enterocolitis; recurrent GIT/URT infections; neurodevelopmental delay, FTT |
| STAT2 loss of negative regulation | STAT2 | AR | 616636 | Increased | Normal | Patient cells hypersensitive to IFN-α, GOF for induction of the late (not early) response to type 1 IFNs due to impaired interaction of mutant STAT2 with USP18, a negative regulator of type 1 IFN responses | Severe fatal early-onset autoinflammation, ↑serum IFN-α, IL-6, TNF-α, phenocopy of USP18 deficiency |
| ATAD3A deficiency | ATAD3A | AD/AR | 617183 | Not assessed | Not assessed | Elevated ISG expression, increased serum type 1 IFNs | Predominantly neurological defects (development delay, spasticity) |
| RELA haploinsufficiency | RELA | AD | 618287 | Normal/increased | Normal | Chronic mucocutaneous ulceration Impaired NF-κB activation; reduced production of inflammatory cytokines | |
| RELA interferonopathya | RELA | AD DN | 618287 | Leukocyte TLR7-dependent type I/III IFN production | Patients with RELA DN mutations shared clinical phenotypes with RELA haploinsufficiency, presenting chronic mucocutaneous ulcerations and autoimmune hematological disorders such as immune thrombocytopenia (ITP) and neutropenia. However, patients with RELA DN mutations additionally presented periodic fever, IBD juvenile idiopathic arthritis (JIA), and skin involvement | ||
| Disease . | Genetic defect . | Inheritance . | OMIM . | Affected cells . | Functional defect . | Associated features . |
|---|---|---|---|---|---|---|
| 2. Defects affecting the inflammasome | ||||||
| Familial Mediterranean fever (FMF) | MEFV** | AR LOF | 249100 | Mature granulocytes, cytokine-activated monocytes | Increased pyrin inflammasome-mediated induction of IL-1β | Recurrent fever, serositis, and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease, SAA amyloidosis |
| AD | 134610 | Mature granulocytes, cytokine-activated monocytes | Usually, M694del variant. Other missense variants in the B-Box and CC domains cause constitutive pyrin activation | |||
| Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia, and hypercalprotectinemia | PSTPIP1 | AD | 604416 | PMNs, monocytes | Activation of the pyrin inflammasome; high production of IL-1 and IL-18 cytokines; interferon signature | Destructive arthritis, inflammatory skin rash, myositis |
| Mevalonate kinase deficiency (hyper-IgD syndrome/HIDS) | MVK | AR | 260920 | Somatic and hematopoietic | Defect in production of isoprenoids, which are synthesized via mevalonate pathway and play a role in regulation of many signaling pathways | Periodic fever and leukocytosis with usually high IgD levels |
| PMVK deficiency | PMVK | AR | NA | Leukocytes | Similar to MVK deficiency, increased IL-1β | Recurrent fever episodes, arthritis, and cytopenia |
| Muckle–Wells syndrome | NLRP3** | AD GOF | 191900 | PMNs Monocytes | Activation of cryopyrin inflammasome results in increased production of IL-1/IL-18 cytokines and cell death via pyroptosis | Urticaria, SNHL, SAA amyloidosis |
| Familial cold autoinflammatory syndrome 1 | AD GOF | 120100 | PMNs, monocytes | Nonpruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure | ||
| Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA) | AD GOF | 607115 | PMNs, chondrocytes | Neonatal-onset rash, chronic meningitis, and arthropathy with fever and inflammation | ||
| Keratitis fugax hereditaria associated with c.61G>C NLRP3 | AD GOF | 606416 | Episodic conjunctival injection, ocular pain, photophobia, foreign body sensation, and excessive tearing during acute attacks. Corneal opacities during attacks | |||
| Familial cold autoinflammatory syndrome 2 | NLRP12 | AD GOF | 611762 | PMNs, monocytes | Nonpruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure | |
