软骨发育不全患儿FGFR3基因突变的检测

为了解软骨发育不全基因突变类型，采用聚合酶链反应－限制性酶切分析的方法，对１２例软骨发育不全患者、２例散发患者的父母和４例健康正常人的成纤维细胞生长因子受体３（ＦＧＦＲ３）基因位点的点突变进行检测。结果显示，１２例患者１１例为ＦＧＦＲ３基因跨膜区１１３８位核苷酸Ｇ→Ａ的转换，１例为Ｇ→Ｃ的颠换，均导致３８０位密码子的错义突变，即由精氨酸替代了甘氨酸。２例散发患者的父母和４例健康正常人未发现突变。结论：软骨发育不全患者出现ＦＧＦＲ３基因跨膜区的点突变，３８０位密码子是软骨发育不全患者突变的热点。     

软骨发育不全患儿的临床特征及FGFR3基因变异分析北大核心CSCD

目的 分析17例软骨发育不全(achondroplasia,ACH)患儿的临床特征及成纤维细胞生长因子受体3(fibroblast growth factor receptor 3,FGFR3)基因变异情况。方法 回顾性分析2009年1月至2021年10月确诊的17例ACH患儿临床资料及FGFR3基因检测结果。结果 ACH最常见的临床表现是不匀称型身材矮小(100%,17/17)、大头畸形(100%,17/17)、三叉戟手畸形(82%,14/17)、膝内翻(88%,15/17)。最普遍的影像学是根茎状长骨缩短(100%,17/17)和腰椎椎间距变窄(88%,15/17)。主要并发症有骨骼异常(100%,17/17)、中耳功能障碍(82%,14/17)、运动及语言发育迟缓(88%,15/17)、慢性疼痛(59%,10/17)、睡眠呼吸暂停(53%,9/17)、肥胖(41%,7/17)、枕骨大孔缩小(35%,6/17)、脑积水(24%,4/17)。17例(100%)均存在FGFR3基因变异,13例为FGFR3基因c.1138G>A的热点突变;2例FGFR3基因c.1138G>C变异;2例为未报道的变异,其中1例FGFR3基因c.1252C>T变异,1例FGFR3基因c.445+2_445+5delTAGG变异。结论 该研究检出FGFR3基因未报道变异位点,扩展了ACH基因变异谱。ACH是一种进行性发展的疾病,其相关并发症由多学科团队协作进行终身管理。     

软骨发育不全和FGFR3基因突变的临床研究

目的 探讨软骨发育不全的临床特点和ＦＧＦＲ３基因突变特点。方法 对２２例软骨发育不全患儿进行临床分析,并应用聚合酶链反应（ＰＣＲ）扩增－单链构象多态性（ＳＳＣＰ）及限制性内切酶酶解技术对其中７例软骨发育不全家系进行ＦＧＦＲ３基因第１０外显子突变分析。结果 ８６％为散发病例,全部患儿均在出生时即表现为头大,７例软骨发育不全患儿均显示出ＦＧＦＲ３基因第１０外显子Ｇ３８０Ｒ突变（ＦＧＦＲ３基因第１０外显     

软骨发育不全研究进展

软骨发育不全（ａｃｈｏｎｄｒｏｐｌａｓｉａ，ＡＣＨ）是一种人类最常见的软骨发育不良，以短肢、躯干相对正常和巨头为特征的遗传性侏儒。近年来ＡＣＨ的基因诊断取得了突破性的进展，揭示出ＡＣＨ与成纤维细胞生长因子受体３（ＦＧＦＲ３）基因跨膜区的点突变密切相关。本文着重对ＡＣＨ临床特征、分子遗传学特征及最新研究进展作一综述。     

