Yapijakis Christos, Gintoni Iphigenia, Chamakioti Myrsini, Koniari Eleni, Papanikolaou Eleni, Kassi Eva, Vlachakis Dimitrios, Chrousos George P
Unit of Orofacial Genetics, 1st Department of Pediatrics, School of Medicine, National Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, 115 27 Athens, Greece.
Choremion Laboratory, Research Institute of Maternal and Child Health and Precision Medicine, "Aghia Sophia" Children's Hospital, 115 27 Athens, Greece.
Genes (Basel). 2025 Jul 24;16(8):871. doi: 10.3390/genes16080871.
Osteodysplastic syndromes comprise a very diverse group of clinically and genetically heterogeneous disorders characterized by defects in bone and connective tissue development, as well as in bone density. Here, we report the case of a 48-year-old female with a complex medical history characterized by bone dysplasia, hyperostosis, and partial tooth agenesis.
Genetic testing was performed using WES analysis and Sanger sequencing. Molecular modeling analysis and dynamics simulation explored the impact of detected pathogenic variants.
The genetic analysis detected multiple pathogenic variants in genes , , , and , each of which has been associated with rare osteodysplastic syndromes. The patient was homozygous for the same rare alleles associated with three of the identified autosomal recessive disorders osteogenesis imperfecta type XVI, primary hypertrophic osteoarthropathy, and metaphyseal dysplasia Pyle type. She also had a variant linked to autosomal dominant endosteal hyperostosis and a variant previously associated with increased risk of osteoporosis and bone fractures. Two of the detected variants are predicted to cause abnormal splicing, while molecular modeling and dynamics simulations analysis suggest that the other three variants probably confer altered local secondary structure and flexibility that may have functionally devastating consequences.
Our case highlights the rare coexistence of multiple osteodysplastic syndromes in a single patient that may complicate differential diagnosis. Furthermore, this case emphasizes the necessity for early genetic investigation of such complex cases with overlying phenotypic traits, followed by genetic counseling, facilitating orchestration of clinical interventions and allowing prevention and/or prompt management of manifestations.
骨发育异常综合征是一组临床和基因上异质性很强的疾病，其特征为骨和结缔组织发育以及骨密度存在缺陷。在此，我们报告一例48岁女性患者，其复杂的病史以骨发育异常、骨质增生和部分牙齿缺失为特征。
使用全外显子组测序（WES）分析和桑格测序进行基因检测。分子建模分析和动力学模拟探究了检测到的致病变异的影响。
基因分析在多个基因中检测到多个致病变异，每个变异都与罕见的骨发育异常综合征相关。该患者对于与三种已确定的常染色体隐性疾病相关的相同罕见等位基因呈纯合状态，这三种疾病分别为十六型成骨不全、原发性肥厚性骨关节病和派尔型干骺端发育异常。她还携带一个与常染色体显性骨内膜增生相关的变异，以及一个先前与骨质疏松和骨折风险增加相关的变异。检测到的两个变异预计会导致异常剪接，而分子建模和动力学模拟分析表明，其他三个变异可能会导致局部二级结构和柔韧性改变，这可能会产生功能上的毁灭性后果。
我们的病例突出了单个患者中多种骨发育异常综合征罕见的共存情况，这可能会使鉴别诊断复杂化。此外，该病例强调了对具有叠加表型特征的此类复杂病例进行早期基因研究的必要性，随后进行遗传咨询，以促进临床干预的协调安排，并实现对症状的预防和/或及时管理。