| NLRC4-MAS (macrophage-activating syndrome) | NLRC4 | AD GOF | 616050 | PMNs, monocytes, macrophages, intestinal epithelial cells | GOF mutation in NLRC4 results in elevated secretion of IL-1β and IL-18, as well as macrophage activation | Severe enterocolitis and macrophage activation syndrome |
| Familial cold autoinflammatory syndrome 4 | 616115 | |||||
| APLAID or autoinflammation, antibody deficiency, and immune dysregulation | Missense variants PLCG2 Small intragenic deletions | AD GOF/LOF | 614878 | B cells, NK, mast cells | Mutations affect the autoinhibitory domains and activate NF-κB and MAPK pathways | Cold urticaria hypogammaglobulinemia, impaired humoral immunity, autoantibodies, autoinflammation, granulomas |
| PLAID or familial cold autoinflammatory syndrome 3 | 614468 | |||||
| Autoinflammation with arthritis and dyskeratosis (AIADK; NLRP1 deficiency) | NLRP1 | AR | 617388 | Keratinocytes and leukocytes | Systemic elevation of IL-18, IL-1β, caspase 1, suggesting activation of NLRP1 inflammasome | Dyskeratosis, autoimmunity, and arthritis |
| NLRP1 GOF | NLRP1 | AD GOF | 615225 | Keratinocytes | Spontaneous production of IL-1β and IL-18 cytokines in keratinocytes | Palmoplantar carcinoma, corneal scarring; recurrent respiratory papillomatosis |
| Autoinflammation with episodic fever and lymphadenopathy/cleavage-resistant RIPK1-induced autoinflammatory syndrome/CRIA | RIPK1 | AD | 618852 | Leukocytes and fibroblasts | TNF-induced cell death via apoptosis and necroptosis | Long-lasting fever episodes, lymphadenopathy, splenohepatomegaly, ulcers, arthralgia, GI features |
| Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) | LPIN2 | AR | 609628 | Neutrophils, bone marrow cells | Dysregulation in cholesterol synthesis impairs the negative regulation of NLRP3 in macrophages resulting in high production of IL-1 | Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders |
| 3. Non-inflammasome–related conditions | ||||||
| TNF receptor–associated periodic syndrome (TRAPS) | TNFRSF1A** | AD | 142680 | PMNs, monocytes | Mutations in the extracellular domain of 55-kD TNF receptor cause protein misfolding and intracellular receptor retention resulting in upregulation of ER stress | Recurrent fever, serositis, rash, and ocular or joint inflammation |
| Blau syndrome | NOD2** | AD | 186580 | Monocytes, intestinal epithelial cells | Mutations in nucleotide binding site of CARD15 result in constitutive activation of NOD2 noadosome nd upregulation of NF-κB signaling | Uveitis, granulomatous synovitis, camptodactyly, rash, and cranial neuropathies; 30% develop Crohn’s colitis |
| ADAM17 deficiency | ADAM17 | AR | 614328 | Leukocytes and epithelial cells | Defective TNF-α production | Early-onset diarrhea and skin lesions |
| DIRA (deficiency of the interleukin-1 receptor antagonist) | IL1RN | AR | 612852 | PMNs, monocytes | Mutations in the IL-1 receptor antagonist allow unopposed action of IL-1α and IL-1β | Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis |
| Loss of IL-1R1 sensitivity to IL-Ra (LIRSA/CRMO3) (1 patient) | IL-1R1 | AD | 259680 | T cells and B cells | Activated myeloid cells. Loss of IL-1R1 biding to endogenous IL-Ra | Arthritis, osteolytic/sclerotic bone lesions, poor growth, no rash, no fever |
| DITRA (deficiency of IL-36 receptor antagonist) | IL36RN | AR | 614204 | Keratinocytes, leukocytes | Mutations in the IL-36 receptor antagonist allow unopposed action of IL-1α and IL-1β | Pustular psoriasis |
| Histiocytosis-lymphadenopathy plus syndrome/H syndrome (ENT3) | SLC29A3 | AR | 602782 | Leukocytes, histiocytes | Defect in nucleoside transport functions of hENT3 leads to histiocytic infiltration of numerous organs | Hyperpigmentation hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally hyperglycemia/diabetes mellitus |
