Bone Abstracts

Objectives: Hajdu–Cheney syndrome (HCS) is an ultra-rare, genetic bone disease caused by mutations in the NOTCH2 gene. HCS is characterised by dysmorphic features, acroosteolysis, and high turnover osteoporosis. Sparse evidence in adult HCS suggests increased BMD and reduced bone turnover during bisphosphonate (BP) therapy. A single paediatric case report indicated beneficial effects of i.v. pamidronate therapy. We present four paediatric patients with HCS, their bone histomorphometric and bone geometric characteristics, and their response to BP therapy.

Methods: Four children with HCS (one female and three males), presented to endocrinologists with severe osteoporosis at the ages of 6.5, 10, 14.5, and 15.5 years. Iliac crest bone biopsies and peripheral quantitative computed tomography (pQCT) were available in two subjects. Their response to various BP therapy regimens (pamidronate, zoledronic acid, and alendronate) was monitored using DXA (n=4) and forearm pQCT (n=2), over 2–3.5 years of continuous treatment.

Results: All children had sporadic mutations and demonstrated typical phenotypic characteristics of HCS but also features not previously described such as delayed puberty, intestinal malrotation, and hip acetabular dysplasia. Histomorphometric results demonstrated increased amount of trabecular bone and increased bone turnover, with normal bone formation indices. pQCT revealed normal trabecular density but very low cortical density Z-scores (−4.3; −4.9), which increased during i.v. BP therapy. In addition, after 1 year of therapy, median size-corrected lumbar spine BMD Z-scores increased from −1.328 to −1.013.

Conclusion: Increased trabecular bone volume and bone turnover, normal bone formation, and low cortical density were characteristic features in our HCS cohort. These features are consistent with the effect of activating NOTCH2 mutations which cause osteoblast proliferation, as well as increased osteoclastogenesis. I.v. BP therapy increased size-corrected lumbar spine BMD and radial cortical density, which provides evidence of beneficial effects in children with HCS. Whether acroosteolysis can be improved with BP therapy remains to be elucidated.

This research was supported (in part) by the Intramural Research Program of the NIH, NIDCR.

Disclosure: The authors declared no competing interests.