NR5A1基因变异致46,XY性发育异常15例的基因型及表型分析

Phenotypic and molecular characterizations of 46,XY disorders of sex development due to variants of NR5A1 gene

目的通过分析15例NR5A1基因变异导致的46,XY性发育异常的临床及分子遗传学特点。方法回顾性分析2016年3月至2021年12月在郑州大学附属儿童医院诊断的46,XY性发育异常患者中NR5A1基因变异患儿的病例资料。对患儿进行全外显子组测序,确认候选位点,并进行Sanger测序验证。根据患儿疾病特点对患儿进行治疗并跟踪随访。结果15例患儿初诊年龄在0.17~14岁,其中5例以女性抚养、10例以男性抚养。性腺组织为睾丸,无残留Müllerian或卵睾丸结构,均有程度不同的外生殖器异常,外生殖器男性化程度(EMS)评分平均为4.8分,包括小阴茎(100.0%)、尿道下裂(86.7%)、阴囊未融合(46.7%)、睾丸位置异常(60.0%),其中尿道下裂为Ⅱ°~Ⅳ°。5例生长迟缓,均无皮肤色素沉着。患儿染色体核型均为46,XY,促肾上腺皮质激素、皮质醇水平、电解质均在正常范围,绒促性素激发试验5例反应正常,9例反应低下。抗苗勒管激素和抑制素B随着年龄增长而异常下降。15例患儿共检出14个NR5A1变异位点,变异多发生在第4外显子,其中9个变异位点为截至2022年12月在HGMD数据库未见收录。结论NR5A1基因变异致46,XY性发育异常临床表型广泛,外生殖器表现为程度不同的雄性化不足,肾上腺受累罕见。

ObjectiveThe clinical and molecular genetic characteristics of 46,XY disorders of sex development caused by NR5A1 gene variants in 15 cases were analyzed to improve the understanding of this disease.MethodsThe clinical data of children with NR5A1 gene variants diagnosed at the Children′s Hospital Affiliated to Zhengzhou University from March 2016 to December 2021 were retrospectively analyzed.Whole exome sequencing was performed to confirm the candidate sites,and Sanger sequencing was performed for validation.The patients were treated and followed up according to their disease characteristics.ResultsAt the initial diagnosis,5 of the 15 cases were raised as females and 10 as males.The gonadal tissue was testis without residual Müllerian or ooticular structure,and all had various degrees of genital abnormalities.The average EMS masculinity score was 4.8(1~9),including micropenis(100.0%),hypospadia(86.7%),unfused scrotum(46.7%),and abnormal testicular position(60.0%),in which the hypospadias wasⅡ°~Ⅳ°.There was no skin pigmentation in 5 patients with growth retardation.Chromosomol karyotypes were 46,XY,adrenocorticotropin and cortisol levels were normal,electrolyte levels were normal,HCG stimulation test in 5 cases had normal response,9 cases had low response.Anti-Müllerian hormone and statin B had decreased abnormally with age.A total of 14 NR5A1 variants were detected in the 15 children,most of which occurred in exon 4,of which 9 variant loci were not included in the HGMD database as of December 2022.ConclusionThe clinical phenotype of 46,XY abnormal sexual development caused by NR5A1 gene variants is extensive,with the external genitals showing varying degrees of insufficient masculinization.Adrenal involvement is rare.