An Unbalanced Rearrangement of Chromosomes 4:20 is Associated with Childhood Osteoporosis and Reduced Caspase-3 Levels

Esther Kinning; Martin McMillan; Sheila Shepherd; Miep Helfrich; Rob vant Hof; Christopher Adams; Heather Read; Daniel M. Wall; S. Faisal Ahmed

doi:10.1055/s-0036-1584359

Journal of Pediatric Genetics, Table of Contents

J Pediatr Genet 2016; 05(03): 167-173
DOI: 10.1055/s-0036-1584359

Case Report

Georg Thieme Verlag KG Stuttgart · New York

An Unbalanced Rearrangement of Chromosomes 4:20 is Associated with Childhood Osteoporosis and Reduced Caspase-3 Levels

Authors

Esther Kinning

¹Department of Clinical Genetics, Laboratory Medicine Building, Southern General Hospital, Glasgow, Scotland
Martin McMillan

²Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland
Sheila Shepherd

²Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland
Miep Helfrich

³Musculoskeletal Programme, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland
Rob vant Hof

⁴Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom
Christopher Adams

⁵National Paediatric Spinal Deformity Service, Royal Hospital for Sick Children, Edinburgh, Scotland
Heather Read

²Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland
Daniel M. Wall

⁶Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland
S. Faisal Ahmed

²Child Health, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Scotland

Abstract

The purpose of this study was to investigate the association of a chromosome 4:20 imbalance with osteoporosis in three related children. Bone biochemistry, bone turnover markers, and dual-energy X-ray absorptiometry (DXA) scanning were performed in all three cases and bone biopsy and histomorphometry in one. The chromosome imbalance was delineated by array comparative genomic hybridization (aCGH) and analyzed for candidate genes. A potential candidate gene within the deleted region is caspase-3, previously linked to low bone mineral density (BMD) in heterozygous mice thus caspase-3 activity was measured in cases and controls. Routine bone biochemistry and markers of bone turnover did not reveal any abnormality. DXA showed reduced total and lumbar spine bone mineral content. aCGH showed an 8 megabase (Mb) deletion of terminal chromosome 4q incorporating a region previously linked to low BMD and a 15 Mb duplication of terminal chromosome 20p. Bone biopsy showed a high bone turnover state, trabecularisation of cortical bone and numerous small osteoclasts coupled with normal bone formation. Basal serum caspase-3 activity was lower in cases compared with controls. We conclude that the early-onset osteoporosis with low basal levels of caspase-3 and abnormal osteoclasts is a feature of this chromosomal translocation. Further investigation of the role of the deleted and duplicated genes and especially caspase-3 is required.

Keywords

osteoporosis - chromosome translocation - bone histomorphometry - osteoclast - caspase

Full Text

References

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