Abstract：
Osteogenesis imperfecta (OI) is a rare low-bone mass skeletal Mendelian disorder characterized by bone fragility leading to bone fractures, with deformities and stunted growth in the more severe phenotypes. Other common, nonskeletal findings include blue sclerae and dentinogenesis imperfecta. It is caused mainly by quantitative or structural defects in type I collagen, although dysregulation of different signaling pathways that play a role in bone morphogenesis has been described to be associated with a small fraction of individuals with OI. Recently, a homozygous variant in the translation start site of CCDC134, showing increased activation of the RAS/MAPK signaling pathway, has been reported in three families of Moroccan origin with a severe, deforming form of OI. We report on a 9-year-old Brazilian boy, harboring the same homozygous variant in CCDC134, also presenting severe bone involvement. This report contributes to the phenotypic delineation of this novel autosomal recessive form of OI, which presents with high prevalence of nonunion fractures considered rare events in OI in general. In addition, it expands the phenotype to include base skull anomalies, potentially leading to serious complications, as seen in severe forms of OI. A poor response to bisphosphonate therapy was observed in these individuals. As the variant in CCDC134 leads to dysregulation of the RAS/MAPK signaling pathway, drugs targeted to this pathway could be an alternative to achieve a better management of these individuals.
摘要：
成骨不全症（OI）是一种罕见的低骨量骨骼性孟德尔疾病，其特征是骨脆性导致骨折，在更严重的表型中具有畸形和发育迟缓。其他常见的，非骨骼的发现包括蓝色巩膜和牙本质发育不全。它主要是由I型胶原蛋白的数量或结构缺陷引起的，尽管在骨形态发生中起作用的不同信号通路的失调已被描述为与一小部分OI个体有关。最近,CCDC134翻译起始位点的纯合变体，显示RAS/MAPK信号通路的激活增加，据报道，在三个摩洛哥裔家庭中，OI的变形形式。我们报道了一个9岁的巴西男孩，在CCDC134中具有相同的纯合变体，也表现出严重的骨受累。该报告有助于这种新型常染色体隐性形式的OI的表型描述，这表明不愈合骨折的患病率很高，被认为是OI中的罕见事件。此外,它将表型扩展到包括颅底异常，可能导致严重的并发症，在严重形式的OI中看到。在这些个体中观察到对双膦酸盐治疗的不良反应。由于CCDC134中的变体导致RAS/MAPK信号通路的失调，针对该途径的药物可能是对这些个体进行更好管理的替代药物.
