影响Turner综合征患儿生长激素疗效的相关因素分析

Analysis of the influencing factors of recombinant human growth hormone effect in the children with Turner syndrom

目的探讨影响Turner综合征患儿生长激素疗效的相关因素。方法对2010年1月—2017年1月在华中科技大学同济医学院附属同济医院儿科经重组人生长激素治疗1年以上的31例Turner综合征患儿的临床资料、核型、生长激素受体（GHR）外显子3多态性等进行回顾性研究分析。利用PCR方法检测GHR外显子3缺失多态性，按GHR外显子3基因型患儿分为GHR全长型、GHR外显子3杂合缺失型及GHR外显子3纯合缺失型三组，按染色体核型将患儿分为45,X核型组与其他核型组，观察身高标准差积分（Ht-SDS）、生长速率的变化。采用t检验、方差分析、多元线性回归分析对结果进行统计分析。结果（1）31例Turner综合征患儿就诊年龄（12.2±2.9）岁，骨龄（8.9±2.4）岁，身高（126.2±10.5）cm，Ht-SDS为－3.5±1.3。染色体核型：45,X 14例，其他核型17例。GHR外显子3基因型：GHR全长型13例（42%）、GHR外显子3杂合缺失型14例（45%）、GHR外显子3纯合缺失型4例（13%）。首诊原因：31例患儿中26例因身材矮小就诊（81%），5例因无第二性征发育就诊。（2）生长激素治疗后，生长速率（cm/年）（7.3±1.4、7.0±3.0、7.0±1.3）及Ht-SDS（－2.8±1.2、－2.5±0.9、－2.2±0.8）明显高于治疗前水平（2.9±0.9、－3.5±1.3），差异均有统计学意义（F=54.12，4.43，均P〈0.05）。rhGH治疗第3年较治疗第1年Ht-SDS（－2.2±0.8、－2.8±1.2）比较，差异有统计学意义（t=－2.3，P〈0.05）。（3）rhGH治疗前，45,X核型组身高明显低于其他核型组身高[（122.1±9.1）cm比（129.9±10.3）cm，t=－2.2，P〈0.05]，rhGH治疗前及治疗后，两组生长速率（cm/年）、Ht-SDS差异无统计学意义，但随着治疗时间延长，其他核型组Ht-SDS比45,X核型组有改善趋势。（4）不同基因型患儿间rhGH短期及长期治疗后生长速率、Ht-SDS差异均无统计学意义。（5）多因素线性回归分析提示，ΔHt-SDS与初治时年龄呈负相关（偏回归系数=－0.098，P〈0.05），与治疗前生长速率呈正相关（偏回归系数=0.202，P〈0.05）。结论Turner综合征患儿开始rhGH治疗年龄越早、治疗前生长速率越快，疗程越长，rhGH疗效越好。rhGH治疗前，45,X核型组身高明显低于其他核型组身高，rhGH治疗前后，两组Ht-SDS及生长速率无显著差异，但随着治疗时间延长，其他核型组Ht-SDS比45,X核型组有改善趋势。GHR外显子3多态性对Turner综合征患儿rhGH疗效无显著影响。

ObjectiveTo analyze the clinical data, karyotype, growth hormone receptor （GHR） exon 3 polymorphism, etc. in Turner syndrome before and after recombinant human growth hormone （rhGH） treatment, and thereby to understand the related factors influencing the rhGH curative effect in children with Turner syndrome.MethodsThis was a retrospective study of 31 cases with Turner syndrome who were treated with growth hormone for more than 1 year in the pediatric outpatient department of Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology from January 2010 to January 2017. The GHR Exon3 polymorphism was detected by PCR assay, Turner syndrome children were divided according to GHR exon3 genotype for homozygous for the full-length GHR isoform （fl/fl-GHR）and carriers of one or two copies of the GHR exon3 allele（fl/d3-GHR;d3/d3-GHR）.According to the karyotype, the children were divided into 45,X karyotype group and other karyotype group. The height standard deviation （Ht-SDS） and growth velocity （GV） as indicators to measure rhGH treatment efficacy, the data were analyzed by the SPSS12.0 software （t test, one-way ANOVA and multiple linear regression analysis）.Results（1） The mean age at diagnosis of 31 cases was （12.2±2.9） years, the bone age was （8.9±2.4） years, the height was （126.2±10.5） cm and the Ht-SDS was （-3.5±1.3） SDS. The karyotype was 45,X in 14 patients, 17 cases had other karyotypes. Thirteen cases were of （fl/fl-GHR） （42%）, 14 cases of fl/d3-GHR （45%） and 4 cases of d3/d3-GHR（13%）.Among the 31 cases, the main reason for 5 patients＇ hospitalization was no secondary sexual characteristics, another 26 cases had short stature （accounting for 81%）.（2） After Growth hormone treatment, growth rate （cm/year）（7.3±1.4, 7.0±3.0, 7.0±1.3） and Ht-SDS （-2.8±1.2, -2.5±0.9, -2.2±0.8） were significantly higher than the pre-treatment levels （2.9±0.9, -3.5±1.3）, the difference was statistically significant （F=54.12, 4.43, P〈0.05） ; the third year Ht-SDS（-2.2±0.8）higher than the first year Ht-SDS（-2.8±1.2）, the difference was statistically significant （t=-2.3, P〈0.05） .（3）Before rhGH treatment, the height of 45,X karyotype group was significantly lower than that of other karyotypes （（122.1±9.1） cm vs. （129.9±10.3） cm, t=-2.2, P〈0.05））. Before and after rhGH treatment, there was no significant difference in growth rate （cm/year） and Ht-SDS, between 45, X karyotype group and other karyotype group, but with the prolongation of treatment time, the Ht-SDS of other karyotype groups had an improvement trend compared with the 45,X karyotype groups. （4） After short-term and long-term treatment with rhGH, there were no significant differences in GV, Ht-SDS between patients with different genotypes （P〉0.05）. （5） Multivariate linear regression analysis showed that ΔHt-SDS was negatively correlated with the age at initial treatment（partial regression coefficient=-0.098, P 〈0.05）, and positively correlated with GV before treatment（partial regression coefficient=0.202, P〈0.05）.ConclusionsIn Turner＇s syndrome children, the earlier the rhGH treatment started, the faster the growth rate before treatment and the longer treatment duration, the better effect of rhGH treatment was obtained. Before rhGH treatment, the height of 45,X karyotype group was significantly lower than that of other karyotypes. Before and after rhGH treatment, there was no significant difference in growth rate （cm/year） and Ht-SDS, but with the prolongation of treatment time, the Ht-SDS of other karyotype groups had an improvement trend compared with the 45,X karyotype groups. GHR exon 3 polymorphism did not significantly affect the efficacy of rhGH in Turner syndrome children, but large-scale long-term studies are still needed.