儿童常见遗传性骨病的临床及分子遗传学研究

Clinical and molecular genetic study of genetic skeletal disorders in children

遗传性骨病是影响骨骼发育的一组极为复杂的疾病,从胎儿期到成年的任何时期均可以发病。根据临床表现、影像学和分子遗传学特征,2019年国际骨骼发育不良学会分类学委员会将其分为42组461种疾病,其中437个致病性基因变异被确定。软骨发育不全是最常见的以非匀称性身材矮小为主要表现遗传性骨病,FGFR3是其主要致病基因。黏多糖贮积症是一组由于酶缺陷造成酸性黏多糖不能完全降解而致的溶酶体贮积病,本病除引起多发性骨骼病变,常累及多系统、多器官。成骨不全和低磷酸酯酶症是影响儿童骨密度的遗传性骨病,前者根据基因型及临床特征分Ⅰ至ⅩⅥ型;后者是因组织非特异性碱性磷酸酶(TNSALP)基因突变所致。假性软骨发育不全是一种以广泛性骨骼发育异常、身材矮小为特征的遗传性骨病,软骨寡聚蛋白基因杂合突变是目前唯一报道的与其发生有关的致病基因。点状软骨发育不良以骨骺软骨的不规则钙盐沉着为特征,根据遗传方式和临床表型严重程度分5型。遗传性骨病总体发病率并不低,由于分子遗传学检测手段的广泛开展,新发基因致病性变异还不断被发现,只有通过对这类疾病的深入研究,才能找到基因治疗方法,前景任重道远。

Genetic skeletal disorders are a group of extremely complex diseases that affect bone development.They can occur in any period from fetal to adult.A total of 461different skeletal diseases are classified into 42groups based on clinical,radiographic,and/or molecular phenotypes by the Nosology Committee of the International Skeletal Dysplasia Society in 2019.Pathogenic variants affecting 437different genes have been found in these disorders.Achondroplasia is the most common genetic bone disease with asymmetrical short stature as the main manifestation,and FGFR3is its main causal gene.Mucopolysaccharidosis is a group of lysosomal storage diseases caused by the complete degradation of acidic mucopolysaccharides due to enzyme defects.According to the enzyme defects,it can be divided into 7types.In addition to causing multiplex dysostosis,such diseases often involve multiple systems and organs.Osteogenesis imperfecta and Hypophosphatasia are hereditary bone diseases that affect bone mineral density in children.The former is divided intoⅠtoⅩⅥtypes according to genotype and clinical manifestations,and the latter is caused by tissue nonspecific alkaline phosphatase(TNSALP)gene mutation.Pseudoachondroplasia is a genetic bone disease characterized by Multiple epiphyseal dysplasia and short stature.Heterozygous mutations in the cartilage oligomeric protein gene are the only reported pathogenic genes related to its occurrence.Chondrodysplasia punctata is characterized by irregular calcium deposition of epiphyseal cartilage,and it is divided into 5types according to the inheritance patterns and the severity of clinical phenotype.In a word,the overall incidence of hereditary/genetic skeletal disorders is not low.Due to the extensive development of molecular genetic testing methods,novel pathogenic genetic variants are still being discovered.Only through the profound study of such diseases can new gene therapeutics be found.Yet much more work remains to be done.