Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis.

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. CONCLUSION NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.

[1]  J. Yagüe,et al.  NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. , 2007, Arthritis and rheumatism.

[2]  C. Rosé,et al.  Interstitial pneumonitis in Blau syndrome with documented mutation in CARD15. , 2007, Arthritis and rheumatism.

[3]  H. Fledelius,et al.  Favourable effect of TNF‐α inhibitor (infliximab) on Blau syndrome in monozygotic twins with a de novoCARD15 mutation , 2006, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[4]  C. Wouters,et al.  Pediatric granulomatous arthritis: an international registry. , 2006, Arthritis and rheumatism.

[5]  F. Martinon,et al.  Gout-associated uric acid crystals activate the NALP3 inflammasome , 2006, Nature.

[6]  J. Rosenbaum,et al.  Blau syndrome mutation of CARD15/NOD2 in sporadic early onset granulomatous arthritis. , 2005, The Journal of rheumatology.

[7]  S. Resnikoff,et al.  Global data on visual impairment in the year 2002. , 2004, Bulletin of the World Health Organization.

[8]  A. Utani,et al.  Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. , 2004, Blood.

[9]  S. Nagai,et al.  Presence of a sporadic case of systemic granulomatosis syndrome with a CARD15 mutation. , 2004, The Journal of investigative dermatology.

[10]  P. Murray,et al.  Role of Nod2 in the Response of Macrophages to Toll-Like Receptor Agonists , 2003, Molecular and Cellular Biology.

[11]  N. Yoshimura,et al.  Ocular manifestations in Blau syndrome associated with a CARD15/Nod2 mutation. , 2003, Ophthalmology.

[12]  E. Mallon,et al.  Juvenile sarcoidosis after BCG vaccination. , 2003, Journal of the American Academy of Dermatology.

[13]  M. Chamaillard,et al.  Nod2 Is a General Sensor of Peptidoglycan through Muramyl Dipeptide (MDP) Detection* , 2003, The Journal of Biological Chemistry.

[14]  J. Hugot,et al.  Gene–environment interaction modulated by allelic heterogeneity in inflammatory diseases , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[15]  S. Foster,et al.  Host Recognition of Bacterial Muramyl Dipeptide Mediated through NOD2 , 2003, The Journal of Biological Chemistry.

[16]  G. Thomas,et al.  CARD15 mutations in Blau syndrome , 2001, Nature Genetics.

[17]  Mourad Sahbatou,et al.  Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease , 2001, Nature.

[18]  Judy H. Cho,et al.  A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease , 2001, Nature.

[19]  S. Yamaoka,et al.  Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κB* , 2001, The Journal of Biological Chemistry.

[20]  K. Miyata,et al.  Early onset sarcoidosis masquerading as juvenile rheumatoid arthritis. , 2000, Journal of the American Academy of Dermatology.

[21]  R. Petty,et al.  Overview and report on international registry of sarcoid arthritis in childhood , 2000, Current rheumatology reports.

[22]  U. Wolf Identical mutations and phenotypic variation , 1997, Human Genetics.

[23]  S. Miyagawa,et al.  Preschool sarcoidosis mimicking juvenile rheumatoid arthritis: The significance of gallium scintigraphy and skin biopsy in the differential diagnosis , 1997, Acta paediatrica Japonica : Overseas edition.

[24]  S. Targan,et al.  Susceptibility locus for inflammatory bowel disease on chromosome 16 has a role in Crohn's disease, but not in ulcerative colitis. , 1996, Human molecular genetics.

[25]  H. Tsutsumi,et al.  Preschool sarcoidosis manifesting as juvenile rheumatoid arthritis: A case report and a review of the literature of Japanese cases , 1994, Acta paediatrica Japonica : Overseas edition.

[26]  A. Mccormick,et al.  Vasculopathy with renal artery stenosis in a child with sarcoidosis. , 1986, The Journal of pediatrics.

[27]  E. Blau Familial granulomatous arthritis, iritis, and rash. , 1985, The Journal of pediatrics.

[28]  F. Arnett,et al.  Familial granulomatous synovitis, uveitis, and cranial neuropathies. , 1985, The American journal of medicine.

[29]  B. Majmudar,et al.  Familial granulomatous arteritis with polyarthritis of juvenile onset. , 1982, The New England journal of medicine.

[30]  C. Fink,et al.  Sarcoid arthritis in children. , 1970, The American journal of medicine.

[31]  C. Fink,et al.  Early onset sarcoidosis: not a benign disease. , 1997, The Journal of rheumatology.

[32]  B. Athreya,et al.  Early onset sarcoidosis with aortitis--"juvenile systemic granulomatosis?". , 1990, The Journal of rheumatology.

[33]  S. Hetherington Sarcoidosis in young children. , 1982, American journal of diseases of children.