Clinical features of Blau syndrome and early-onset sarcoidosis and associating CARD15/NOD2 gene mutations

Abstract

Sarcoidosis is a systemic inflammatory disease clinically characterized by swelling of bilateral hilar lymph nodes and histologically defined by non-caseating epithelioid cell granulomas. Among child cases, a special subtype, called the early-onset sarcoidosis, is known to appear in children younger than 4 years of age and to be characterized by a distinct triad of skin, joint and eye disorders without pulmonary involvement. On the other hand, autosomal dominantly-transmitted disease with a characteristic features similar to those of early-onset sarcoidosis has been reported as Blau syndrome. By a linkage analysis, the responsible gene for Blau syndrome has been mapped close to the IBD (Inflammatory Bowel Disease) 1 locus. After CARD15 (NOD2), originally identified as the susceptibility gene for Crohn's disease, was also proved to be responsible for Blau syndrome, the same gene mutations have been found in sporadic early-onset sarcoidosis cases. Nod2 recognizes a signal from bacterial cell wall component in the cytoplasm of monocytic cells to activate NF-kappaB, and thus can work as an intracellular sensor of bacteria. While the loss-of-function mutations in its LRR domain are associated with Crohn's disease, Blau syndrome and early-onset sarcoidosis are autoinflammatory diseases that are caused by the gain-of-function mutations in its NOD domain.