Abstract: Objective To analyze the difference on initial therapeutic responses in patients with congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations, stratified by residual enzymatic activity, in order to provide basis for clinical diagnosis, management, and prognosis prediction. Methods A retrospective analysis was conducted on the clinical data of 34 patients who were screened and genetically confirmed at the Qingdao Neonatal Disease Screening Center between January 2010 and July 2023. Multiplex Ligation-dependent Probe Amplification (MLPA) combined with Sanger sequencing was employed to detect pathogenic CYP21A2 mutations. Patients were grouped according to the residual enzymatic activity of mutated CYP21A2 into five genotypic categories: Null (activity=0), Group A (<1%), Group B (2% - 11%), Group C (20% - 50%), and Group D (activity unknown). Differences in diagnostic and treatment indicators among these mutation severity groups were analyzed. Results 1) In addition to the large fragments, mutations were more frequently detected in intron region 2(29.82%), exon 4(28.87%), and exon 10(12.28%), with exon 10 exhibiting the greatest variety of mutations than other areas. 2) Excluding 3 cases in Group D with unknown enzymatic activity, the positive predictive value of genotype-phenotype correlation for the remaining 31 patients was 90.32%.3) All children in the Null group and group A in Qingdao area started treatment within 1 month. Statistically significant differences were observed among Null, A, B, and C groups for the initiation time of treatment (H=11.568), progesterone (H=13.864), testosterone (H=13.249), sodium (H=17.370), potassium levels (H=19.613), and 17-hydroxyprogesterone concentrations (H=10.720) (P<0.05). However, no significant differences were noted in the time to normalization of 17-OHP levels or the initial dose of hydrocortisone among the four genotypic groups (P>0.05). Conclusions The gene mutations of 34 patients in Qingdao are prone to intron 2, exon 4 and exon 10, and there are many kinds of mutations in exon 10. There is a strong correlation between genotype and phenotype, which decreased with the decrease of enzyme activity. Mutation severity significantly influences the timing of treatment initiation and levels of 17-OHP, and rogens, and electrolytes, while having no significant effect on the time to 17-OHP normalization or the initial dosage of hydrocortisone required.

Key words: 21-hydroxylase deficiency, CYP21A2 gene mutation, genotype-phenotype, neonatal disease screening

摘要： 目的 分析21-羟化酶缺乏症CYP21A2基因不同突变程度的初始治疗效果的差异性,为临床诊治及预后提供依据。 方法 回顾性分析2010年1月—2023年7月期间在青岛市新生儿疾病筛查中心筛查并基因确诊的34例患者的临床资料,联合应用多重链接依赖探针扩增技术及Sanger测序对致病基因CYP21A2进行检测,根据CYP21A2基因突变的残留酶活性,分为5个不同的基因型组:Null组(酶活性=0)、A组(酶活性<1%)、B组(酶活性2%~11%)、C组(酶活性约20%~50%)、D组(酶活性未知),探讨基因不同突变程度之间诊治指标的差异性。 结果 1)除外大片段缺失,34例患者中基因突变发生在内含子2区(29.82%)、第4外显子(28.07%)、第10外显子(12.28%)的比例较高,且第10外显子发生的突变种类较其他地区多。2)除外D组3例患儿(酶活性未知),本研究31例患儿的基因型-表型阳性预测值为90.32%。3)Null组、A组患儿均在1月内开始治疗,Null组、A组、B组、C组开始治疗的时间(H=11.568)、孕酮(H=13.864)、睾酮(H=13.249)、钠离子(H=17.370)、钾离子(H=19.613)、17-羟孕酮浓度(H=10.720)差异均有统计学意义(P<0.05);4个基因组间17-羟孕酮恢复正常时间、初始氢化可的松用量差异无统计学意义(P>0.05)。 结论 青岛地区34例患者的基因突变易发生在内含子2区、第4外显子、第10外显子,且第10外显子发生的突变种类较多。基因型-表型具有良好相关性,随酶活性降低而降低。基因突变程度对开始治疗的时间、17-羟孕酮、雄激素、电解质有显著影响,对17-羟孕酮恢复正常的时间、初始醋酸氢化可的松药量无显著影响。

关键词: 21-羟化酶缺乏症, CYP21A2基因突变, 基因型-表型, 新生儿疾病筛查