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J Zhejiang Univ (Med Sci)  2019, Vol. 48 Issue (4): 358-366    DOI: 10.3785/j.issn.1008-9292.2019.08.02
    
Progress on evaluation, diagnosis and management of disorders of sex development
CHEN Guangjie(),WANG Xiaohao,TANG Daxing*()
Department of Urology, the Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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Abstract  

Disorders of sex development (DSD) refer to a group of diseases characterized by abnormal congenital development of chromosomes, gonad or genitals with different pathophysiological changes and clinical manifestations. DSD is more common in neonates and adolescents, and neonates often show genital abnormalities while adolescents show abnormal sexual development during puberty. It is the international consensus that the scope of DSD should include basic clinical evaluation (internal and external genitalia and endocrine hormones), diagnostic confirmation (chromosome, genetic diagnosis), psychological assessment for children and family, treatment (sex assignment, hormone replacement and surgical intervention), potential fertility protection and long-term follow-up, which require the expertise of pediatric endocrinology, pediatric urology, clinical psychology, genetic disciplines, medical images and other related disciplines; that is, individualized management of children with DSD requires an experienced multidisciplinary team (MDT). This article reviews the recent progress on the evaluation, diagnosis and management of disorders of sex development.



Key wordsDisorders of sex development/diagnosis      Disorders of sex development/therapy      Benchmarking      Review     
Received: 13 March 2019      Published: 30 October 2019
CLC:  R726.9  
Corresponding Authors: TANG Daxing     E-mail: dr.chenguangjie@zju.edu.cn;tangdx0206@zju.edu.cn
Cite this article:

CHEN Guangjie,WANG Xiaohao,TANG Daxing. Progress on evaluation, diagnosis and management of disorders of sex development. J Zhejiang Univ (Med Sci), 2019, 48(4): 358-366.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2019.08.02     OR     http://www.zjujournals.com/med/Y2019/V48/I4/358


性别发育异常的评估、诊断和治疗研究进展

性别发育异常(DSD)是指由于先天性的染色体、性腺或性别解剖结构发育出现异常,导致疾病谱广泛、有不同病理生理改变且临床表现各异的一组疾病,新生儿常表现为生殖器异常,而青少年则表现为青春发育期异常的性发育。随着对DSD的深入研究,国际上已形成共识,即DSD的基本临床评估(内外生殖器及内分泌激素)、诊断建立(包括染色体、基因诊断)、患儿及家庭的心理评估、治疗(包括性别分配、激素的替代及外科手术选择)、潜在的生育能力保护及长期的追踪随访等一系列工作已非小儿泌尿外科单一学科能承担,需要小儿内分泌科,小儿泌尿外科、临床心理科、遗传学科、影像学科及其他相关学科的共同参与。本文就近年来DSD的评估、诊断和治疗等方面的进展作一综述。


