A Novel Pathogenic NOD2 Variant in a Mother and Daughter with Blau Syndrome

Blau syndrome (BS) is a rare dominantly-inherited autoinflammatory disorder characterized by the triad of arthritis, uveitis and dermatitis that is consequence of gain-of-function NOD2 mutations. We describe the clinical features and genetic basis of a family with two affected members in consecutive generations affected with childhood onset arthritis and uveitis.

Clinical features were retrospectively collected from clinical records. Genetic studies were performed using the Sanger method of DNA sequencing.

The proband is a 44 years-old female, who was diagnosed with juvenile onset arthritis at the age of 9 years. She subsequently developed uveitis at age 12 and since then she was managed between the uveitis and rheumatology services. The proband's daughter developed episcleritis at the age of 7 years, and arthritis with bilateral intermediate uveitis two years later. NOD2 analyses revealed in both patients the heterozygous c.1494A>C transversion, predicted to lead the novel, missense p.E498D variant in the NOD2 protein. Additional studies including databases searches and in silico bioinformatic predictions strongly support the "likely pathogenic" classification for this novel variant.

We report a novel pathogenic NOD2 variant in a multiplex family with clinical features compatible with the BS diagnosis. This condition is inherited as a dominant trait in its familial form and should be considered in patients with granulomatous uveitis in association with arthritis and/or dermatitis. Further insight into NOD2 variants and their downstream effects may have implications in the treatment of BS and other inflammatory granulomatous diseases.