SUMMARY
1. Blau Syndrome is an autosomal dominant disease resulting in granulomatous inflammation of the skin, eyes, joints, and visceral organs. The onset of clinical symptoms typically occurs before 5 years of age and includes the following:
Dermatitis
Arthritis
Uveitis
Additional clinical findings may include fever, cranial neuropathies, vasculitis, and liver/lymph node granulomas.
2. Blau syndrome is caused by dominant mutations in the CARD15 (also known as NOD2) gene. The mutations occur in the NACTH region of CARD15 resulting in a gain of function for the CARD15 protein this appears to result in increased NF-kB activity and an exaggerated inflammatory response.
3. The diagnosis is made based on classic clinical criteria. The demonstration of granulomatous inflammation on synovial or skin biopsies may be useful. Sequencing of the CARD15 (NOD2) gene can confirm the diagnosis.
4. The mainstay of therapy is treatment with corticosteroids. Clinical efficacy with anti-TNF alpha therapy has been reported. The use of IL-1 blocking agents (anakinra) has not been effective.
OVERVIEW
Blau Syndrome is an autosomal dominant disease resulting in granulomatous inflammation of the skin, eyes, joints, and visceral organs. The onset of clinical symptoms typically occurs before 5 years of age and includes the following:
-Dermatitis This consists of small papules or tan-colored, scaly, ichthyosiform rash (88% of patients). An erythema nodosum-like rash may also develop.
-Arthritis Polyarticular synovitis (96% of patients) resulting in joint swelling and progressive flexion contractures of the fingers (camptodactyly). Biopsy may reveal synovial granulomas.
-Uveitis Approximately one-third of patients develop granulomatous uveitis which can lead to glaucoma, cataracts, and blindness.
-Additional clinical findings may include fever, cranial neuropathies, vasculitis, and liver/lymph node granulomas.
PATHOGENESIS
Blau syndrome is caused by dominant mutations in the CARD15 (also known as NOD2) gene. The mutations occur in the NACTH region of CARD15 resulting in a gain of function for the CARD15 protein this appears to result in increased NF-kB activity and an exaggerated inflammatory response. Mutations in the same gene have also been associated with Crohns disease (although the mutations occur in the leucine rich repeat region which leads to a loss of function of the protein product).
EVALUATION
The diagnosis should be suspected in young children with the classic clinical triad of dermatitis, arthritis, and uveitis.
Step 1: Screening studies
-
-C reactive protein / Erythrocyte sedimentation rate
-Tissue Biopsy
-Eye Exam
-CRP and ESR may be elevated
-Granulomatous inflammation may be evident on skin or synovial biopsy
-An eye exam should be performed to assess patients for uveitis
Step 2: Genetic Confirmation
-CARD15 (NOD2) gene sequencing
-This is the definitive test for establishing a diagnosis of Blau syndrome. Sequencing for this gene is currently commercially available. The R334W and R334Q mutations are the most common.
MANAGEMENT
The mainstay of therapy is treatment with corticosteroids. Clinical efficacy with anti-TNF alpha therapy has been reported. The use of IL-1 blocking agents (anakinra) has not been effective.
RESOURCES
Diagnostic Resources
1. ST.FRANCIS - CARD15, NOD2 gene sequencing
Literature Resources
1. Rose 2006
Pediatric granulomatous arthritis international registry