41例46,XY性别发育异常临床诊治及基因筛查结果分析

目的探讨儿童46,XY性别发育异常的诊疗策略,并总结其诊疗经验。方法回顾性分析41例2011年9月至2018年11月于中国医科大学附属盛京医院确诊为46,XY DSD患儿的临床表现、实验室及影像学检查结果、基因检测结果和病理结果等资料,并总结其临床特征。结果41例中社会性别男28例(68.3%),女13例(31.7%),初诊年龄3个月至15岁。外生殖器完全女性化3例,外生殖器明显男性化17例,外生殖器模糊21例。染色体检查结果均为46,XY,且SRY基因阳性。35例行HCG激发试验,23例行性别发育相关基因筛查,8例行组织学检查。其中性腺发育异常17例,雄激素合成或作用缺陷16例,苗勒氏管永存综合征6例,Kallmann综合征2例。6例接受性腺切除术,10例接受外生殖器整形术,11例接受睾丸固定术,2例接受性别重新认定,10例未进行性别选择,其余29例维持原来社会性别。结论46,XY DSD患儿临床表现个体间差异较大,除性腺发育异常及睾丸消失综合征外,其余患儿最终需要结合基因检测结果以明确诊断。性别选择是46,XY DSD治疗的关键,需要全面评估后进行慎重选择。对于睾丸功能良好的患儿,最好让患儿自己参与性别的选择,尽量避免不可逆的性腺切除及外生殖器手术。     

46, XY 性发育障碍儿童 NR5A1 基因突变 1 例报告及文献复习

目的探讨NR5A1基因突变导致的46,XY性发育障碍(DSD)的临床表现和分子诊断。方法回顾分析1例社会性别为女性的46,XY DSD患儿的临床资料,并复习相关文献。结果社会性别为女性的11.5岁患儿,因偶然发现阴蒂肥大半个月就诊;初步系列实验室检查诊断考虑支持46,XY DSD,高促性腺激素性发育不良。全基因组外显子组DNA测序提示NR5A1基因,c.937 CT,p.Arg313Cys杂合突变;母亲为杂合突变携带者,父亲无异常。结论临床表现为46,XY DSD,性腺发育不良、外生殖器女性化合并肾上腺功能不足;提示存在SF1基因突变的可能性,全基因组外显子基因测序可帮助明确诊断。     

106例性别发育异常患儿性腺病理学特征及其临床意义的初步探讨

目的总结分析性发育异常(disorders of sex cdevelopmemt,DSD)患儿性腺的病理学特点及其临床意义。方法收集2010年8月至2018年1月间于浙江大学医学院附属儿童医院就诊并获取性腺病理学检查结果的DSD患儿临床资料,同时根据染色体结果分成性染色体DSD组、46,XX DSD组、46,XY DSD组共3组进行对比分析。结果共有106例DSD患儿获得性腺病理检查结果,肿瘤发生率为1. 8%。3组间EMS评分无统计学差异。性染色体DSD组21例,其中卵睾型DSD 10例(47.6%)、原始性腺7例(33.3%)、发育不良卵巢1例(4.8%)、发育不良睾丸3例(14.3%)。46,XX DSD组25例,其中卵睾型DSD 11例(44%)、原始性腺3例(12%)、发育不良卵巢9例(36%)、发育不良睾丸2例(8%)。46,XY DSD组60例,其中卵睾DSD 2例(3.3%)、原始性腺7例(11.7%)、发育不良卵巢5例(8.3%)、发育不良睾丸44例(73.3%)、性腺母细胞瘤2例(3.3%)。不同DSD染色体分型中各种病理类型的构成比存在统计学差异(P0.05)。结论对于诊断结果尚不明确、需要接受性腺病理检查的DSD患儿,EMS得分及性腺病理结果与染色体核型不存在较为明显的对应关系。性腺病理检查仍是DSD诊断及治疗的重要评估手段,这对DSD患儿的个体化处理具有重要意义。此外,性腺发生恶变的机率较小。     

