416例性发育异常患者临床表现、分子遗传学及性腺病理分析——单中心队列研究

Clinical Manifestations,Molecular Genetics and Gonadal Pathology of 416 Patients with Disorders of Sex Development:A Single-Center Cohort Study

目的探讨性发育异常(DSD)患者临床表现、分子遗传学及性腺病理特点,总结从常见症状中发现罕见病的临床经验。方法回顾性分析2018年5月至2023年8月在广州医科大学附属妇女儿童医疗中心DSD多学科中心诊疗的416例DSD患者的临床资料,归纳统计与讨论。结果416例DSD患者按照染色体核型分类:性染色体核型异常者92例(22.1%)、46,XY核型者285例(68.5%)和46,XX核型者39例(9.4%)。92例性染色体核型异常患者中,按男性抚养59例,主诉阴茎短小合并尿道下裂及隐睾18例(30.5%);92例中最常见核型是45,X/46,XY,共58例(63.0%)。285例染色体核型46,XY患者中,按男性抚养238例,主诉阴茎短小合并尿道下裂63例(26.5%);按女性抚养47例,主诉腹股沟包块13例(27.7%)。216例46,XY核型患者进行全外显子组检测,发现155例(71.8%)存在与临床表型相符的分子致病原因。39例染色体核型46,XX患者按男性抚养19例,主诉阴茎短小合并尿道下裂8例(42.1%),性腺活检18例,显示性腺含睾丸组织者17例,行全外显子组测序14例中发现NR5A1基因杂合变异、SRY基因变异和SOX3基因变异各2例(均14.3%);按女性抚养20例,主诉阴蒂肥大14例(70.0%),性腺活检8例,活检显示卵睾7例(87.5%),发现NR5A1基因杂合变异1例(14.3%)。结论DSD患者病因复杂多样,临床表现异质性大,可以表现为尿道下裂、小阴茎、隐睾等泌尿系统常见症状体征,不同病因的治疗抉择不同,因此,可以通过染色体核型、分子遗传学检测及性腺病理等检查明确病因,尤其对于罕见病,可提高检出率减少漏诊率,确保合理治疗,尤其是性别选择。

Objective To investigate the clinical manifestations,molecular genetics and gonadal pathology characteristics of patients with disorders of sex development(DSD),and to summarize the clinical experience of identifying rare diseases from common symptoms.Methods The clinical data of 416 patients with DSD diagnosed and treated in the multidisciplinary center of DSD of Guangzhou Women and Children′s Medical Center from May 2018 to August 2023 were retrospectively analyzed,summarized and discussed.Results According to chromosome karyotype,416 cases of DSD were classified into three types:92 cases(22.1%)of abnormal sex chromosome karyotype,285 cases(68.5%)of 46,XY karyotype and 39 cases(9.4%)of 46,XX karyotype.Among the 92 patients with abnormal sex chromosome karyotype,59 cases were raised as males,18 cases(30.5%)complained of short penis with hypospadias and cryptorchidism.The most common karyotype was 45,X/46,XY(58 cases,63.0%).Among the 285 patients with 46,XY karyotype,238 cases were raised as males,and 63 cases(26.5%)complained of short penis and hypospadias;47 cases were raised as females,and 13 cases(27.7%)complained of inguinal mass.A total of 216 patients with 46,XY karyotype were subjected to whole exome gene detection,and 155 cases(71.8%)were found to have molecular pathogenesis with the clinical phenotype.Among the 39 patients with 46,XX karyotype,19 cases were raised as males,and 8 cases(42.1%)complained of short penis and hypospadias.In the 18 cases of gonad biopsy,17 cases showed testicular tissue in gonads.Whole exome sequencing was performed in 14 cases.NR5A1 gene heterozygous mutation,SRY gene mutation and SOX3 gene mutation were found in 2 cases,respectively(14.3%).Twenty cases were raised as females,and 14 cases(70.0%)complained of clitoral hypertrophy.Gonad biopsy was performed in 8 cases,with 7 cases of ovotestis(87.5%)and 1 case of NR5A1 gene heterozygous mutation(14.3%).Conclusions The etiologies of DSD are complex and diverse,and the clinical manifestations are various,which can be manifested as hypospadias,micropenis,cryptorchidism and other common symptoms of the urinary system.Different etiologies have different treatment options.Therefore,chromosome karyotype,molecular genetic testing and gonadal pathology can be used to clarify the cause of disease,especially for rare diseases,improve the detection rate,reduce the rate of missed diagnosis,and ensure reasonable treatment,especially sex selection.