经典型21-羟化酶缺乏症女童男性化程度与基因型的关系

Association between the genotype and the degree of virilization in girls with classic 21-hydroxylase deficiency

目的探讨21-羟化酶缺乏症(21-OHD)女童CYP21A2基因型与其男性化程度之间的关系,以加深对21-OHD女童男性化程度的认识,指导产前诊断和遗传咨询。方法纳入2010年8月至2019年3月武汉儿童医院收治的23例染色体性别为46,XX的经典型21-OHD初诊患儿。将纳入女童的外生殖器男性化程度进行Prader分级,记录患儿的17-羟孕酮、雄烯二酮、睾酮、硫酸脱氢表雄酮水平与基因型。将基因变异进行分组[Null组(酶活性完全受损)、A组(保留正常酶活性的1%)、B组(保留正常酶活性的2%)、C组(保留正常酶活性的20%~60%)]。观察不同Prader分级基因变异与对应的各基因分组的相关性。结果23例女童均表现出不同程度的外生殖器男性化。Prader分级与基因变异类型呈正相关(rs=0.695,P<0.001)。基因A组、Null组与女童外阴PraderⅣ级的匹配性高达77.8%,外阴PraderⅡ级和PraderⅢ级的女童中有80%基因分类为B组。PraderⅣ级组女童初诊的睾酮水平显著高于PraderⅡ级组[4.6(4.0,15.0)μg/L比0.63(0.40,1.39)μg/L],差异有统计学意义(χ^(2)=15.117,P<0.05)。结论经典型21-OHD女童外生殖器男性化程度与基因变异导致的酶活性缺乏程度存在显著的正相关。可为携带CYP21A2基因的父母双方在产前诊断、遗传咨询和个体化诊疗提供重要价值。

Objective To explore the association between the CYP21A2 genotype and the virilization severity in girls with classic 21-hydroxylase deficiency(21-OHD),so as to further the understanding of virilization in females and provide guidance for prenatal diagnosis and genetic counseling.Methods A total of 23 patients with two X chromosomes(46,XX)who were newly diagnosed with classic 21-OHD in Wuhan Children′s Hospital from August 2010 to March 2019 were included.These patients were divided into 3 groups according to the Prader grades of the degree of external genitalia masculinization.The 17-hydroxyprogesterone(17-OHP)level,androstenedione(AND)level,testosterone(T)level,dehydroepiandrosterone sulphate(DHEAS)level and genotypes were recorded.The gene mutations were divided into the Null group(the enzyme activity was completely impaired),group A(1%of the normal enzyme activity was retained),group B(2%of the normal enzyme activity was retained)and group C(20%-60%of the normal enzyme activity was retained).The correlation between the gene variation of different Prader grades and the corresponding gene groups were analyzed.Results All 23 girls showed different degrees of external genitalia masculi-nization.There was a significant positive correlation between the Prader grades and the type of gene variation(rs=0.696,P<0.001).The gene group A and Null group were highly matched with the PraderⅣ(the matching rate:77.8%).Eighty percent of girls with PraderⅡand PraderⅢwere classified as the gene group B.The testosterone le-vel of girls with PraderⅣat first diagnosis was significantly higher than that of girls with PraderⅡ[4.6(4.0,15.0)μg/L vs.0.63(0.40,1.39)μg/L](χ^(2)=15.117,P<0.05).Conclusions There is a significantly positive and strong correlation between the degree of external genitalia masculinization and the degree of deficiency of enzyme activity caused by gene variation in girls with typical 21-OHD.It can provide reference for both parents carrying CYP21A2 gene in prenatal diagnosis,genetic counseling and individualized diagnosis and treatment.