Genetics, physiopathology and therapeutic options in a novel monogenic multisystem inflammatory disorder due to DNAse II deficiency

From birth, we have taken care of a child, now aged 16, for a severe and complicated disease, which began with liver damage, followed by episodes of inflammatory fever, arthritis and progressive kidney damage. All taken together, the symptoms did not suggest any known diagnosis, so the child was treated for the disease that better matched his symptoms. Unfortunately, response to drugs resulted always unsatisfactory. So, it was thought that he might have a rare genetic disorder, such as an "autoinflammatory" disease or a genetic form of Systemic Lupus Erythematosus: however, candidate genes for these diseases, analysed in the "traditional" way, resulted normal. Thanks to a new technology of DNA analysis, it was possible to analyse all the genes of the patient. With this, we found a defect in a protein called DNase2, involved in removal of useless or harmful DNA originate from self damaged cells. This defect causes an accumulation of DNA that is recognized as hazardous by the immune system that tries to eliminate it, similarly to what happen with viral DNA. However, in this case there is no infection to eradicate, but a continuous accumulation of self-DNA that enhances the disease. On one hand, with this research we aim to better understand the mechanisms of this disease in order to identify a possible treatment. On the other hand, we aim to evaluate candidate drugs by understanding the mechanisms of action and testing their effectiveness in vitro, before proposing their clinical use. The expertise acquired will be also useful for other children who develop, early in life, multiple episodes of inflammation with worsening trend that, so far, would be orphans of diagnosis and then of specific therapies.