BLAU SYNDROME. CLINICAL PRESENTATION IN A FAMILY CARRYING A NEW MUTATION ON THE CARD15 GENE

Background: Blau syndrome, a rare familial granulomatous condition affecting joints, eyes and skin has been quite recently linked to the presence of missense mutations in the nucleotide-binding domain (NBD) of CARD15 gene.Objectives: To report a previously unknown mutation of the CARD15 gene found in three members of a family, two of them initially diagnosed as having juvenile idiopathic arthritis (JIA) and lately diagnosed as Blau syndrome, and their different clinical history, at presentation and folow-up.Methods: All members of the family were screened for mutations in the 12 exons and intronic flanking sequences of CARD15 gene after the initiation of a severe uveitis in one of the two children suffering from, so called, systemic onset JIA. Clinical charts of the members of the family with relapsing fever and/or musculoskeletal symptoms were reviewed.Results: Patient 1. Relapsing fever began at the age of 4 yr. Two years later she developed soft, fixed, cystic swelling on the retromaleolar area and dorsum of the wrists, that responded quite well to local steroid injections but not to systemic medications (deflazacort, methotrexate); at the age of 10 yr. because of the persistance of the fever and the presence of a new cystic lesion on the palmar area of her right forearm, leflunomide was added to the previous treatment with only partial response. Three years later, she presented with a painful, red eye and a severe, bilateral, anterior, intermedia and posterior uveitis was found in ophtalmologic examination. Mofetil mycophenolate (MMF) abrogated all the systemic symptoms but no the musculoskeletal complains. Anakinra, however, was able to eliminate the fever and clearly decrease the tendon sheats inflammation. Genetic studies revealed the presence of a new missense mutation, R587C, in heterozygous state on the CARD15 gene, and the diagnosis of Blau syndrome was established. Patient 2 (older sister of patient 1). Symptoms began earlier in life, at the age of 21 months, with the same relapsing fever plus a more persistent articular component (knees, ankles and small joints of the hands). Cystic, soft lesions were also present. At the age of 12 yr. posterior sinequiae were found bilaterally, but she had not complained of any ocular symptom. Later on, systemic and articular components clearly worsened during the pre-menstrual days. At the age of 18 yr. she began to suffer from painful, skin plaque-like lesions, similar to those reported in the first description of the syndrome. She carries also the R587C mutation. Patient 3 (mother of patients 1 and 2). She is carrier of the same mutation. She recalls having a flare of skin plaque-like lesions three times in her life; after surgery for a suprarrenal adenoma, at the age of 40 yr., she developed persistent fever that needs continue steroid treatment for its control.Conclusion: Blau syndrome was the final diagnosis of the three patients once the genetic testing was performed. Reporting the features of this family, we would like to emphasize the enormous variety of the clinical presentation of this disease in patients carrying the same disease-associated mutation. Other genes still unknown as wells as environmental, hormonal or infectious factors must play a role in modulating its clinical expression.References: 1. Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr 1985;107:689-93.2. Miceli-Richard C., Lesage S., Prieur AM. et al. CARD15 mutations in Blau syndrome. Nature Gen 2001; 29:19-20.3. Becker ML, Rose CD. Blau syndrome and related genetic disorders causing childhood arthritis. Curr Rheumatol Rep 2005;7: 427-33.Citation: Ann Rheum Dis, volume 65, supplement II, year 2006, page 446Session: Paediatric rheumatology