45例两性畸形患儿的诊断及治疗分析

目的 探讨儿童两性畸形的诊断及治疗方法.方法 回顾性分析复旦大学附属儿科医院1987 ～ 2005年收治的45例两性畸形患儿临床资料,分析其病史特征、临床表现、诊断及治疗经过.结果 45例中,真两性畸形8例;男性假两性畸形21例;女性假两性畸形10例;其他6例,包括46 XX男性综合征1例,XO/XY性腺发育不全2例,46 XX/46,XY性腺发育不全1例,混合性性腺发育不良2例.临床多以出生后外生殖器畸形就诊,男性表现为尿道下裂、隐睾等,女性表现为阴蒂肥大、外阴畸形.39例患儿住院期间接受手术,切除与抚养性别不符的性腺,矫正外生殖器畸形.结论 两性畸形的早期诊断和正确治疗对患儿生理及性心理发育具有重要意义,最终性别的选择需根据外生殖器发育情况、性腺优势、染色体核型及家属意愿综合考虑决定.     

混合性性腺发育不良的临床特点与误诊分析

目的探讨混合性性腺发育不良(mixed gonadal dysgenesis,MGD)患儿的临床特点、导致误诊的原因及处理方式。方法回顾性分析2013年5月至2018年4月收治的24例MGD患儿的临床资料。24例患儿的年龄在10~39个月,平均21个月;身高71~97 cm,平均83 cm,其中10例患儿身高低于同年龄段平均身高2个标准差;就诊时22例抚养性别为男,2例抚养性别为女。Prader分级Ⅱ级3例,Ⅲ级15例,Ⅳ级6例。分析患儿性激素测定、性发育相关基因检测结果。对8例常规核型分析性染色体为46,XY的患儿采用荧光原位杂交(fluorescence in situ hybridization,FISH)方法复测,光学显微镜观察患儿切除或活检的性腺组织。结果本组患儿AMH值在16.57~189.92 ng/ml,均值为69.42 ng/ml;hCG刺激实验后睾酮值在0.71~8.09 nmol/L,均值为4.93 nmol/L。基因检测发现WT1基因致病突变,合并低蛋白血症和蛋白尿1例,诊断为Denys-Drash综合征。核型分析示,12例核型为45,X/46,XY,10例为46,XY(其中8例完成FISH检查证实性染色体为X嵌合XY),1例为45,X/46,XY/47,XYY,1例为45,X/47,XYY/48,XYYY。24例均存在阴道,22例探查到子宫或半角子宫。送检48份性腺组织,其中24份有发育不良的睾丸,其中1份睾丸性腺中可见未分化性腺组织。19份有纤维条索性腺,1份未分化性腺组织曾被误诊为卵巢。4份可见条索状性腺伴性索状结构。所有性腺组织均未见肿瘤征象。结论MGD患儿以外阴性别模糊多见常伴苗勒管残件。临床中对考虑诊断MGD的患儿不能仅采用染色体核型分析,可疑者应完善外周血FISH性染色体嵌合型检查。MGD患儿性腺病理检查可见未分化性腺类型,病理易将其识别为卵巢组织,从而将混合性性腺发育不良误诊为卵睾型DSD。     

