Association of gene mutation degree with initial biochemical indices and therapeutic effect of 21-hydroxylase deficiency in Qingdao area
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.
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