IEI with predominant rheumatologic manifestations
| Classification . | Clinical syndrome . | Rheumatologic/autoimmune manifestations . | Examples of genes identified . |
|---|---|---|---|
| Disorders of immune dysregulation | APECED | Chronic mucocutaneous candidiasis, hypoparathyroidism, primary adrenal insufficiency, diabetes mellitus, and JIA | AIRE |
| ALPS | Lymphoproliferation, lymphadenopathy, splenomegaly, and autoimmune cytopenias | FAS and FADD | |
| Tregopathies | IPEX (T1D, autoimmune enteropathy, eczema, dermatitis, alopecia, and psoriasis-like lesions) | FOXP3, CD25, STAT5B, LRBA, CTLA4, and DEF6 | |
| Multi-organ lymphocytic infiltration | |||
| T1D, hypoparathyroidism, and JIA | |||
| Disorders of cytokine signaling | T1D, cytopenias, SLE, lymphadenopathy, and multi-organ autoimmunity | STAT1, STAT3, STAT4, STAT6, JAK1, SOCS1, PTPN2, ISG15, and USP18 | |
| HLH | Fever, cytopenias, elevated ferritin, hypertriglyceridemia, and encephalitis | PRF1, STX11, STXBP2, and UNC13D | |
| Innate immune defects | Monogenic lupus | SLE | Complement genes, DNASE1, DNASE1L3, TLR7, and UNC93B1 |
| Disorders of complement regulators | Vasculopathies and aHUS | CFH (factor H), CFI (factor I), CD45 (membrane cofactor protein), and autoantibodies targeting factor H | |
| Autoinflammatory disorders | Interferonopathies | Severe neurologic findings | AGS (TREX1, RNAASEH2A, RNASEH2B, RNASEH2C, TREX1, ADAR, and IFIH1), COPA, STING1, and ADA2 |
| Skin manifestations (chilblain-like lesions) | |||
| Interstitial lung disease | |||
| Inflammasomopathies | Periodic fevers, peritonitis, synovitis, and pleuritis | MEFV (FMF), NLRP3, PLCG2, and NLRC4 | |
| Non-inflammasomopathy inflammatory disorders | Oral and genital ulcers, arthritis, erythema nodosum, recurrent fevers, and very early onset IBD | TNFRSF1A (TRAPS) TNFAIP3 (A20), RELA, and IKBKG | |
| VEXAS syndrome | Alveolitis, chondritis, thromboembolisms, dermatoses, and cutaneous vasculitis | UBA1 (somatic) |
| Classification . | Clinical syndrome . | Rheumatologic/autoimmune manifestations . | Examples of genes identified . |
|---|---|---|---|
| Disorders of immune dysregulation | APECED | Chronic mucocutaneous candidiasis, hypoparathyroidism, primary adrenal insufficiency, diabetes mellitus, and JIA | AIRE |
| ALPS | Lymphoproliferation, lymphadenopathy, splenomegaly, and autoimmune cytopenias | FAS and FADD | |
| Tregopathies | IPEX (T1D, autoimmune enteropathy, eczema, dermatitis, alopecia, and psoriasis-like lesions) | FOXP3, CD25, STAT5B, LRBA, CTLA4, and DEF6 | |
| Multi-organ lymphocytic infiltration | |||
| T1D, hypoparathyroidism, and JIA | |||
| Disorders of cytokine signaling | T1D, cytopenias, SLE, lymphadenopathy, and multi-organ autoimmunity | STAT1, STAT3, STAT4, STAT6, JAK1, SOCS1, PTPN2, ISG15, and USP18 | |
| HLH | Fever, cytopenias, elevated ferritin, hypertriglyceridemia, and encephalitis | PRF1, STX11, STXBP2, and UNC13D | |
| Innate immune defects | Monogenic lupus | SLE | Complement genes, DNASE1, DNASE1L3, TLR7, and UNC93B1 |
| Disorders of complement regulators | Vasculopathies and aHUS | CFH (factor H), CFI (factor I), CD45 (membrane cofactor protein), and autoantibodies targeting factor H | |
| Autoinflammatory disorders | Interferonopathies | Severe neurologic findings | AGS (TREX1, RNAASEH2A, RNASEH2B, RNASEH2C, TREX1, ADAR, and IFIH1), COPA, STING1, and ADA2 |
| Skin manifestations (chilblain-like lesions) | |||
| Interstitial lung disease | |||
| Inflammasomopathies | Periodic fevers, peritonitis, synovitis, and pleuritis | MEFV (FMF), NLRP3, PLCG2, and NLRC4 | |
| Non-inflammasomopathy inflammatory disorders | Oral and genital ulcers, arthritis, erythema nodosum, recurrent fevers, and very early onset IBD | TNFRSF1A (TRAPS) TNFAIP3 (A20), RELA, and IKBKG | |
| VEXAS syndrome | Alveolitis, chondritis, thromboembolisms, dermatoses, and cutaneous vasculitis | UBA1 (somatic) |
A summary of the major IEI that present with rheumatologic, autoimmune, and autoinflammatory conditions as their primary manifestations. FMF, familial Mediterranean fever; TRAPS, tumor necrosis factor receptor-associated periodic syndrome.