卵睾型性发育异常单中心临床诊治分析

目的 总结卵睾型性发育异常的临床特点及诊治经验.方法 回顾性分析1993年1月至2015年12月就诊于医院并通过病理确诊卵睾型性发育异常的32例患儿临床资料和随访资料.社会性别:男30例,女2例.12.5％呈女性外貌,生殖器类别模糊,阴蒂1～3 cm,小阴唇发育差,有乳房发育;87.5％呈男性外貌,阴茎发育极差,重度下弯,尿道开口异常(位于阴囊处或会阴部),阴囊不同程度女性化,外形近阴唇貌,其中46.9％(15/32)伴有隐睾.染色体核型分析:46,XX卵睾型DSD 11例;46,XY卵睾型DSD 1例;性染色体异常DSD中的卵睾型性发育异常20例(嵌合性46,XY/46,XX6例;混合型14例).结果 11例行泌尿生殖系彩超和排泄性尿道阴道造影,二者结合检出率为100％(11/11).5例行SYR基因筛查,1例45,X卵睾型DSD及1例45,X/46,XY卵睾型DSD为SYR阳性,1例45,X/46,XY SYR基因为阴性,余2例46,XX卵睾型DSD中,50％SYR基因为阴性.64个性腺中16个卵睾,25个睾丸,23个卵巢.性腺畸形:双侧型5例,单侧型6例,片侧型21例.30例按男性抚养者均完成阴茎矫直术和尿道重建术.对29例患儿进行8个月～9年的随访,其中3例术后反复发生尿瘘,多次行尿瘘修补术,阴茎及睾丸发育极差,生活质量差;4例术后尿道开口位于冠状沟部或阴茎体部,排尿可;3例进入青春期后有乳房发育;2例阴茎、睾丸发育稍差;余阴茎形态可,长2.5～4.0 cm,睾丸测值较同龄人稍小.2例按女性抚养者均完成阴蒂矫形术,均获得满意的外观,1例处于青春期发育阶段,另1例予雌激素替代治疗后获得青春期发育,外阴形态可,有乳房发育.结论 早期诊断,确诊后是否立刻性别选择行手术治疗仍有争议,我们认为应将患儿的心理性别、社会性别作为参考的首要标准结合激素水平评估、优势性腺评估最后选择性腺切除或重建手术并辅以激素治疗.对于维持患儿正常的性生理、性心理及社会生活具有重要的意义.     

74例46,XX性发育异常患儿性腺探查结果及分析

目的 分析总结我院46,XX性发育异常患儿性腺探查结果并分析.方法 回顾性分析2006年1月至2015年12月期间就诊我科染色体核型为46,XX的性发育异常患儿98例,其中24例因内分泌科明确诊断CAH无需行性腺探查.另74例46,XX DSD为明确诊断行手术探查性腺,并取病理活检.根据术中探查所见内生殖器分布情况以及术后患儿的病理结果汇报归纳总结74例46,XX患儿性腺探查情况并分析.结果 除CAH外余74例46,XX DSD患儿中社会性别为:男48例,女26例.为明确诊断均行性腺探查术.其中单纯腹腔镜手术49例,腹腔镜联合开放手术12例,开放手术13例.性腺探查病理结果如下:双侧性腺均为卵睾25例(33.78％);一侧性腺为卵巢,一侧为睾丸13例(17.57％);一侧卵睾,一侧睾丸12例(16.22％);一侧卵睾,一侧卵巢18例(24.32％);双侧均为原始性腺2例(2.7％);一侧原始性腺,一侧卵巢2例(2.7％);一侧原始性腺,一侧睾丸2例(2.7％).31例含有卵巢性腺患儿中14例卵巢分布在左侧,占45.16％.25例含有睾丸性腺的患儿中11例睾丸位于右侧,占44％.结论 性腺探查及病理活检是46,XX DSD中除CAH外明确性发育障碍患儿的诊断及治疗方案重要的评估手段,对早期明确诊断、合理的选择性别及手术重建治疗具有重要的意义.     

