Early-onset sarcoidosis (EOS) and inheritable Blau syndrome (BS) share characteristic clinical features of juvenile-onset systemic granulomatosis syndrome that mainly affects skin, joints, and eyes. However, no direct evidence has been shown for the possible common origin of these 2 diseases. Recent discovery of CARD15 mutations in BS families encouraged us to investigate similar CARD15 mutations in EOS patients. Among 10 EOS cases retrospectively collected in Japan, heterozygous missense mutations were found in 9 cases; 4 showed a 1000C>T (R334W in amino acid change) that has been reported in BS, 4 showed novel 1487A>T (H496L) , IntroductionSarcoidosis is a multiorganic inflammatory disease with unknown etiology, characterized by the histologic features of noncaseating epithelioid granulomas. In childhood, 2 distinct types of sarcoidosis have been described. 1 Usually the disease is detected in older children by chest radiography and the clinical manifestations are characterized by a classical triad of lung, lymph node, and eye involvement, similar to those in adults. In contrast, early-onset sarcoidosis (EOS), which usually appears in those younger than 4 years of age, is quite rare and has a distinct triad of skin, joint, and eye disorders, without apparent pulmonary involvement. Compared with an asymptomatic and sometimes naturally disappearing course of the disease in older children, EOS is progressive and in many cases causes severe complications, such as blindness, joint destruction, and visceral involvement. 2 Blau syndrome (BS), also showing early-onset granulomatous arthritis, uveitis, and skin rash, is a rare familial disease transmitted in an autosomal dominant manner. 3 By linkage analysis, the responsible locus for BS was mapped to chromosome 16,4 in which CARD15 has recently been identified as the susceptibility gene. 5 CARD15 (NOD2) is a member of the growing family of nucleotide-binding oligomerization domain (NOD) proteins and composed of 2 amino-terminal caspase recruitment domains (CARDs), one NOD, and carboxy-terminal leucinerich repeats (LRRs). 6,7 While mutations in LRRs are reportedly associated with Crohn disease (CD) and psoriatic arthritis, 8-10 3 types of missense point mutations in the NOD, 1000CϾT (R334W in amino acid change), 1001GϾA (R334Q), and 1405CϾT (L469F), have been discovered in BS families. 5,11,12 It has been discussed since the first report of BS whether EOS and BS are the same diseases. 13 However, no direct evidence of their common origin has been shown and confusion still remains. 14 In the first paper describing genetic abnormalities in BS, the authors recognized no CARD15 mutation in 2 EOS patients and therefore proposed a different etiology of BS and EOS. 5 However, we have recently described a sporadic case of systemic granulomatosis syndrome with clinical features of EOS that showed the same CARD15 mutation as detected in BS. 15 In this report, therefore, we retrospectively collected Japanese EOS cases and searched for CARD15 mutations, to further evaluate the re...

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Objective. Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-B activity predict the Blau syndrome/ EOS clinical phenotype.Methods. Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-B activity, which was defined as the ratio of NF-B activity without a NOD2 ligand, muramyldipeptide, to NF-B activity with muramyldipeptide.Results. All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligandindependent NF-B activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-B activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment.

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the coldinduced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in "mutation-negative" patients, due to a low frequency of mosaicism. To determine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutationnegative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients. (Blood. 2008;111: 2132-2141)

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