软骨发育不全一家系成纤维细胞生长因子受体3基因G1138A 突变研究北大核心CSCD

目的：检测和分析一先天性软骨发育不全（ACH）家系4人成纤维细胞生长因子受体3（FGFR3）基因突变位点,并观察重组人生长激素（rhGH）对 ACH 患儿身高的改善作用。方法采集该家系成员4人外周血样本,应用 PCR-DNA 测序方法,对该家系各成员 FGFR3基因第10号外显子的核苷酸序列进行测定,并对先证者给予 rhGH[0.15 U/（kg＆#183;d）]治疗。结果 DNA 测序显示该家系中患儿-患儿母亲及患儿姐姐 FGFR3基因第10号外显子上均发生 c.1138G ﹥ A 杂合突变,使得其所编码蛋白 FGFR3的第380位氨基酸由甘氨酸变为精氨酸,其父亲第10号外显子未发生突变;给予 rhGH 治疗6个月,先证者身高增加了3.8 cm。结论FGFR3基因跨膜区1138位核苷酸 G ﹥ A 转换突变是该 ACH 家系的主要发病原因,说明了该突变为热点突变。在该家系中,先证者母亲表现为新发突变,然后遗传给其2个女儿。rhGH 对 ACH 患者的身高增长近期疗效较好。     

假性软骨发育不全一家系临床特征和COMP基因突变分析

假性软骨发育不全（pseudoachondroplasia, PSACH）是较罕见的常染色体显性遗传性脊柱骨骺发育不良疾病。该文分析总结一个5岁2月龄PSACH患儿及其父母的临床资料,对COMP基因的所有19个外显子及其侧翼序列进行PCR扩增和直接测序,并对外显子10进行分子克隆明确突变性质。患儿有手指粗短、弓形腿、短肢侏儒、长骨干骺端增宽和脊柱椎体前突等临床及影像学表现,其COMP基因外显子10检出突变c.1048_1116del（p.Asn350_Asp372del）。患儿父亲外显子10携带同样突变,但缺乏临床表现。结合临床和影像学特征,通过COMP突变分析明确了PSACH诊断。该文报道的COMP基因突变在PSACH中的不穿透现象属于首次报道。     

椎体软骨发育不良伴免疫调节异常1 例基因诊断及文献复习

目的探讨1例罕见的矮小症伴多系统异常病例的临床和实验室诊断。方法采用全外显子组测序技术,结合高通量数据分析流程进行基因检测,并采用Sanger测序进行验证。结果患儿,男,14岁,发现身材矮小5年余。身高132cm,有面部色素沉着斑点和甲癣。外翻足已手术矫正,因自身免疫性溶血性贫血长期口服泼尼松治疗。头颅CT示两侧基底节、两侧额叶及左侧顶叶多发性钙化。脊柱平片示胸腰椎椎体变扁。全外显子组测序结合Sanger测序验证,发现ACP5基因纯合致病突变(c.643GA,p.G215R),确诊为罕见的椎体软骨发育不良伴免疫调节异常(SPENCDI)。结论全外显子组测序是确诊疑难罕见病的有效方法之一。     

软骨发育不全与软骨发育低下家系的FGFR3基因突变分析

目的了解临床诊断为软骨发育异常类疾病患儿及其家系成员的成纤维细胞生长因子受体3(FGFR3)基因突变情况。方法应用聚合酶链式反应(PCR)和DNA测序技术分析7例患儿及其家系成员的FGFR3基因突变热点分布区域第10外显子以及第13外显子的序列。结果 4例患儿存在FGFR3基因第10外显子c.1138GA(p.Gly380Arg)杂合突变,确诊为软骨发育不全(ACH),其父母未见突变。1例症状较轻微的患儿及其有同样表型的母亲存在FGFR3基因第13外显子c.1620CA(p.Asn540Lys)杂合突变,确诊为软骨发育低下(HCH)。2例患儿未发现以上两个位点的突变。结论检测FGFR3基因第10、第13外显子可诊断大部分ACH或HCH病例,但少数患儿尚有必要检测FGFR3基因其他区域及其他相关基因以明确诊断。     

