7例假性软骨发育不良患儿的临床特征及遗传学分析

Clinical characteristics and genetic analysis of 7 children with pseudoachondroplasia

目的:分析假性软骨发育不良(pseudoachondroplasia,PSACH)儿童患者的临床特征及软骨低聚物基质量蛋白(cartilage oligomer matrix protein,COMP)基因突变位点。方法:收集7例江西省儿童医院诊断的PSACH患者(2~9岁,其中男童4例,女童3例)相关临床特征、实验室检查、影像学检查、基因报告结果和家族史等。以“PSACH”“PSEUDOACHONDROPLASIA”“假性软骨发育不良”“COMP基因”“COMP”为检索词,分别检索Pub Med、在线人类孟德尔遗传数据库(OMIM)、中国知网数据库(CNKI)和万方数据库,对PSACH进行文献复习,分析7例患儿基因突变位点是否与国外已知报道的热点突变一致,是否存在新发突变而扩展基因突变谱。结果:研究对象身高均落后于同龄同性别儿童的3个标准差以上,婴幼儿期外观和体型正常,2岁左右出现生长速率减慢和骨骼异常,行走鸭步状,智力、面容、视力、听力均未见明显异常。研究对象X线片表现相似,为脊柱椎体扁平,前缘舌状突出,椎间隙正常,髋臼发育较浅,髋关节毛糙,股骨远端、胫腓骨近端干骺端增宽,形态不规则,毛糙感,长骨粗短,血钙和血磷、PTH等代谢指标均正常,全外显子检测均发现COMP基因位点突变,其中2例为新突变,突变类型为错义突变为主(6/7)。本研究的7例患者均处在8~14号外显子,其中13号外显子有5例且均处于T3_(6~7)。结论:对于2岁左右出现生长速率明显减慢、短指畸形、四肢不匀称和软骨骨骺发育异常、脊柱椎体扁圆形、行走步态呈鸭步的患儿应怀疑PSACH,应进行COMP基因检查以助诊断,另外检测血浆COMP水平也是一种很好的诊断方法 ,当临床表型难以诊断PSACH时,可通过COMP突变所处的外显子区域和结构域进行鉴别,PASCH为常染色体显性遗传,遗传概率高,因此早期诊断、早期处理并发症对于改善生活质量以及优生优育有极大的帮助。

Objective:To analyze the clinical characteristics of children with pseudoachondroplasia(PSACH)and gene mutation sites of cartilage oligomer matrix protein(COMP). Methods:The clinical characteristics,laboratory examination,imaging examination,gene report results and family history were collected from 7 patients diagnosed with PSACH in Jiangxi Provincial Children’s Hospital(including 4 boys and 3 girls,aged from 2 to 9 years old). With “PSACH”,“PSEUDOACHONDROPLASIA”,“COMP gene” and “COMP”as keywords,the literature of PSACH was retrieved respectively from the Pub Med,Online Mendelian Inheritance in Man(OMIM),China National Knowledge Infrastructure(CNKI) and WANFANG databases,and it was analyzed that whether the gene mutation sites of these 7 children were consistent with those reported abroad and whether there were newly developed mutations and extended gene mutation spectrum. Results:The stature of the subjects were all 3 standard deviations lower than those of children of the same age and gender,and their appearance and body shape were normal in infancy. At about 2 years old,they showed slowed growth rate and skeletal abnormalities,and walked like a duck. There were no obvious abnormalities in intelligence,face,vision and hearing. The X-ray film performance of the subjects were similar,including flat spinal vertebral body,prominent frontal ligule,normal intervertebral disc,shallow acetabulum development,coarse hip,broadened distal femur and stem epiphyseal end of proximal tibia and fibula,irregular shape,rough feeling,stubby long bones,blood calcium and blood phosphorus,and normal PTH metabolic indexes. Besides, all exons tests found COMP gene locus mutation, among which, 2 were new mutations, and most of them were missense mutations(6/7). The 7 patients in this study were all located in exon 8-14,including 5 in exon 13 and all located in T3_(6~7).Conclusion:Children around 2 years old who have significant slowed growth rate,short deformity,asymmetrical limb and cartilage epiphyseal dysplasia,oblate spinal vertebral,and duck-like walking gait should be suspected with PSACH,and COMP gene check should be conducted to help diagnose. In addition,other COMP test is also a good diagnostic method. When it is difficult to diagnose PSACH through the clinical phenotype,it can be identified by exon region and domain where COMP mutation is located. PASCH is an autosomal dominant inheritance with high genetic probability. Therefore,early diagnosis and early treatment of complications are of great help to improve the quality of life and healthy birth and breeding.