关键词: 性发育障碍/诊断,  性发育障碍/治疗,  规范,  综述 
基因 蛋白质 基因座 遗传特性 性腺 米勒管结构 外生殖器 伴发临床特点
AD:常染色体显性遗传;AR:常染色体隐性遗传;CAH:先天性肾上腺皮质增生.
单个基因
WT1 转录因子 11p13 AD 发育不全睾丸 阳性/阴性 模棱两可至完全女性外阴 WAGR综合征、Denys-Drash和Frasier综合征
SF1 核受体转录因子 9q33 AD/AR 发育不全睾丸 阳性/阴性 模棱两可至完全女性外阴 严重者合并原发性肾上腺功能衰竭、轻者单发部分性性腺发育不全
SRY 转录因子 Yp11.3 Y连锁遗传 发育不全睾丸或卵睾 阳性/阴性 模棱两可至完全女性外阴
SOX9 转录因子 17q24~25 AD 发育不全睾丸或卵睾 阳性/阴性 模棱两可至完全女性外阴 躯干发育异常
DHH 信号分子 12q13.1 AR 发育不全睾丸 阳性 完全女性外阴 严重者合并微束神经病变
ATRX 解旋酶 Xq13.3 X连锁遗传 发育不全睾丸 阴性 男性、模棱两可或完全女性外阴 合并α地中海贫血、智力发育迟缓
引起染色体改变的关键候补基因
DMRT1 转录因子 9P24.3 单体缺失 发育不全睾丸 阳性/阴性 模棱两可至完全女性外阴 智力发育迟缓
DAX1 核受体转录因子 Xp21.3 Xp21复制 发育不全睾丸或卵巢 阳性/阴性 模棱两可至完全女性外阴 合并智力发育迟缓、唇腭裂等畸形
WNT4 信号分子 1p35 1p35复制 发育不全睾丸 阳性 模棱两可 合并智力发育迟缓、唇腭裂、宫内发育迟缓、小头畸形、法洛四联症等
导致激素合成或作用异常的基因
LHGCR G蛋白受体 2p21 AR 睾丸 阴性 模棱两可至完全女性外阴或小阴茎 Leydig细胞发育不全
DHCR7 11q12~13 AR 睾丸 阴性 男性、模棱两可或完全女性外阴 Smith-Lemli-Opitz综合征
STAR 线粒体膜蛋白 8p11.2 AR 睾丸 阴性 完全女性外阴 先天性类脂性肾上腺增生、青春期发育障碍
CYP11A1 15q23~24 AR 睾丸 阴性 模棱两可或完全女性外阴 CAH、青春期发育障碍
HSD3B2 1p13.1 AR 睾丸 阴性 模棱两可 CAH、原发性肾上腺功能衰竭
CYP17 10q24.3 AR 睾丸 阴性 模棱两可至完全女性外阴或小阴茎 CAH、高血压
POR(P450氧化还原酶) CYP酶电子供体 7q11.2 AR 睾丸 阴性 男性,模棱两可 Antley-Bixler综合征
HSD17B3 9q22 AR 睾丸 阴性 模棱两可或完全女性外阴 青春期男性化不全
SRD5A2 2p23 AR 睾丸 阴性 模棱两可或小阴茎 青春期男性化不全
AMH 信号分子 19p13.3~13.2 AR 睾丸 阳性 正常男性表型 米勒管永存综合征
AMH受体 丝氨酸/苏氨酸激酶跨膜受体 12q13 AR 睾丸 阳性 正常男性表型 米勒管永存综合征、双侧隐睾
AR 核受体转录因子 Xq11~12 X连锁遗传 睾丸 阴性 男性、模棱两可、小阴茎或完全女性外阴 完全性雄激素不敏感综合征、部分性雄激素不敏感综合征
Tab 1 Genes associated with 46, XY disorders of sex development
风险 疾病 恶变概率(%) 推荐方案
aGBY基因(包括TSBY基因)阳性.GD:性腺发育不良;PAIS:部分性雄激素不敏感综合征;CAIS:完全性雄激素不敏感综合征;17β-HSD:17β羟类固醇脱氢酶.
GD(有Y染色体) a腹腔内性腺 15~35 性腺切除(诊断时)
PAIS(性腺不位于阴囊内) 50 性腺切除(诊断时)
Frasier综合征 60 性腺切除(诊断时)
Denys-Drash综合征(有Y染色体) 40 性腺切除(诊断时)
中等 特纳综合征(有Y染色体) 12 性腺切除(诊断时)
17β-HSD 28 密切观察
GD(有Y染色体) a阴囊内性腺 未知 活检(青春期)+放疗
PAIS(性腺位于阴囊内) 未知 活检(青春期)+放疗
CAIS 2 活检(青春期)
卵巢睾丸性别发育异常 3 去除睾丸组织
特纳综合征(无Y染色体) 1
Tab 2 Risk of germ cell malignancy according to diagnosis
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