儿童短肢型遗传性骨代谢性疾病的临床分析及基因诊断

目的：分析软骨发育不全（ACH）、软骨发育低下（HCH）及假性软骨发育不全（PSACH）3种短肢型遗传性骨代谢性疾病的临床表现、骨骼X线表现及基因结果。方法：对基因确诊的10例短肢型遗传性骨代谢性疾病患儿（其中4例为ACH,3例为HCH,3例为PSACH）的临床特点、骨骼X线表现及基因结果进行分析。结果：10例患儿的平均身高为-3.69±1.79 SD,平均坐高/身高比值为0.65±0.03,平均指间距/身高比值为0.93±0.04。4例ACH患儿及3例PSACH患儿具有典型骨骼X线表现,3例HCH患儿中1例表现为坐骨大切迹变小,1例表现为椎弓根间距未增宽。4例ACH患儿中3例检测到FGFR3基因G380R突变,1例检测到Y278C突变;3例HCH患儿均检测到FGFR3基因N540K突变;3例PSACH患儿检测到COMP基因的杂合突变。结论：ACH及PSACH患儿的矮小程度及骨骼畸形程度较HCH患儿重,HCH患儿临床表现轻,不典型;骨骼X线及基因分析有助于3种疾病的诊断及鉴别诊断;3种疾病涉及2个基因,分别有各自的突变热点,有利于临床基因诊断。     

尿道下裂患儿包皮组织中FGFR2表达检测及意义

目的 检测成纤维细胞生长因子受体2(fibroblast growth factor receptor 2,FGFR2)蛋白和mRNA在包皮环切组和尿道下裂组包皮组织中的表达情况,初步探究FGFR2蛋白表达、基因功能和尿道下裂的关系.方法 采用Western blotting(免疫印迹)方法和RT-PCR方法;检测两组中FGFR2表达情况;结果包皮环切组和尿道下裂组FGFR2蛋白相对定量值分别为0.39±0.12和0.19±0.09(P＜0.05),尿道下裂组较包皮环切组降低.尿道下裂轻、中、重度三组间FGFR2蛋白相对定量值分别为0.27±0.08、0.16±0.04、0.09±0.03;中度和重度之间比较无统计学差异(P＞0.05).包皮环切组和尿道下裂组FGFR2 mRNA表达量分别为1.30±0.069和1.22±0.052,包皮环切组高于尿道下裂组(P＜0.05).尿道下裂轻、中、重度三组间FGFR2 mRNA定量值分别为1.23±0).054、1.24±0.034、1.16±0.020;轻度和中度之间之间无统计学差异(P＞0.05),重度尿道下裂FGFR2mRNA表达量低于其他两组.结论 尿道下裂患儿包皮组织中FGFR2蛋白和mRNA较包皮环切组表达下调.提示FGFR2和尿道下裂关系密切,进一步研究FGFR2蛋白和基因功能有助于明确FGFR2在尿道下裂发病机制中的重要地位,有可能揭示尿道下裂的发病机制.     

Mutation in the gene encoding the fibroblast growth factor receptor-3 in Korean children with achondroplasia

Abstract Background. Achondroplasia (ACH) is the most common form of osteochondrodysplasia, and is mostly associated with a point mutation in the gene on the transmembrane domain of fibroblast growth factor receptor-3 (FGFR-3) on chromosome 4p.
Methods: We investigated the mutations in the gene encoding FGFR-3 in 15 Korean children with ACH, using polymerase chain reaction (PCR) coupled with direct sequencing.
Results: In this study, all children with ACH showed the same mutation as those reported in France, USA and Japan; a G→A transition at position 1138 of the coding sequence, resulting in the substitution of arginine for glycine at position 380 of the mature protein.
Conclusions: This consistent point mutation of Korean children with ACH indicates there is no significant racial difference in the pathogenesis of ACH, compared with data from Caucasian and Japanese children with ACH.     

Association of achondroplasia with Down syndrome: Difficulty in prenatal diagnosis by sonographic and 3‐D helical computed tomographic analyses

Achondroplasia and Down syndrome are relatively common conditions individually. But co‐occurrence of both conditions in the same patient is rare and there have been no reports of fetal analysis of this condition by prenatal sonographic and three‐dimensional (3‐D) helical computed tomography (CT). Prenatal sonographic findings seen in persons with Down syndrome, such as a thickened nuchal fold, cardiac defects, and echogenic bowel were not found in the patient. A prenatal 3‐D helical CT revealed a large head with frontal bossing, metaphyseal flaring of the long bones, and small iliac wings, which suggested achondroplasia. In a case with combination of achondroplasia and Down syndrome, it may be difficult to diagnose the co‐occurrence prenatally without typical markers of Down syndrome.     

