They are associated with inflammatory diseases such as Crohn's disease and Blau syndrome
. In one of our reported cases (case 9), we observed a NOD2 mutation associated with fever of unknown origin, which has not been reported in the literature.
The diseases described in this scope include FMF, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD-HIDS), NLRP12- related syndrome (NLRP12AD), Blau syndrome, pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPAs), early-onset sarcoidosis (EOS), Majeed syndrome (MS), interleukin-1 receptor antagonist deficiency (DIRA), cryopyrin associated periodic syndromes (CAPS), IL-36 receptor antagonist deficiency (DITRA), CARD14-mediated pustular psoriasis (CAMPS) and chronic atypical neutrophilic dermatosis, lypodistrophy, and elevated temperature (CANDLE).
Blau syndrome is a rare autosomal dominant, autoin-flammatory disease that predominantly occurs in Caucasians and is characterized by granulomatous recurrent uveitis, dermatitis, and symmetrical arthritis.
Next-generation sequencing was performed for the remaining two patients; an NOD2 mutation was observed in one of these patients and Blau syndrome was diagnosed instead of CAPS in this patient (25).
Caveats and truths in genetic, clinical, autoimmune and autoinflammatory issues in Blau syndrome
and early onset sarcoidosis.
Blau syndrome (BS), first reported in 1985 as "juvenile systemic granulomatosis," is a rare autosomal-dominant disease caused by NOD2/CARD15 gene mutations; the gene was individuated in 2001 on the locus 16q12.1-13, which also contains the genetic susceptibility region for Crohn's disease and early-onset sarcoidosis (EOS) [70, 71], and codifies for NOD2, a sensor of bacterial antigens which induces NF-[kappa]B activation .
Rybojad et al., "CARD15 mutations in Blau syndrome," Nature Genetics, vol.
To date, there are twelve known MAISs: familial Mediterranean fever (FMF); tumor necrosis factor receptor-associated periodic syndrome (TRAPS); cryopyrin-associated periodic syndrome (CAPS), a group which includes familial cold urticaria syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurological cutaneous articular (CINCA) syndrome; mevalonate kinase deficiency (MKD); NLRP12-associated autoinflammatory disorder (NLRP12AD); granulomatous MAISs which include Blau syndrome (BS) and early-onset sarcoidosis (EOS); and, finally, the hereditary pyogenic disorders including PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, Majeed syndrome (MS), and deficiency of the IL-1 receptor antagonist (DIRA).
Granulomatous autoinflammatory diseases include Blau syndrome (BS, OMIM 186580) and early-onset sarcoidosis (EOS, OMIM 609464); both are caused by mutations in the NOD2/CARD15 gene, with subsequent dysregulation of the inflammatory response and formation of noncaseous granulomas (Table 1) .
Punzi, "Blau syndrome, clinical and genetic aspects," Autoimmunity Reviews, vol.
Podswiadek et al., "Clinical and genetic aspects of Blau syndrome: a 25-year follow-up of one family and a literature review," Autoimmunity Reviews, vol.