165例儿童性发育异常疾病的临床、遗传学与病理学分析

Clinical, genetic, and pathological analysis in 165 children with disorders of sex development

摘要:

目的 探讨性发育异常疾病（disorders of sex development, DSD）患儿的临床表型、遗传特点和病理学特征。方法 回顾性分析2008年8月—2022年12月河北省儿童医院和唐山市妇幼保健院收治的165例DSD住院患儿的流行病学、临床表型、染色体核型、性腺病理及基因检测等资料。结果 165例DSD患儿中，首诊原因以矮小（62/165，37.6%）、阴蒂肥大（33/165，20.0%）、隐睾（28/165，17.0%）、尿道下裂（24/165，14.5%）、皮肤黑和/外阴色素沉着（19/165，11.5%）较常见。127例进行了染色体核型分析，结果显示36例（28.3%）为46,XX DSD，34例（26.8%）为46,XY DSD，57例（44.9%）为性染色体异常。在性染色体异常核型中，以45,X核型（11/57，19%）和45,X伴其他核型嵌合（36/57，63%）多见。16例进行了性腺组织病理学活检，获得25份性腺组织。性腺组织活检显示3份为睾丸，3份为发育不良睾丸，6份为卵巢，11份为卵睾，条索状性腺和性腺缺如各1份。基因检测显示23例（23/36，64%）携带致病性/可能致病性变异，其中12例为CYP21A2基因致病变异导致的21-羟化酶缺乏性先天性肾上腺皮质增生症。结论 矮小、阴蒂肥大、隐睾、尿道下裂、皮肤色素沉着为DSD患儿的常见表型；45,X伴其他核型嵌合和CYP21A2基因复合杂合变异是DSD患儿的主要病因；患儿性腺活检以卵睾、卵巢和睾丸/发育不良睾丸常见。

Abstract:

Objective To investigate the clinical phenotypes, genetic characteristics, and pathological features of children with disorders of sex development (DSD).Methods A retrospective analysis was conducted on epidemiological, clinical phenotype, chromosomal karyotype, gonadal pathology, and genotype data of 165 hospitalized children with DSD at Children's Hospital of Hebei Province and Tangshan Maternal and Child Health Hospital from August 2008 to December 2022.Results Among the 165 children with DSD, common presenting symptoms were short stature (62/165, 37.6%), clitoromegaly (33/165, 20.0%), cryptorchidism (28/165, 17.0%), hypospadias (24/165, 14.5%), and skin pigmentation abnormalities/exteriorized pigmented labia majora (19/165, 11.5%). Chromosomal karyotype analysis was performed on 127 cases, revealing 36 cases (28.3%) of 46,XX DSD, 34 cases (26.8%) of 46,XY DSD, and 57 cases (44.9%) of sex chromosome abnormalities. Among the sex chromosome abnormal karyotypes, the 45,X karyotype (11/57, 19%) and 45,X/other karyotype mosaicism (36/57, 63%) were more common. Sixteen children underwent histopathological biopsy of gonadal tissues, resulting in retrieval of 25 gonadal tissues. The gonadal tissue biopsies revealed 3 cases of testes, 3 cases of dysplastic testes, 6 cases of ovaries, 11 cases of ovotestes, and 1 case each of streak gonad and agenesis of gonads. Genetic testing identified pathogenic/likely pathogenic variants in 23 cases (23/36, 64%), including 12 cases of 21-hydroxylase deficiency congenital adrenal hyperplasia caused by CYP21A2 pathogenic variants.Conclusions Short stature, clitoromegaly, cryptorchidism, hypospadias, and skin pigmentation abnormalities are common phenotypes in children with DSD. 45,X/other karyotype mosaicism and CYP21A2 compound heterozygous variants are major etiological factors in children with DSD. The most commonly observed gonadal histopathology in children with DSD includes ovotestes, ovaries, and testes/dysgenetic testes.