| CAMPS (CARD14-mediated psoriasis) | CARD14 | AD | 602723 | Mainly in keratinocytes | Mutations in CARD14 activate the NF-κB pathway and production of IL-8 | Psoriasis |
| Cherubism | SH3BP2 | AD | 118400 | Stromal cells, bone cells | Hyperactivated macrophages and osteoclasts, increased NF-κB signaling | Bone degeneration in jaws |
| PRAAS-CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) | PSMB8* | AR and AD | 256040 | Keratinocytes, B-cell adipose cells | Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature | Contractures, panniculitis, ICC, fevers |
| PSMG2 | AR | 609702 | Lymphocytes | Panniculitis, lipodystrophy, autoimmune hemolytic anemia | ||
| PSMB10 | AR | 619175 | Lymphocytes | Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature | Periorbital and hand–foot annular rash (neutrophilic dermatosis), microcytic anemia, long slender fingers, hepatomegaly and splenomegaly | |
| PSMB9 | AR or digenic or DN | 617591 | Lymphocytes | Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature | ||
| PSMB4 | AR or digenic | 617591 | Lymphocytes | Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature | Panniculitis, lipodystrophy, autoimmune hemolytic anemia | |
| PRAID | POMP | AD | 618048 | Lymphocytes | Increased accumulation of ubiquitinated proteins and ER stress with increased IFN signaling mediated by increased PKR signaling | CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)/ interstitial lung disease in one patient, liver disease in one patient. Recurrent and opportunistic infections. Low CD8 T cells, skewing toward naïve T cells. Low B cells and positive autoantibodies |
| PSMB9 deficiency (G156D) | PSMB9 | AD (DN LOF) | 617591 | Leukocytes (mild pancytopenia) | Decreased protein expression and reduced proteasome activities. Elevated levels of inflammatory cytokines (IL-6, IL-18, IP-10, IFN-α), liver enzymes in blood and CSF (IFN-α), hyperactivation of IFN-α, pSTAT1 | Severe autoinflammatory phenotype (neonatal-onset fever, skin rash, myositis, severe pulmonary hypertension, basal ganglia calcification), periodic inflammatory exacerbation; immunodeficiency. Partial phenocopy of PRAAS |
| Autoinflammation with neurodevelopmental disease | PSMD12 | AR | 617516 | CNS, lymphocytes | ↑ peripheral blood type I IFN gene signature has been reported for some patients | Intellectual disability, developmental delay, urticarial skin rash, elevated interferon signature |
| COPA syndrome | COPA | AD | 601924 | PMN and tissue-specific cells | Defective intracellular transport via the coat protein complex I (COPI). Exacerbated STING-mediated type I interferon response | Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production |
| Otulipenia/ORAS | OTULIN | AR/AD | 615712 | Leukocytes, fibroblasts | Increase LUBAC induction of NF-κB and interferon activation leading to high proinflammatory cytokine levels. Increase in TNF-induced cell death | Fever, diarrhea, skin abscesses, panniculitis |
| Dominant negative OTULIN-related autoinflammatory syndrome (3 patients) | OTULIN | AD | 615712 | Lymphocytes and fibroblasts | Decreased catalytic activity, accumulation of linear ubiquitin chains, increased TNF-induced cell death, | Spontaneous systemic inflammation |
| OTULIN haploinsufficiency | OTULIN | AD | 615712 | Epithelial cells | Increased activity of caveolin-1 stabilizes ADAM10 receptor for S. aureus toxin | Susceptibility to S. aureus infections in epithelial cells |
| Haploinsufficiency of A20/HA20 | TNFAIP3 | AD | 616744 | Lymphocytes | Defective inhibition of NF-κB signaling pathway | Arthralgia, mucosal ulcers, ocular inflammation |
