Summary

Summary
Studies in single patients, such as the cases highlighted above, have paved the way for the establishment of a causal relationship between genotype and phenotype in autoinflammatory disease.1 Since the identification of MEFV and NLRP3 in the late 1990s, more than 30 genes have been discovered as the underlying etiology behind autoinflammatory disorders, with significant benefit from increasing access to next-generation sequencing. These disorders cover all aspects of genetics from dominant to recessive inheritance, X-linked, and somatic mosaicism.41 Understanding of the molecular pathways underlying these diseases has allowed for the creation of sub-categories of autoinflammatory disease including IL-1-mediated autoinflammatory diseases, interferon-mediated autoinflammatory diseases, autoinflammatory diseases caused by increased NF-κB signaling, and autoinflammatory diseases caused by persistent macrophage activation.5,8 Still, a substantial portion of patients remain unclassified.42,43 The cases above illustrate how careful clinical phenotyping and molecular genetic evaluations can guide the clinician towards an autoinflammatory diagnosis and targeted therapy.