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

Sophia Sakka, Rachel I Gafni, Justin Davies, Bart Clarke, Peter Tebben, Mark Samuels, Vrinda Saraff, Klaus Klaushofer, Nadja Fratzl-Zelman, Paul Roschger, Frank Rauch, Wolfgang Högler

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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 (3 males) aged between 6.7 and 15.3 years.
Interventions: Various BP regimens (pamidronate, zoledronic acid, alendronate) were used for between one and ten years.

Main Outcome Measures: Pre-treatment transiliac bone biopsy specimens and peripheral quantitative computed tomography (pQCT) 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 pQCT.

Results: Three patients had novel 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.

Précis: High resorption, heterogenous mineralization, woven bone and low cortical thickness are characteristic of HJCYS bone. Reduced bone density and cortical thickness increased during bisphosphonate therapy.
Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Early online date8 Sept 2017
Publication statusE-pub ahead of print - 8 Sept 2017


  • Hajdu-Cheney syndrome
  • bone density
  • NOTCH2
  • bisphosphonates
  • bone biopsy
  • pQCT


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