| AP1S3 deficiency | AP1S3 | AR | 615781 | Keratinocytes | Disrupted TLR3 translocation | Pustular psoriasis |
| ALPI deficiency | ALPI | AR | 171740 | Intestinal epithelial cells | Deficient inhibition of LPS in intestine | Inflammatory bowel disease |
| TRIM22 | TRIM22 | AR | 606559 | Macrophages, intestinal epithelial cells | Granulomatous colitis | Inflammatory bowel disease |
| T-cell lymphoma subcutaneous panniculitis-like (TIM3 deficiency) | HAVCR2 | AR | 618398 | Leukocytes | Increased inflammasome activity due to defective checkpoint signaling | Panniculitis, HLH, polyclonal cutaneous T-cell infiltrates or T-cell lymphoma |
| C2orf69 deficiency (28 patients) | C2orf69 | AR | 619423 | Outer mitochondrial membrane of all cells | C2orf69 regulates mitochondrial function; protein deficiency causes respiratory chain defects | Early-onset severe autoinflammation disorder, often fatal. Global developmental delay, with recurrent seizures, muscle weakness due to glycogen deposits |
| SYK GOF | SYK | AD GOF | 619381 | Lymphocytes, osteoclasts | Increased SYK phosphorylation, enhanced NF-κB, JNK, and ERK signaling. Mutated T cells are hypersensitive to stimulation and produce various proinflammatory chemokines and cytokines (IL-17, IL-22, TNF, IFN-γ) | Recurrent infections, multi-organ inflammation/inflammatory disease (gut, skin, CNS, lung, liver), B-cell lymphoma reported in 2 pts |
| HCK GOF | HCK | AD GOF | 620296 | Lymphocytes | Increased kinase activity of HCK mutant in vitro; ↑ production of inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), ROS | Cutaneous vasculitis, inflammatory leukocyte infiltration of the lungs (pulmonary fibrosis) and skin, anemia, hepatosplenomegaly |
| NEMO exon 5 deletion | IKBKG | XL | 301081 | Leukocytes | Mutant NEMO lacks exon 5 (NEMO-Dex5), fails to bind TBK1; NEMO-Dex5 stabilized IKKi, strong NF-κB, and interferon gene expression signatures | Fever, skin rash, systemic autoinflammation, infections, CNS involvement, panniculitis, uveitis, hepatosplenomegaly, ectodermal dysplasia |
| TBK1 deficiency | TBK1 | AR | 620880 | Leukocytes | Autoinflammation driven by TNF-induced RIPK1-dependent cell death | Chronic systemic autoinflammation (polyarthritis, vasculitis, rash); delayed neurocognitive development |
| Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) | ALPK1 | AD | 614979 | Lymphocytes | Immune activation with increased NF-κB signaling, STAT1 phosphorylation, and interferon gene expression signature | Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache, fever, arthritis, colitis, dental abnormalities |
| LYN GOF Systemic autoinflammatory disease with vasculitis, SAIDV | LYN | AD GOF | 620376 | Endothelial cells and neutrophils | Activated endothelial cells, constitutively active neutrophils | Diffuse purpuric rash/atopic dermatitis, fever, hepatosplenomegaly, liver fibrosis/calcifications, arthritis, periorbital edema, respiratory insufficiency, colitis, poor growth |
| SHARPIN deficiency | SHARPIN | AR | 620795 | Impaired development of germinal centers in secondary lymphoid organs, low CD20+cells, increased memory B cells | Defect in LUBAC function, attenuated canonical NF-κB responses, increased TNF-induced cell death | Arthritis, fever, colitis, amylopectinosis |
| Disabling pansclerotic morphea of childhood | STAT4 | AD GOF | 620443 | Low CD4 T cells | Unstimulated fibroblasts produce high levels of IL-6 | Skin sclerosis, poor wound healing, joint contractures, mucosal ulcerations |
| Disease . | Genetic defect . | Inheritance . | OMIM . | Affected cells . | Functional defect . | Associated features . |
|---|---|---|---|---|---|---|
| 2. Defects affecting the inflammasome | ||||||
