Childhood-onset osteoporosis is a rare but clinically significant condition. Studies have shown pathogenic variants in more than 20 different genes as causative for childhood-onset primary osteoporosis. The X-chromosomal PLS3, encoding Plastin-3, is one of the more recently identified genes. In this study, we describe five new families from four different European countries with PLS3-related skeletal fragility. The index cases were all hemizygous males presenting with long bone and vertebral body compression fractures. All patients had low lumbar spine bone mineral density (BMD). The age at the first clinical fracture ranged from 1.5 to 13 years old. Three of the identified PLS3 variants were stop-gain variants and two were deletions involving either a part or all exons of the gene. In four families the variant was inherited from the mother. All heterozygous women reported here had normal BMD and no bone fractures. Four patients received bisphosphonate treatment with good results, showing a lumbar spine BMD increment and vertebral body reshaping after 10 months to 2 years of treatment. Our findings expand the genetic spectrum of PLS3-related osteoporosis. Our report also shows that early treatment with bisphosphonates may influence the disease course and reduce the progression of osteoporosis, highlighting the importance of early diagnosis for prompt intervention and appropriate genetic counseling.

儿童期发病的骨质疏松症是一种罕见但具有临床意义的疾病。研究表明，20 多个不同基因的致病变异是儿童期原发性骨质疏松症的病因。X 染色体PLS3编码 Plastin-3，是最近发现的基因之一。在这项研究中，我们描述了来自四个不同欧洲国家的五个患有PLS3相关骨骼脆弱性的新家庭。指示病例均为患有长骨和椎体压缩性骨折的半合子男性。所有患者的腰椎骨密度（BMD）均较低。首次临床骨折的年龄为 1.5 至 13 岁。已鉴定的PLS3变体中的三个是停止增益变体，两个是涉及该基因的部分或全部外显子的缺失。在四个家庭中，该变异是从母亲遗传的。这里报道的所有杂合女性的 BMD 均正常，没有骨折。4例患者接受双磷酸盐治疗，效果良好，治疗10个月至2年后腰椎BMD增加，椎体重塑。我们的研究结果扩大了PLS3相关骨质疏松症的遗传谱。我们的报告还表明，早期使用双磷酸盐治疗可能会影响病程并减少骨质疏松症的进展，这凸显了早期诊断对于及时干预和适当遗传咨询的重要性。