Zervou Zografia, Bruggenwirth Hennie T, Demirdas Serwet, Zillikens M Carola
Department of Internal Medicine, Erasmus MC Bone Center, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Department of Clinical Genetics, Erasmus MC, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
JBMR Plus. 2025 Apr 24;9(6):ziaf046. doi: 10.1093/jbmrpl/ziaf046. eCollection 2025 Jun.
X-linked osteoporosis, caused by plastin 3 () genetic variants, is a rare disease, characterized by low BMD and early-onset fractures, primarily affecting men. Our aim was to further elucidate the phenotypic characteristics, including sex-differences and genotype-phenotype analysis, in individuals with variants. Our cohort comprises of 28 patients from 11 families, 18 men and 10 women, with a different variant in each family. Demographic, clinical, and genetic features, imaging and laboratory tests, and treatment details were retrospectively reviewed. Men, (median age 47.0 y), demonstrated low Z-scores of the lumbar spine (-2.8 ± 1.7) and femoral neck (-1.7, IQR: -2.9-0.8). Most women (median age 49.5 y) had normal BMD, two had osteoporosis and one osteopenia. Moreover, men experienced a higher total number of fractures than women (men: 12.0, IQR: 6.7, 18.5, women: 2.0, IQR: 0.7, 5.2). Within one large family ( = 10) there was considerable heterogeneity regarding BMD and fractures, which might be explained by differences in factors like physical exercise (PE) or in (poly) genetic background. Extra-skeletal characteristics such as (mild) blue discoloration of the sclerae (men: 33.3%, women: 30.0%), joint hypermobility (44.4%, 70.0%) and skin hyperlaxity (50.0%, 20.0%) were observed. No relation was found between types and locations of variants and various clinical endpoints in men, using data from our cohort and the literature. Regarding treatment, all men and 40% of women received bone-active therapy, mostly oral bisphosphonates. Adult men demonstrated a 16.6% mean increase in the BMD of the lumbar spine ( = .03), after a median treatment duration of 6 y. In summary, this is so far the largest study of patients with X-linked osteoporosis, including an extensive genotype-phenotype analysis. A potential protective role of increasing weight-bearing PE in osteoporosis severity, as well as effects of penetrance, genetic background, or other environmental or lifestyle factors, need further study.
由丝束蛋白3（PLS3）基因变异引起的X连锁骨质疏松症是一种罕见疾病，其特征为骨密度低和早发性骨折，主要影响男性。我们的目的是进一步阐明PLS3变异个体的表型特征，包括性别差异和基因型-表型分析。我们的队列包括来自11个家庭的28名患者，18名男性和10名女性，每个家庭有不同的PLS3变异。对人口统计学、临床和遗传特征、影像学和实验室检查以及治疗细节进行了回顾性分析。男性（中位年龄47.0岁）腰椎（Z值为-2.8±1.7）和股骨颈（Z值为-1.7，四分位间距：-2.9至0.8）的Z值较低。大多数女性（中位年龄49.5岁）骨密度正常，2名女性患有骨质疏松症，1名女性患有骨量减少。此外，男性骨折总数高于女性（男性：12.0，四分位间距：6.7，18.5；女性：2.0，四分位间距：0.7，5.2）。在一个大家庭（n = 10）中，骨密度和骨折情况存在相当大的异质性，这可能由体育锻炼（PE）等因素或（多）基因背景的差异来解释。观察到一些骨骼外特征，如巩膜（轻度）发蓝（男性：33.3%，女性：30.0%）、关节活动过度（44.4%，70.0%）和皮肤松弛（50.0%，20.0%）。利用我们队列的数据和文献，未发现男性变异类型和位置与各种临床终点之间存在关联。关于治疗，所有男性和40%的女性接受了骨活性治疗，主要是口服双膦酸盐。成年男性在中位治疗持续时间6年后，腰椎骨密度平均增加了16.6%（P = 0.03）。总之，这是迄今为止关于X连锁骨质疏松症患者的最大规模研究，包括广泛的基因型-表型分析。增加负重体育锻炼对骨质疏松严重程度的潜在保护作用，以及外显率、基因背景或其他环境或生活方式因素的影响，需要进一步研究。