46,XY性别发育异常的性腺处理

性分化异常是指先天性染色体、性腺和表型性别的发育异常或不匹配。根据芝加哥会议分型,46,XY DSD是病因最复杂的一类性分化异常。目前46,XY DSD患者的性腺处理仍存在一定争议。本文通过文献复习结合笔者临床经验,从性腺活检及探查、性腺恶变风险、性腺随访策略、性腺切除时机及指征等方面讨论46,XY DSD的性腺处理。     

Frasier综合征1例报告及基因分析

目的分析Frasier综合征的临床病理及致病基因特征。方法回顾分析1例Frasier综合征患儿的临床、病理特点,基因检测结果及诊治过程,并复习相关文献。结果患儿具有女性外生殖器,染色体核型46,XY,性腺发育不良(双侧卵巢未发育);肾病起病年龄为6岁,激素治疗无效。先后使用他克莫司、利妥昔单抗,虽血清白蛋白、胆固醇有所改善,肾功能无异常,但尿蛋白始终不能转阴。肾脏活检病理示局灶节段性肾小球硬化症,非特殊型,伴部分肾小球硬化。未发现性腺肿瘤、Wilms瘤等。基因检测WT1基因外显子9的c.1432+5GA剪接突变,为自发突变,已报道与Frasier综合征致病相关。结论 Frasier综合征临床表现主要为进展性肾病、男性假两性畸形、泌尿生殖系统畸形,与WT1基因突变有关。     

165例儿童性发育异常疾病的临床、遗传学与病理学分析北大核心CSCD

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。     

Laparoscopy versus ultrasonography for the evaluation of Mullerian structures in children with complex disorders of sex development

Purpose

The diagnosis of children with disorders of sex development (DSD) requires a karyotype, different biochemical and radiological investigations in the context of a multidisciplinary team. The aim of this study was to compare the diagnostic accuracy of laparoscopy (L) versus ultrasonography (US) in the assessment of children with complex DSD.

Methods

We retrospectively examined the theatre database searching for children with DSD who underwent laparoscopic surgery from 1999 to 2011. The medical and radiological records were reviewed.

Results

Eighteen patients were identified. Age at diagnosis ranged from birth to 14?years (mean 2.5?years). There were seven patients with 46XY dysgenetic testicular DSD (4 mosaic Turner, 3 mixed gonadal dysgenesis), seven patients with 46XY non-dysgenetic testicular DSD (4 persistent Mullerian duct syndrome, 2 complete androgen insensitivity syndrome, one unknown), two patients with ovotesticular DSD, one patient with 46XX DSD (congenital adrenal hyperplasia) and one patient with 46XY DSD complete sex reversal. Fifteen underwent ultrasonography prior to laparoscopy. Both modalities identified Mullerian structures in seven (47?%) patients, in one (7?%) patient US and L confirmed the absence of Mullerian structures, while in six (40?%) patients there was discordance, with US failing to visualize pelvic Mullerian structures. In the last patient with 46XY non-dysgenetic testicular DSD, the rectum was thought to be a dilated uterus on ultrasonography.

Conclusions

Pelvic ultrasonography failed to identify Mullerian structures in 40?% of patients with complex DSD. On the contrary, laparoscopy allowed excellent visualization of pelvic structures and gonads in children with complex DSD.     

The clinical and genetic heterogeneity of mixed gonadal dysgenesis: does “disorders of sexual development (DSD)” classification based on new Chicago consensus cover all sex chromosome DSD?

Clinical findings illustrate the wide spectrum of the phenotypic manifestations of 45,X/46,XY mosaicism in the sex chromosome disorders of sex differentiation (DSD). The objective of study is to evaluate the characteristics of 45,X/46,XY patients and questioning of their place within the DSD categorization. The clinical findings of 11 patients with 45,X/46,XY mosaicism are described including the presentation, gonadal morphology, genital anatomy, and the hormone levels among 285 patients with DSD evaluated. Sixty-seven patients were diagnosed with sex chromosome DSD (50 Turner, three Klinefelter, ten 45,X/46,XY gonadal disgenesis, one 45X/46,XY ovotesticular DSD, one 47,XYY ovotesticular DSD, and two 46,XX/46,XY ovotesticular DSD). The type and the percentage of patients with 45,X/46,XY mosaicism were as follows: Four cases of mix gonadal dysgenesis, four cases of partial gonadal dysgenesis, two cases of complete gonadal dysgenesis, one case of ovotesticular DSD. On the other hand, another patient that has 45,X/46,XX mosaicism was diagnosed with MGD with the presence of the streak gonad on the right side and the testis on the other side. Conclusion: We suggest that sex chromosome DSD categorization can include 45,X/46,XY PGD and 45,X/46,XY CGD. Mixed gonadal dysgenesis may be also placed among the disorders of testicular differentiation of 46,XY DSD subdivision.     

