Bone structural characteristics and response to bisphosphonate treatment in children with Hajdu-Cheney syndrome

Sakka, Sophia, Gafni, Rachel I., Davies, Justin H., Clarke, Bart, Tebben, Peter, Samuels, Mark, Saraff, Vrinda, Klaushofer, Klaus, Fratzl-zelman, Nadja, Roschger, Paul, Rauch, Frank and Högler, Wolfgang (2017) Bone structural characteristics and response to bisphosphonate treatment in children with Hajdu-Cheney syndrome. The Journal of Clinical Endocrinology & Metabolism, 102 (11), 4163-4172. (doi:10.1210/jc.2017-01102).

Abstract

Context
Hajdu-Cheney syndrome (HJCYS) is a rare, multisystem bone disease caused by heterozygous mutations in the NOTCH2 gene. Histomorphometric and bone ultrastructural analyses in children have not been reported and sparse evidence exists on response to bisphosphonate (BP) therapy.

Objective
To investigate clinical and bone histomorphometric characteristics, bone matrix mineralization, and the response of bone geometry and density to BP therapy.

Patients
Five children with HJCYS (three males) between 6.7 and 15.3 years of age.

Interventions
Various BP regimens (pamidronate, zoledronic acid, and alendronate) were used for between 1 and 10 years.

Main Outcome Measures
Pretreatment transiliac bone biopsy specimens and peripheral quantitative computed tomography results were available in four and three subjects, respectively. Bone histomorphometry and quantitative backscattered electron imaging were performed in two patients. The response to BP was monitored using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography.

Results
Three patients had previously unreported NOTCH2 mutations. Histomorphometry demonstrated increased bone resorption and osteoclast numbers, increased heterogeneity of mineralization, and immature, woven bone. Trabecular bone formation was normal or elevated. Radius cortical thickness and density and lumbar spine bone mineral density were reduced at baseline and increased in response to BP therapy, which was not sustained after therapy discontinuation.

Conclusions
Increased bone resorption and low cortical thickness are consistent with the effect of activating NOTCH2 mutations, which stimulate osteoclastogenesis. The increase in lumbar spine bone density and radial cortical thickness and density by BP therapy provides evidence of beneficial treatment effects in children with HJCYS.

This record has no associated files available for download.

Contributors

Download statistics