| Familial Mediterranean fever (FMF) | MEFV** | AR LOF | 249100 | Mature granulocytes, cytokine-activated monocytes | Increased pyrin inflammasome-mediated induction of IL-1β | Recurrent fever, serositis, and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease, SAA amyloidosis |
| AD | 134610 | Mature granulocytes, cytokine-activated monocytes | Usually, M694del variant. Other missense variants in the B-Box and CC domains cause constitutive pyrin activation | |||
| Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia, and hypercalprotectinemia | PSTPIP1 | AD | 604416 | PMNs, monocytes | Activation of the pyrin inflammasome; high production of IL-1 and IL-18 cytokines; interferon signature | Destructive arthritis, inflammatory skin rash, myositis |
| Mevalonate kinase deficiency (hyper-IgD syndrome/HIDS) | MVK | AR | 260920 | Somatic and hematopoietic | Defect in production of isoprenoids, which are synthesized via mevalonate pathway and play a role in regulation of many signaling pathways | Periodic fever and leukocytosis with usually high IgD levels |
| PMVK deficiency | PMVK | AR | NA | Leukocytes | Similar to MVK deficiency, increased IL-1β | Recurrent fever episodes, arthritis, and cytopenia |
| Muckle–Wells syndrome | NLRP3** | AD GOF | 191900 | PMNs Monocytes | Activation of cryopyrin inflammasome results in increased production of IL-1/IL-18 cytokines and cell death via pyroptosis | Urticaria, SNHL, SAA amyloidosis |
| Familial cold autoinflammatory syndrome 1 | AD GOF | 120100 | PMNs, monocytes | Nonpruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure | ||
| Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA) | AD GOF | 607115 | PMNs, chondrocytes | Neonatal-onset rash, chronic meningitis, and arthropathy with fever and inflammation | ||
| Keratitis fugax hereditaria associated with c.61G>C NLRP3 | AD GOF | 606416 | Episodic conjunctival injection, ocular pain, photophobia, foreign body sensation, and excessive tearing during acute attacks. Corneal opacities during attacks | |||
| Familial cold autoinflammatory syndrome 2 | NLRP12 | AD GOF | 611762 | PMNs, monocytes | Nonpruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure | |
| NLRC4-MAS (macrophage-activating syndrome) | NLRC4 | AD GOF | 616050 | PMNs, monocytes, macrophages, intestinal epithelial cells | GOF mutation in NLRC4 results in elevated secretion of IL-1β and IL-18, as well as macrophage activation | Severe enterocolitis and macrophage activation syndrome |
| Familial cold autoinflammatory syndrome 4 | 616115 | |||||
| APLAID or autoinflammation, antibody deficiency, and immune dysregulation | Missense variants PLCG2 Small intragenic deletions | AD GOF/LOF | 614878 | B cells, NK, mast cells | Mutations affect the autoinhibitory domains and activate NF-κB and MAPK pathways | Cold urticaria hypogammaglobulinemia, impaired humoral immunity, autoantibodies, autoinflammation, granulomas |
| PLAID or familial cold autoinflammatory syndrome 3 | 614468 | |||||
| Autoinflammation with arthritis and dyskeratosis (AIADK; NLRP1 deficiency) | NLRP1 | AR | 617388 | Keratinocytes and leukocytes | Systemic elevation of IL-18, IL-1β, caspase 1, suggesting activation of NLRP1 inflammasome | Dyskeratosis, autoimmunity, and arthritis |
| NLRP1 GOF | NLRP1 | AD GOF | 615225 | Keratinocytes | Spontaneous production of IL-1β and IL-18 cytokines in keratinocytes | Palmoplantar carcinoma, corneal scarring; recurrent respiratory papillomatosis |
| Autoinflammation with episodic fever and lymphadenopathy/cleavage-resistant RIPK1-induced autoinflammatory syndrome/CRIA | RIPK1 | AD | 618852 | Leukocytes and fibroblasts | TNF-induced cell death via apoptosis and necroptosis | Long-lasting fever episodes, lymphadenopathy, splenohepatomegaly, ulcers, arthralgia, GI features |
| Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome) | LPIN2 | AR | 609628 | Neutrophils, bone marrow cells | Dysregulation in cholesterol synthesis impairs the negative regulation of NLRP3 in macrophages resulting in high production of IL-1 | Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders |
| 3. Non-inflammasome–related conditions | ||||||
| TNF receptor–associated periodic syndrome (TRAPS) | TNFRSF1A** | AD | 142680 | PMNs, monocytes | Mutations in the extracellular domain of 55-kD TNF receptor cause protein misfolding and intracellular receptor retention resulting in upregulation of ER stress | Recurrent fever, serositis, rash, and ocular or joint inflammation |
| Blau syndrome | NOD2** | AD | 186580 | Monocytes, intestinal epithelial cells | Mutations in nucleotide binding site of CARD15 result in constitutive activation of NOD2 noadosome nd upregulation of NF-κB signaling | Uveitis, granulomatous synovitis, camptodactyly, rash, and cranial neuropathies; 30% develop Crohn’s colitis |
| ADAM17 deficiency | ADAM17 | AR | 614328 | Leukocytes and epithelial cells | Defective TNF-α production | Early-onset diarrhea and skin lesions |
| DIRA (deficiency of the interleukin-1 receptor antagonist) | IL1RN | AR | 612852 | PMNs, monocytes | Mutations in the IL-1 receptor antagonist allow unopposed action of IL-1α and IL-1β | Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis |
| Loss of IL-1R1 sensitivity to IL-Ra (LIRSA/CRMO3) (1 patient) | IL-1R1 | AD | 259680 | T cells and B cells | Activated myeloid cells. Loss of IL-1R1 biding to endogenous IL-Ra | Arthritis, osteolytic/sclerotic bone lesions, poor growth, no rash, no fever |
| DITRA (deficiency of IL-36 receptor antagonist) | IL36RN | AR | 614204 | Keratinocytes, leukocytes | Mutations in the IL-36 receptor antagonist allow unopposed action of IL-1α and IL-1β | Pustular psoriasis |
| Histiocytosis-lymphadenopathy plus syndrome/H syndrome (ENT3) | SLC29A3 | AR | 602782 | Leukocytes, histiocytes | Defect in nucleoside transport functions of hENT3 leads to histiocytic infiltration of numerous organs | Hyperpigmentation hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally hyperglycemia/diabetes mellitus |
| CAMPS (CARD14-mediated psoriasis) | CARD14 | AD | 602723 | Mainly in keratinocytes | Mutations in CARD14 activate the NF-κB pathway and production of IL-8 | Psoriasis |
| Cherubism | SH3BP2 | AD | 118400 | Stromal cells, bone cells | Hyperactivated macrophages and osteoclasts, increased NF-κB signaling | Bone degeneration in jaws |
| PRAAS-CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) | PSMB8* | AR and AD | 256040 | Keratinocytes, B-cell adipose cells | Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature | Contractures, panniculitis, ICC, fevers |
| PSMG2 | AR | 609702 | Lymphocytes | Panniculitis, lipodystrophy, autoimmune hemolytic anemia | ||
| PSMB10 | AR | 619175 | Lymphocytes | Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature | Periorbital and hand–foot annular rash (neutrophilic dermatosis), microcytic anemia, long slender fingers, hepatomegaly and splenomegaly | |
| PSMB9 | AR or digenic or DN | 617591 | Lymphocytes | Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature | ||
| PSMB4 | AR or digenic | 617591 | Lymphocytes | Proteasome dysfunction with accumulation of ubiquitinated proteins and ER stress. Increased interferon signature | Panniculitis, lipodystrophy, autoimmune hemolytic anemia | |
