NOD2 – Blau syndrome

Blau syndrome is a rare autosomal dominant granulomatous autoinflammatory disorder characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis and recurrent uveitis. Onset typically occurs in early childhood and may include fever, hepatosplenomegaly and camptodactyly. NOD2 (CARD15) gain-of-function mutations have been consistently identified as the genetic cause, resulting in constitutive NF-κB activation and granuloma formation. These findings support the use of NOD2 sequencing in the differential diagnosis of early-onset sarcoidosis and juvenile uveitis.

In total, 136 affected individuals from 28 families and 4 sporadic cases have been reported to carry heterozygous NOD2 variants in exon 4, demonstrating autosomal dominant inheritance with full segregation in familial cases (PMID:18718560). De novo mutations account for several sporadic presentations, with R334Q (c.920G>A (p.Arg307Gln)) and R334W (c.919C>T (p.Arg307Trp)) being recurrent hotspots across multiple ethnicities.

The variant spectrum in Blau syndrome comprises predominantly missense substitutions affecting the central nucleotide-binding domain and adjacent helical regions. Key pathogenic alleles include c.920G>A (p.Arg307Gln), c.919C>T (p.Arg307Trp) and c.1406A>T (p.His469Leu), all of which disrupt intramolecular autoinhibition and lead to ligand-independent receptor activation. Rare splice-site and frameshift mutations have also been described, further broadening the allelic heterogeneity.

Functional assays in patient-derived cells and transfected HEK293 systems reveal that Blau-associated NOD2 variants confer constitutive NF-κB signaling, heightened IL-1β and IL-6 secretion, and exaggerated responses to muramyl dipeptide. In vivo, knock-in murine models of the 1007fs‐insC variant recapitulate the multisystem granulomatous pathology, confirming a gain-of-function mechanism (PMID:15459013).

Phenotypic expansion beyond the classic triad includes hepatic granulomas, renal involvement, large-vessel arteritis and central nervous system granulomata. Recognition of these atypical features is crucial for timely genetic testing and targeted therapy, including anti-TNF and IL-1 blockade.

Overall, NOD2 sequencing yields a definitive molecular diagnosis in >90% of patients with the Blau phenotype, enabling genetic counseling, early initiation of biologics and prevention of vision loss and joint deformities. Identification of somatic mosaicism in gonosomal cases further informs recurrence risk and prenatal testing strategies.

Key Take-home: Testing for NOD2 exon 4 variants is essential in children with unexplained granulomatous dermatitis, arthritis and uveitis, as it directly informs prognosis, family counseling and personalized treatment.

References

• Nature genetics • 2001 • CARD15 mutations in Blau syndrome. PMID:11528384
• Blood • 2005 • Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. PMID:15459013
• Autoimmunity reviews • 2009 • Clinical and genetic aspects of Blau syndrome: a 25-year follow-up of one family and a literature review. PMID:18718560
• Rheumatology (Oxford, England) • 2015 • Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes. PMID:25416713

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