Metabolomics Study Identifies Potential Biomarkers for Craniometaphyseal Dysplasia

Changes in purine and lipid metabolism may provide leads for biomarkers of craniometaphyseal dysplasia (CMD), according to research presented at the American Society for Bone and Mineral Research (ASBMR) 2026 meeting. The investigators examined urine from patients and serum from 2 mouse models. The findings identify lipid dysregulation as a previously unrecognized component of CMD, but the proposed biomarkers have not been validated for clinical use.

CMD is a rare genetic disorder marked by progressive thickening of craniofacial bones and flaring of the metaphyses of long bones. An autosomal dominant form involves mutations in ANKH, while an autosomal recessive form involves mutations in GJA1, which encodes connexin 43. The investigators had previously found increased energy expenditure in mouse models of both forms, prompting them to examine whether circulating metabolites differed as well.

The researchers performed untargeted metabolomics on serum from 8-week-old AnkKI/KI mice and wild-type littermates (8 to 10 per group), as well as 5- to 6-month-old Cx43KI/KI mice and wild-type littermates (10 to 14 per group). Both sexes were included. They also analyzed urine from 18 patients with CMD (aged 2 to 57 years) and 13 healthy controls (aged 14 to 71 years).

In AnkKI/KI mice, purine metabolism was the most significantly affected pathway. ADP and dGDP were decreased, while guanosine, inosine, and hypoxanthine were increased. In Cx43KI/KI mice, the affected pathways included linolenic acid metabolism, phospholipid biosynthesis, and sphingolipid metabolism.

The investigators also found decreased levels of several metabolites involved in sphingolipid metabolism in patients with CMD, alongside altered purine metabolism. Additional analyses supported the mouse findings on lipid dysregulation: serum lipidomics showed altered lipid metabolism, osmium staining showed increased bone marrow fat, and bone marrow-derived adipocyte cultures from both mouse models showed increased adipogenesis.

The authors concluded that byproducts of purine and lipid metabolism may serve as CMD biomarkers. Further work is needed to establish whether specific metabolites can reliably identify CMD.

Reference

Washitani K, Hatori A, Fujii Y, Reichenberger EJ, Chen IP. Identification of biomarkers for craniometaphyseal dysplasia by metabolomics studies in humans and mice. ASBMR 2026 Annual Meeting; October 9-12, 2026; Boston, MA. Accessed October 7, 2026. https://eppro01.ativ.me/web/index.php?page=Session&project=ASBMR26&id=p9278-487