Abstract
Bruck syndrome is a rare autosomal recessive form of osteogenesis imperfecta (OI), which is mainly characterized by joint contractures and recurrent fragility fractures. Mutations in FKBP10 and PLOD2 were identified as the underlying genetic defects of Bruck syndrome. Here we investigated the phenotypes and the pathogenic mutations of three unrelated Chinese patients with Bruck syndrome. Clinical fractures, bone mineral density (BMD), bone turnover biomarkers, and skeletal images were evaluated in detail. The pathogenic mutations were identified by targeted next-generation sequencing and subsequently confirmed by Sanger sequencing and cosegregation analysis. We also evaluated the effects of zoledronic acid on bone fracture incidence and BMD of the patients. Three patients had congenital joint contractures, recurrent fragility fractures, camptodactyly, clubfoot, scoliosis, but without dentinogenesis imperfecta and hearing loss. Five novel heterozygous mutations were detected in PLOD2, including three heterozygous missense mutations (c.1138C>T, p.Arg380Cys; c.1153T>C, p.Cys385Arg; and c.1982G>A, p.Gly661Asp), one heterozygous nonsense mutation (c.2038C>T, p.Arg680X), and one heterozygous splice-site mutation (c.503-2A>G). Their parents were all heterozygous carriers of these mutations in PLOD2. No clear genotype–phenotype correlations were found in these patients with PLOD2 mutations. Z-score of BMD was significantly increased, but scoliosis progressed and new bone fractures occurred during the treatment of zoledronic acid. Our findings expanded the spectrum of gene mutations of Bruck syndrome.
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Acknowledgements
We thank the staff at the radiology department, Peking Union Medical College Hospital for measurement of bone mineral density and interpretation of radiographs. We also thank the patients with PLOD2 mutations and their families for participation in this research and thank all unaffected, unrelated individuals for providing control DNA samples.
Funding
This study was supported by the National Natural Science Foundation of China (No. 81570802), the National Key Research and Development Program of China (No. 2016YFC0901501), and the CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2 M-3-003).
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Fang Lv, Xiaojie Xu, Yuwen Song, Lujiao Li, Asan, Jian Wang, Huanming Yang, Ou Wang, Yan Jiang, Weibo Xia, Xiaoping Xing, and Mei Li state that they have no conflicts of interest.
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The study was approved by the Medical Ethics Committee of the PUMCH and written consent was obtained from all patients who responded and were included in the study.
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Lv, F., Xu, X., Song, Y. et al. Novel Mutations in PLOD2 Cause Rare Bruck Syndrome. Calcif Tissue Int 102, 296–309 (2018). https://doi.org/10.1007/s00223-017-0360-6
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DOI: https://doi.org/10.1007/s00223-017-0360-6