Bone structural characteristics and response to bisphosphonate treatment in children with hajdu-cheney syndrome

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

Research output: Contribution to journalArticle

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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. (J Clin Endocrinol Metab 102: 4163-4172, 2017).

Original languageEnglish (US)
Pages (from-to)4163-4172
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number11
DOIs
StatePublished - Jan 1 2017

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Hajdu-Cheney Syndrome
Diphosphonates
Bone
Bone and Bones
Bone Density
pamidronate
zoledronic acid
Bone Resorption
Osteogenesis
Mutation
Spine
Therapeutics
Tomography
Alendronate
Physiologic Calcification
Bone Matrix
Bone Diseases
Photon Absorptiometry
Osteoclasts
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

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; Högler, Wolfgang.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 102, No. 11, 01.01.2017, p. 4163-4172.

Research output: Contribution to journalArticle

Sakka, S, Gafni, RI, Davies, JH, Clarke, B, Tebben, P, Samuels, M, Saraff, V, Klaushofer, K, Fratzl-Zelman, N, Roschger, P, Rauch, F & Högler, W 2017, 'Bone structural characteristics and response to bisphosphonate treatment in children with hajdu-cheney syndrome', Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 11, pp. 4163-4172. https://doi.org/10.1210/jc.2017-01102
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 ; Högler, Wolfgang. / Bone structural characteristics and response to bisphosphonate treatment in children with hajdu-cheney syndrome. In: Journal of Clinical Endocrinology and Metabolism. 2017 ; Vol. 102, No. 11. pp. 4163-4172.
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AU - Gafni, Rachel I.

AU - Davies, Justin H.

AU - Clarke, Bart

AU - Tebben, Peter

AU - Samuels, Mark

AU - Saraff, Vrinda

AU - Klaushofer, Klaus

AU - Fratzl-Zelman, Nadja

AU - Roschger, Paul

AU - Rauch, Frank

AU - Högler, Wolfgang

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N2 - 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. (J Clin Endocrinol Metab 102: 4163-4172, 2017).

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