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J Clin Endocrinol Metab. 2017 Nov 1;102(11):4163-4172. doi: 10.1210/jc.2017-01102.

Bone Structural Characteristics and Response to Bisphosphonate Treatment in Children With Hajdu-Cheney Syndrome.

Author information

1
Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom.
2
Section on Skeletal Disorders and Mineral Homeostasis, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
3
Department of Endocrinology, Southampton Children's Hospital, Southampton SO16 6YD, United Kingdom.
4
Department of Internal Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
5
Centre de Recherché du Centre Hospitalier Universitaire Ste-Justine, Université de Montréal, Montreal H3T 1C5, Canada.
6
Department of Medicine, Université de Montréal, Montreal H3C 3J7, Canada.
7
Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK, 1140 Vienna, Austria.
8
AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, 1120 Vienna, Austria.
9
Shriners Hospital for Children and McGill University, Montreal, Quebec H4A 0A9, Canada.
10
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.

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.

PMID:
28938420
PMCID:
PMC5673271
DOI:
10.1210/jc.2017-01102
[Indexed for MEDLINE]
Free PMC Article

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