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.