Impact of laparoscopy for diagnosis and treatment in patients with disorders of sex development

ObjectiveTo review laparoscopy in patients with disorders of sex development (DSD) in order to clarify its usefulness in diagnosis, devising subsequent therapeutic strategies and managing patients with various conditions.Patients and methodsBetween April 1992 and December 2012, 29 laparoscopic surgeries were performed in 25 DSD patients. Among them, ten were diagnostic laparoscopy including gonadal biopsy, and 19 were therapeutic laparoscopy. Surgical procedures and complications were evaluated.ResultsFor diagnostic laparoscopy, laparoscopic gonadal biopsy was performed in three patients. Inspection, with or without open gonadal biopsy, was performed on four out of seven patients with 46XY DSD or mixed gonadal dysgenesis (MGD). Additional surgery was planned and performed based on diagnostic laparoscopic findings in six out of seven patients. In the three patients with ovotesticular DSD, the gonadal pathology was diagnosed as: testis/ovary in one, testis/ovotestis in one and ovary/ovotestis in one – this was from the laparoscopic inspection and/or gonadal biopsy. However, the final diagnoses were bilateral ovotestis in two patients and ovary/ovotestis in one patient.For therapeutic laparoscopy, surgical procedures were: gonadectomy in 17 patients (bilateral in 13, unilateral in three, partial in two); hysterectomy in two patients; orchiopexy in one; and sigmoid vaginoplasty in one patient (included multiple procedures). There were no severe perioperative complications. In the four patients with a history of diagnostic laparoscopy, no severe intra-abdominal adhesions that would disturb therapeutic laparoscopic surgery were observed.ConclusionWhile diagnostic laparoscopy was helpful in devising a therapeutic surgical strategy in most of the patients with DSD who were suspected as having complex gonadal status or Müllerian duct derivatives, attention must be paid to precisely diagnosing the gonadal status in ovotesticular DSD. On the other hand, therapeutic laparoscopic surgeries were valuable procedures in treating DSD patients, even with a history of previous diagnostic laparoscopy.     

Disorders of gonadal development: a broad clinical, cytogenetic and histopathologic spectrum

The most complicated group of sexual differentiation disorders is that of gonadal development. Disorders of gonadal development form a wide clinical, cytogenetic and histopathological spectrum. There are still some unsolved difficulties of diagnosis, development of malignancy and the sex rearing of these patients. We reviewed 23 cases of gonadal developmental disorders among 169 patients with ambiguous genitalia or delayed puberty. Among 169 patients, 87 patients were 46,XY disorders of sex development (DSD), 59 patients were 46,XX DSD without disorders of gonadal development and the remaining 23 patients had disorders of gonadal development. Nine of these 23 patients were diagnosed as 46,XY gonadal dysgenesis, 7 patients had ovotesticular DSD, 5 patients had 45,X/46,XY mixed gonadal dysgenesis. Fourteen patients with disorders of gonadal development had genital ambiguity, 5 patients had a female genital phenotype with a palpable gonad and/or delayed puberty. Four patients had the male genital phenotype. Disorder of gonadal development is a very important clinical problem with different aspects of diagnosis, treatment, rearing sex and prophylaxis. Each patient should be evaluated individually employing a multidiciplinary approach.     

