Early-Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen.
Early-Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen.
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DOI：
10.1002/jbmr.4668
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发表时间：
2022-09
期刊：
影响因子：
--
通讯作者：
Mäkitie O
中科院分区：
文献类型：
--
作者：
Costantini A;Mäkitie RE;Hartmann MA;Fratzl-Zelman N;Zillikens MC;Kornak U;Søe K;Mäkitie O
早发性骨质疏松症(EOOP)，以低骨密度(BMD)和骨折为特征，影响儿童、绝经前妇女和50岁男性。EOOP可能是慢性疾病、长期用药、营养缺乏等的次要原因。如果没有确定这些原因，EOOP被认为是主要的，然后可能与在骨骼内稳中起关键作用的基因的罕见变异有关。如果病因不明，EOOP被认为是特发性的。这篇综述的范围是通过对EOOP的临床和遗传学诊断进行指导，总结关于罕见的单基因形式的EOOP的现有知识，并描述骨活检样本的分析如何有助于更好地了解该病的发病机制。EOOP的诊断途径通常很复杂，可能需要广泛的评估才能可靠地排除继发性原因。由于EOOP和其他骨脆性疾病的各种遗传形式的遗传异质性和重叠特征，基因诊断通常需要使用下一代测序来同时研究多个基因。最近的发现阐明了疾病发病机制的复杂性，包括遗传结构和骨组织水平的病理。两种罕见的EOOP单基因形式是由于参与典型WNT途径的基因缺陷：LRP5和WNT1。编码纤溶酶-3(PLS3)和鞘磷脂合成酶2(SGMS2)的基因变异也在患有骨骼脆性的儿童和年轻人中被发现。从基因缺陷到临床表现的分子机制往往还不完全清楚。对患者来源的暂时性骨活检的详细分析为了解疾病的发病机制提供了有价值的信息，将EOOP与其他骨脆性疾病区分开来，并指导患者治疗，但在临床环境中并不广泛使用。尽管在这一领域取得了很大进展，但EOOP仍然是一个探索不足的实体，需要进一步研究以优化诊断和治疗方法。©2022作者。《骨与矿物研究杂志》由Wiley期刊有限责任公司代表美国骨与矿物研究学会(ASBMR)出版。
Early‐onset osteoporosis (EOOP), characterized by low bone mineral density (BMD) and fractures, affects children, premenopausal women and men aged <50 years. EOOP may be secondary to a chronic illness, long‐term medication, nutritional deficiencies, etc. If no such cause is identified, EOOP is regarded primary and may then be related to rare variants in genes playing a pivotal role in bone homeostasis. If the cause remains unknown, EOOP is considered idiopathic. The scope of this review is to guide through clinical and genetic diagnostics of EOOP, summarize the present knowledge on rare monogenic forms of EOOP, and describe how analysis of bone biopsy samples can lead to a better understanding of the disease pathogenesis. The diagnostic pathway of EOOP is often complicated and extensive assessments may be needed to reliably exclude secondary causes. Due to the genetic heterogeneity and overlapping features in the various genetic forms of EOOP and other bone fragility disorders, the genetic diagnosis usually requires the use of next‐generation sequencing to investigate several genes simultaneously. Recent discoveries have elucidated the complexity of disease pathogenesis both regarding genetic architecture and bone tissue‐level pathology. Two rare monogenic forms of EOOP are due to defects in genes partaking in the canonical WNT pathway: LRP5 and WNT1. Variants in the genes encoding plastin‐3 (PLS3) and sphingomyelin synthase 2 (SGMS2) have also been found in children and young adults with skeletal fragility. The molecular mechanisms leading from gene defects to clinical manifestations are often not fully understood. Detailed analysis of patient‐derived transiliac bone biopsies gives valuable information to understand disease pathogenesis, distinguishes EOOP from other bone fragility disorders, and guides in patient management, but is not widely available in clinical settings. Despite the great advances in this field, EOOP remains an insufficiently explored entity and further research is needed to optimize diagnostic and therapeutic approaches. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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