Achondroplasia in Sweden caused by the G1 138A mutation in FGFR3

Achondroplasia, an autosomal dominant inherited disorder, is one of the most common forms of skeletal dysplasia resulting in disproportionate extreme shortness. Recently, two point mutations, both affecting nucleotide 1138 in the fibroblast growth factor receptor type 3 (FGFR3) gene, were found to be the cause of the disorder. We investigated DNA from 16 Swedish patients with achondroplasia for the presence of these mutations. All patients were found to be heterozygous for the G to A transition at nucleotide 1138. Our data thus support previous reports showing a striking genetic homogeneity, in that almost all achondroplasia patients have the FGFR3 G380R mutation at the protein level.     

Skeletal development of achondroplasia: Analysis of genotyped patients

BACKGROUND: Achondroplasia is a skeletal dysplasia caused by substitution of arginine for glycine at codon 380 (G380R) mutation of the fibroblast growth factor receptor 3. To date, the developmental course of the phenotype (short stature and skeletal characteristics) has not been clarified in the genotyped population. METHODS: The relationship between age and clinical data (height, arm span and measurements of skeletal radiographs) were statistically analyzed from 27 achondroplasia patients with the G380R genotype. RESULTS: The height standard deviation score had positive correlation and decreased with age, while span-to-height ratio did not. Among measurements of skeletal radiographs, the pelvic index, which represents the squared pelvis deformity, were correlated and increased with age. However, interpedicular distance of the first and fourth lumbar vertebrae (L1:L4) ratio as an index for the caudally narrowed pattern of the lumbar spinal canal and fibula-to-tibia ratio for the disproportionally long fibulae were not correlated and did not increase with age. CONCLUSION: In making a clinical diagnosis of achondroplasia in early infancy, it should be noted that short stature and squared pelvis deformity are not prominent.     

Identification of Mutations in the Gene Encoding the Fibroblast Growth Factor Receptor 3 in Japanese Patients with Achondroplasia

Abstract We examined mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) in nine Japanese patients diagnosed as typical achondroplasia (ACH) and two patients with hypochondroplasia (HCH) using polymerase chain reaction (PCR) coupled with direct sequencing. In our present cases, equivalent to previously reported cases in France and the U. S. A., all mutations affected with ACH were the same nucleotide change, a G→A transition at position 1,138, resulting in the substitution of arginine for glycine at position 380 of the mature protein. Therefore, the gene mutation of ACH indicates no significant differences between the Caucasian and the Japanese. On the other hand, PCR products from genomic DNA of HCH did not show the same mutation.     

Common mutations in the gene encoding fibroblast growth factor receptor 3 account for achondroplasia, hypochondroplasia and thanatophoric dysplasia

The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (Gly380Arg) in the gene encoding fibroblast growth factor receptor 3 (FGFR-3) has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dysplasia (TD; types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity: 100% of patients examined exhibited mutations in the transmembrane domain of FGFR-3. Although most cases of hypochondroplasia were accounted for by a recurrent missense substitution (Asn540Lys) in the first tyrosine kinase domain of FGFR-3, a significant proportion (40%) of the patients in the present study did not possess this Asn540Lys mutation. Furthermore, in three families with hypochondroplasia, the genetic defect was not linked to the FGFR-3 locus, thus supporting the clinical heterogeneity of this disease. In TD, a recurrent mutation located in the second tyrosine kinase domain of FGFR-3 has been detected in all TDII patients. By contrast, seven distinct mutations in three different protein domains were identified in 25 out of 26 TDI patients in this study. This suggests that TD, like achondroplasia, is a genetically homogeneous skeletal disorder.     

A Common Mutation in the Tyrosine Kinase Domain of the Fibroblast Growth Factor Receptor 3 Gene in Two Japanese Patients with Hypochondroplasia

We examined two Japanese patients with hypochondroplasia (HCH) whether they had mutations in the gene (FGFR3) encoding the fibroblast growth factor receptor 3 using polymerase chain reaction (PCR) coupled with direct sequencing. In both of our patients, a C→A transversion was detected in nucleotide 1659, predicting a substitution of asparagine for lysine at position 540 of the mature protein which corresponds a part of the tyrosine kinase 1 (TK1) domain. Our results suggest that a common mutation specific for HCH in the TK1 domain of FGFR3 exists among Japanese patients with HCH.