| PRAID | POMP | AD | 618048 | Lymphocytes | Increased accumulation of ubiquitinated proteins and ER stress with increased IFN signaling mediated by increased PKR signaling | CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)/ interstitial lung disease in one patient, liver disease in one patient. Recurrent and opportunistic infections. Low CD8 T cells, skewing toward naïve T cells. Low B cells and positive autoantibodies |
| PSMB9 deficiency (G156D) | PSMB9 | AD (DN LOF) | 617591 | Leukocytes (mild pancytopenia) | Decreased protein expression and reduced proteasome activities. Elevated levels of inflammatory cytokines (IL-6, IL-18, IP-10, IFN-α), liver enzymes in blood and CSF (IFN-α), hyperactivation of IFN-α, pSTAT1 | Severe autoinflammatory phenotype (neonatal-onset fever, skin rash, myositis, severe pulmonary hypertension, basal ganglia calcification), periodic inflammatory exacerbation; immunodeficiency. Partial phenocopy of PRAAS |
| Autoinflammation with neurodevelopmental disease | PSMD12 | AR | 617516 | CNS, lymphocytes | ↑ peripheral blood type I IFN gene signature has been reported for some patients | Intellectual disability, developmental delay, urticarial skin rash, elevated interferon signature |
| COPA syndrome | COPA | AD | 601924 | PMN and tissue-specific cells | Defective intracellular transport via the coat protein complex I (COPI). Exacerbated STING-mediated type I interferon response | Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production |
| Otulipenia/ORAS | OTULIN | AR/AD | 615712 | Leukocytes, fibroblasts | Increase LUBAC induction of NF-κB and interferon activation leading to high proinflammatory cytokine levels. Increase in TNF-induced cell death | Fever, diarrhea, skin abscesses, panniculitis |
| Dominant negative OTULIN-related autoinflammatory syndrome (3 patients) | OTULIN | AD | 615712 | Lymphocytes and fibroblasts | Decreased catalytic activity, accumulation of linear ubiquitin chains, increased TNF-induced cell death, | Spontaneous systemic inflammation |
| OTULIN haploinsufficiency | OTULIN | AD | 615712 | Epithelial cells | Increased activity of caveolin-1 stabilizes ADAM10 receptor for S. aureus toxin | Susceptibility to S. aureus infections in epithelial cells |
| Haploinsufficiency of A20/HA20 | TNFAIP3 | AD | 616744 | Lymphocytes | Defective inhibition of NF-κB signaling pathway | Arthralgia, mucosal ulcers, ocular inflammation |
| AP1S3 deficiency | AP1S3 | AR | 615781 | Keratinocytes | Disrupted TLR3 translocation | Pustular psoriasis |
| ALPI deficiency | ALPI | AR | 171740 | Intestinal epithelial cells | Deficient inhibition of LPS in intestine | Inflammatory bowel disease |
| TRIM22 | TRIM22 | AR | 606559 | Macrophages, intestinal epithelial cells | Granulomatous colitis | Inflammatory bowel disease |
| T-cell lymphoma subcutaneous panniculitis-like (TIM3 deficiency) | HAVCR2 | AR | 618398 | Leukocytes | Increased inflammasome activity due to defective checkpoint signaling | Panniculitis, HLH, polyclonal cutaneous T-cell infiltrates or T-cell lymphoma |
| C2orf69 deficiency (28 patients) | C2orf69 | AR | 619423 | Outer mitochondrial membrane of all cells | C2orf69 regulates mitochondrial function; protein deficiency causes respiratory chain defects | Early-onset severe autoinflammation disorder, often fatal. Global developmental delay, with recurrent seizures, muscle weakness due to glycogen deposits |
| SYK GOF | SYK | AD GOF | 619381 | Lymphocytes, osteoclasts | Increased SYK phosphorylation, enhanced NF-κB, JNK, and ERK signaling. Mutated T cells are hypersensitive to stimulation and produce various proinflammatory chemokines and cytokines (IL-17, IL-22, TNF, IFN-γ) | Recurrent infections, multi-organ inflammation/inflammatory disease (gut, skin, CNS, lung, liver), B-cell lymphoma reported in 2 pts |
