PDF(Pubmed)
Abstract：
Marfan syndrome is a genetic connective tissue disorder affecting skeletal, ocular, and cardiovascular organ systems. Previous research found that pathogenic variants clustered in exons 24-32 of fibrillin-1 (FBN1) gene result in more severe clinical phenotypes. Furthermore, genotype-phenotype correlation studies suggested that more severe cardiovascular phenotypes were related to variants held responsible for haploinsufficiency. Our objective was to analyze the differences in clinical manifestations and genotypes of individuals with early-onset Marfan syndrome and to assess their impact on management strategies.
We analyzed clinical and genetic data of a new patient with early-onset Marfan syndrome together with 51 previously reported ones in the PubMed database between 1991 and 2022.
Analysis showed 94% (49/52) of pathogenic variants clustered in exons 24-32 of the FBN1. The most common skeletal features were arachnodactyly (98%), reduced elbow extension (48%), pectus deformity (40%), and scoliosis (39%). Haploinsufficiency variants were reported as having poor outcome in 87.5% of the cases. Among patients carrying variants that substitute a cysteine for another amino acid and those that do not change cysteine content, cardiac intervention was found to be associated with a better outcome (p = 0.035 vs. p = 0.002). Variants that create an extra cysteine residue were found to be associated with a higher risk of ectopia lentis. Additionally, children up to 36-months-old were more often reported as still alive at the time of publication compared to newborns (p < 0.01).
Our findings have implications for prognosis, because different genotype groups and their resulting phenotype may require personalized care and management.
We analyzed clinical and genetic data of a new patient with early-onset Marfan syndrome together with 51 previously reported ones in the PubMed database between 1991 and 2022.
Analysis showed 94% (49/52) of pathogenic variants clustered in exons 24-32 of the FBN1. The most common skeletal features were arachnodactyly (98%), reduced elbow extension (48%), pectus deformity (40%), and scoliosis (39%). Haploinsufficiency variants were reported as having poor outcome in 87.5% of the cases. Among patients carrying variants that substitute a cysteine for another amino acid and those that do not change cysteine content, cardiac intervention was found to be associated with a better outcome (p = 0.035 vs. p = 0.002). Variants that create an extra cysteine residue were found to be associated with a higher risk of ectopia lentis. Additionally, children up to 36-months-old were more often reported as still alive at the time of publication compared to newborns (p < 0.01).
Our findings have implications for prognosis, because different genotype groups and their resulting phenotype may require personalized care and management.
摘要：
背景：马凡综合征是一种影响骨骼的遗传性结缔组织疾病，眼,和心血管器官系统。先前的研究发现，聚集在纤丝蛋白1（FBN1）基因外显子24-32中的致病变异会导致更严重的临床表型。此外，基因型-表型相关性研究提示,更严重的心血管表型与导致单倍体功能不全的变异相关.我们的目的是分析早发性马凡综合征患者的临床表现和基因型的差异，并评估其对管理策略的影响。
方法：我们分析了1991年至2022年PubMed数据库中一名新出现的早发性马凡综合征患者的临床和遗传数据以及先前报道的51例。
结果：分析显示94%（49/52）的致病变异聚集在FBN1的外显子24-32。最常见的骨骼特征是蛛网膜畸形（98％），减少肘部延伸（48%），胸膜畸形（40%），和脊柱侧弯（39%）。据报道，单倍功能不全变异在87.5%的病例中具有较差的结果。在携带将半胱氨酸替换为另一种氨基酸的变体和不改变半胱氨酸含量的患者中，发现心脏干预与更好的结果相关(p=0.035vs.p=0.002)。发现产生额外半胱氨酸残基的变体与小扁桃体的高风险相关。此外,与新生儿相比,报告发表时36个月以下儿童仍存活的频率更高(p<0.01).
结论：我们的发现对预后有影响，因为不同的基因型组及其产生的表型可能需要个性化的护理和管理。
方法：我们分析了1991年至2022年PubMed数据库中一名新出现的早发性马凡综合征患者的临床和遗传数据以及先前报道的51例。
结果：分析显示94%（49/52）的致病变异聚集在FBN1的外显子24-32。最常见的骨骼特征是蛛网膜畸形（98％），减少肘部延伸（48%），胸膜畸形（40%），和脊柱侧弯（39%）。据报道，单倍功能不全变异在87.5%的病例中具有较差的结果。在携带将半胱氨酸替换为另一种氨基酸的变体和不改变半胱氨酸含量的患者中，发现心脏干预与更好的结果相关(p=0.035vs.p=0.002)。发现产生额外半胱氨酸残基的变体与小扁桃体的高风险相关。此外,与新生儿相比,报告发表时36个月以下儿童仍存活的频率更高(p<0.01).
结论：我们的发现对预后有影响，因为不同的基因型组及其产生的表型可能需要个性化的护理和管理。
