Case Report

Blau Syndrome Mutation of CARD15/NOD2 in Sporadic Early Onset Granulomatous Arthritis

CARLOS D. ROSÉ, TRUDY M. DOYLE, GAIL McILVAIN-SIMPSON, JESSICA E. COFFMAN, JAMES T. ROSENBAUM, MICHAEL P. DAVEY, and TAMMY M. MARTIN

ABSTRACT.

Patients with sporadic early-onset granulomatous arthritis are clinically identical to Blau syndrome, but without the family history. Blau syndrome is an autosomal dominant inherited disease and is known to be caused by mutations in the CARD15 gene (also called NOD2). We investigated the hypothesis that an individual with sporadic early onset granulomatous arthritis may have a Blau syndrome mutation in CARD15/NOD2. Our patient's genomic DNA isolated from a buccal swab sample was subjected to amplification to include the region of exon 4 from the CARD15/NOD2 gene that contains known mutations that cause Blau syndrome. This region was screened for mutations by direct DNA sequencing in both directions. One of the mutations in CARD15/NOD2 attributed to Blau syndrome was found in the DNA sample. The nucleotide change encodes an amino acid substitution from arginine to tryptophan at position 334 of the protein. This mutation has been found in some Blau syndrome pedigrees reported in the literature. These data suggest that sporadic granulomatous arthritis may in fact be the sporadic form of Blau syndrome, but arising from a spontaneous neomutation. This would explain the profound clinical identity and the lack of disease history in the parents. (J Rheumatol 2005;32:373-5)

Key Indexing Terms:

SARCOIDOSIS
BLAU SYNDROME
CARD 15
ARTHRITIS
UVEITIS

---

From Thomas Jefferson University, duPont Children's Hospital, Wilmington, Delaware; Department of Ophthalmology, Casey Eye Institute; Department of Molecular Microbiology and Immunology; Division of Rheumatology, Department of Medicine; Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon; and Department of Veterans Affairs Medical Center, Portland, Oregon, USA.

Supported by a Research to Prevent Blindness Career Development Award (Dr. Martin); a Research to Prevent Blindness Senior Scholar Award (Dr. Rosenbaum); Research to Prevent Blindness (Casey Eye Institute); the Rosenfeld Family Trust (Dr. Rosenbaum); and the National Institutes of Health, grant EY13139 (Dr. Martin).

C.D. Rosé, MD, CIP, Director, Pediatric Rheumatology, du Pont Children's Hospital, Professor of Pediatrics, Thomas Jefferson University; T.M. Doyle, BS, Senior Research Assistant, Casey Eye Institute; G.M. Simpson, APN, Clinical Nurse Specialist; J.E. Coffman, BS, Research Assistant, Casey Eye Institute; J.T. Rosenbaum, MD, Professor of Ophthalmology, Medicine and Cell and Developmental Biology, Chief, Division of Arthritis and Rheumatic Diseases, Oregon Health and Science University; M.P. Davey, MD, PhD, Associate Chief of Staff/R&D, Portland VAMC, Professor of Medicine and Molecular Microbiology and Immunology, Oregon Health and Science University; T.M. Martin, PhD, Research Assistant Professor, Casey Eye Institute, Department of Molecular Microbiology and Immunology, Oregon Health and Science University.

Address reprint requests to Dr. C.D. Rosé, Division of Rheumatology, duPont Children's Hospital, 1600 Rockland Road, Wilmington, DE 19899. E-mail: crose@nemours.org

Submitted January 19, 2004; revision accepted September 16, 2004.

---