| HCK GOF | HCK | AD GOF | 620296 | Lymphocytes | Increased kinase activity of HCK mutant in vitro; ↑ production of inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), ROS | Cutaneous vasculitis, inflammatory leukocyte infiltration of the lungs (pulmonary fibrosis) and skin, anemia, hepatosplenomegaly |
| NEMO exon 5 deletion | IKBKG | XL | 301081 | Leukocytes | Mutant NEMO lacks exon 5 (NEMO-Dex5), fails to bind TBK1; NEMO-Dex5 stabilized IKKi, strong NF-κB, and interferon gene expression signatures | Fever, skin rash, systemic autoinflammation, infections, CNS involvement, panniculitis, uveitis, hepatosplenomegaly, ectodermal dysplasia |
| TBK1 deficiency | TBK1 | AR | 620880 | Leukocytes | Autoinflammation driven by TNF-induced RIPK1-dependent cell death | Chronic systemic autoinflammation (polyarthritis, vasculitis, rash); delayed neurocognitive development |
| Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache (ROSAH) | ALPK1 | AD | 614979 | Lymphocytes | Immune activation with increased NF-κB signaling, STAT1 phosphorylation, and interferon gene expression signature | Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache, fever, arthritis, colitis, dental abnormalities |
| LYN GOF Systemic autoinflammatory disease with vasculitis, SAIDV | LYN | AD GOF | 620376 | Endothelial cells and neutrophils | Activated endothelial cells, constitutively active neutrophils | Diffuse purpuric rash/atopic dermatitis, fever, hepatosplenomegaly, liver fibrosis/calcifications, arthritis, periorbital edema, respiratory insufficiency, colitis, poor growth |
| SHARPIN deficiency | SHARPIN | AR | 620795 | Impaired development of germinal centers in secondary lymphoid organs, low CD20+cells, increased memory B cells | Defect in LUBAC function, attenuated canonical NF-κB responses, increased TNF-induced cell death | Arthritis, fever, colitis, amylopectinosis |
| Disabling pansclerotic morphea of childhood | STAT4 | AD GOF | 620443 | Low CD4 T cells | Unstimulated fibroblasts produce high levels of IL-6 | Skin sclerosis, poor wound healing, joint contractures, mucosal ulcerations |
IFN, interferon; HSM, hepatosplenomegaly; CSF, cerebrospinal fluid; SLE, systemic lupus erythematosus; TORCH, toxoplasmosis, other, rubella, cytomegalovirus, and herpes infections; SNHL, sensorineural hearing loss; AGS, Aicardi-Goutières syndrome; BSN, bilateral striatal necrosis; FCL, familial chilblain lupus; ICC, intracranial calcification; IFN, interferon type I; pDCs, plasmacytoid dendritic cells; SP, spastic paraparesis; SMS, Singleton–Merten syndrome; ss, single-stranded; ADA, adenosine deaminase; CNS, central nervous system; IBD, inflammatory bowel disease; autoAbs, autoantibodies.
* variants in PSMB4, PSMB9, PSMA3, and POMP have been proposed to cause a similar CANDLE phenotype in compound heterozygous monogenic (PSMB4), digenic (PSMA3/PSMB8, PSMB9/PSMB4, PSMB4/PSMB8), and AD monogenic (POMP) models (119). Only G156D mutation in PSMB9 has been shown to cause an autoinflammatory phenotype with immunodeficiency in patients and mouse model (120).
Total number of disorders in Table 7: 69.
New IEIs: 11, STAT4 GOF, PMVK, ALPK1, LYN GOF, SHARPIN, LSM11, RNU71, ARF1, OTULIN (two new entries), and RELA (84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94).
** depicts that somatic mutations mimicking the germline disorder have been described for this gene.
RELA previously described as causing combined immunodeficiency a second entry included here as DN mutations are associated with an inflammatory phenotype with different mechanism of disease. OTULIN is repeated three times as different mechanisms of disease give rise to different phenotypes. NLRP1 is also repeated twice as AR and AD forms result in different phenotypes.