Gender role across development in adults with 46,XY disorders of sex development including perineoscrotal hypospadias and small phallus raised male or female

Self-rated degree of femininity and masculinity across development were evaluated for 40 adults affected by 46,XY disorders of sex development (DSDs) who presented at birth with a small phallus and perineoscrotal hypospadias, raised either male (n = 22) or female (n = 18). Most participants were confirmed or presumed to be affected by partial androgen insensitivity syndrome (n = 14), partial gonadal dysgenesis (n = 11), or were considered to have a poorly defined case of 46,XY DSD including ambiguous external genitalia (n = 15). Participants retrospectively evaluated their degree of masculinity and femininity during their childhood, adolescence, adulthood, and in the past 12 months of filling out a questionnaire pertaining to their psychosexual development. Participants raised male reported more masculinity than those raised female due to an increase in masculinization during adolescence and adulthood. Participants raised male also reported less femininity than those raised female throughout development. Participants raised female reported more femininity than those raised male due to an increase in feminization during adolescence and adulthood. Participants raised female also reported less masculinity than those raised male throughout development. These data support the proposition that some aspects of gender role (GR), such as masculinity and femininity, are capable of proceeding along female- or male-typic patterns depending on sex of rearing among individuals affected by specific types of 46,XY DSD. Furthermore, regardless of male or female rearing, GR increasingly corresponds with assigned sex as individuals proceed through sexual maturity and into adulthood. These results are consistent with the idea that socialization/learning contributes to GR development in humans in addition to data from others demonstrating endocrine influences.     

The use of laparoscopy in intersex patients

The management of intersex patients is a challenge. Although in the majority of patients the diagnosis may be made on the basis of cytogenetic and biochemical tests, there is a selective group of patients with difficulties in the establishment of final diagnosis and gender assignment. Since laparoscopy has been used in the management of impalpable gonads in the normal male population, it may be an alternative method for the diagnosis and surgical management of intersex patients. Thus we have evaluated our experience with laparoscopy in intersex population. Over the last 10 years (1995–2005) more than 80 intersex patients underwent surgical correction at our department. Out of those, 14 patients with a median age of 3 years (range 2–18 years) underwent laparoscopic surgery. Laparoscopic gonadectomy with subsequent estrogen replacement was performed following gonadal biopsy in five patients with androgen insensitivity syndrome (AIS). In three patients with mixed gonadal dysgenesis (MGD) gonadal biopsy was performed. In two of those the initial diagnosis was changed to true hermaphroditism, and they underwent removal of ovotestis from one side and orchidopexy of the normal testis on the other. In one patient with MGD, timed gonadectomy following laparoscopic biopsy was performed due to malignant potential of the streak gonads. In two patients with persistent müllerian duct syndrome (PMDS), laparoscopic orchidopexy was performed following gonadal biopsy. Three patients with total gonadal dysgenesis (TGD) underwent laparoscopic gonadectomy and one with true hermaphroditism underwent laparoscopic biopsy followed by bilateral inguinal orchiectomy with preservation of the ovarian tissue. Our data show that the laparoscopic gonadal biopsy remains the only way to obtain morphologic gonadal structure and to establish a final diagnosis in doubtful cases. Magnification and easy access to the pelvic cavity allow removal of gonads or ductal structures with the advantages of minimally invasive procedure.     

Pediatric disorders of sex development

The management of disorders of sexual differentiation (DSD) involves a multidisciplinary approach. The main aim of analysis was to study the phenotype-karyotype correlation in North Indian children with DSD. The records of pediatric DSD were retrieved and characteristics noted. Of total of 58 children, 43 (74.1%) and 10 (17.2%) were raised as males and females respectively. The mean age at presentation was 31.3±9 months. The karyotype was 46XY in 45 (77.6%) and 46XX in 12 (20.7%). CAH was commonest cause of DSD (36.2%), followed by gonadal dysgenesis. Of the 15 patients of 46 XY CAH, there were 5 with 17-α hydroxylase deficiency, 2 with 3-β HSD deficiency and one case of lipoid adrenal hyperplasia. There was an excess of genetic males, possibly due to prevalent socio-cultural factors and gender bias favoring males. There is a need to improve the diagnostic facilities and incorporate a team approach in management of DSD.