TBXAS1 deficiency: a novel monogenic cause of chronic nonbacterial osteomyelitis responsive to COX inhibitors

BACKGROUND: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease characterized by sterile bone inflammation. While monogenic causes are rare and typically present with early-onset, distinct skin or lytic bone lesions, the contribution of COX-pathway genes remains underexplored. TBXAS1 gene variants are classically associated with Ghosal hematodiaphyseal dysplasia (GHDD), which causes osteosclerosis and hematologic abnormalities. RESEARCH DESIGN AND METHODS: In this single-center, cross-sectional study, whole-exome sequencing first revealed the TBXAS1 variants in the index case, a 6-year-old boy with multifocal CNO and good clinical response to NSAIDs. Afterward, we performed next-generation sequencing (NGS) of the TBXAS1 gene in a single-center CNO cohort. RESULTS: Among 16 patients within the CNO cohort, NGS revealed two siblings with the same variants who were also presented with CNO, but without signs of osteosclerosis or hematologic involvement. CONCLUSIONS: These findings suggest a potential link between TBXAS1 deficiency and a distinct, milder CNO phenotype potentially mediated by the COX pathway. However, it remains uncertain whether TBXAS1 mutations define a new CNO subtype or represent an attenuated form of GHDD. Further functional and genetic studies targeting COX-pathway-related genes are needed to clarify the role of TBXAS1 in the pathogenesis of CNO and to identify novel disease mechanisms.