title: Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis.
abstract: 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-kappaB 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-kappaB activity, which was defined as the ratio of NF-kappaB activity without a NOD2 ligand, muramyldipeptide, to NF-kappaB 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 ligand-independent NF-kappaB 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-kappaB 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.
  
  
  CONCLUSIONS
  NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.
authors.affiliation: Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Okafuji
authors.forename: Ryuta
authors.initials: R
authors.lastname: Nishikomori
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kanazawa
authors.forename: Naotomo
authors.initials: N
authors.lastname: Kambe
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fujisawa
authors.forename: Shin
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Megumu
authors.initials: M
authors.lastname: Saito
authors.forename: Takakazu
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kawai
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Sakai
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tanizaki
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Miyachi
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001168:Arthritis / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D011237:Predictive Value of Tests; D012507:Sarcoidosis / Q000235:genetics* / Q000503:physiopathology; D012871:Skin Diseases / Q000235:genetics* / Q000503:physiopathology; D013577:Syndrome; D014605:Uveitis / Q000235:genetics* / Q000503:physiopathology; D015354:Vision, Low / Q000235:genetics / Q000503:physiopathology; D055815:Young Adult
chemical_list: D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein