Newly recognized Mendelian disorders with rheumatic manifestations

We review newly discovered monogenic immune-dysregulatory disorders that were reported in Pubmed over the last year.

Fourteen novel monogenic immune-dysregulatory disorders that present with innate and acquired/adaptive immune dysregulation and inflammatory clinical phenotypes were identified. These include autosomal-dominant gain-of function mutations in viral innate immune sensors or their adaptors, TMEM173/STING IFIH1/MDA5 and DDX58/RIG-I that cause complex clinical syndromes distinct from IL-1-mediated diseases and present with a chronic type I interferon (IFN Type I) signature in peripheral blood. Gain-of-function mutations in NLRC4 add a novel inflammasome disorder associated with predisposition to macrophage-activation syndrome and highly elevated IL-18 levels. Mutations in ADA2, TRNT1 and COPA, AP1S3, and TNFRSF11A cause complex syndromes; loss-of-function mutations in enzymes and molecules are linked to the generation of 'cellular stress' and the release of inflammatory mediators that likely cause the inflammatory disease manifestations. A monogenic form of systemic-onset juvenile idiopathic arthritis is caused by homozygous mutations in LACC1. Lastly, mutations in PRKDC (recessive), STAT3, CTLA4, and PIK3R1 (all dominant) lead to impaired central and peripheral T-cell tolerance and present with variable disease manifestations of immunodeficiency and immune dysregulation/autoimmunity.

A number of novel monogenic diseases that present with innate and/or acquired immune dysregulation reveal novel immune pathways that cause human inflammatory diseases and suggest potential novel targets for treatment.