333例智力低下发育迟缓患儿染色体分析

染色体异常是先天性智力低下及先天畸形的主要原因之一，也是儿科遗传性疾病的重要组成部分，我们总结1992年以来，333例智力低下、发育迟缓、两性畸形等患儿进行外周血染色体核型分析，现报告如下。     

手术治疗8例两性畸形临床分析

两性畸形属胚胎期性分化异常所致，是常染色体或X性连锁隐性遗传病。临床上以性腺发育、染色体核型、内外生殖器及第二性征表现分为真性、男性及女性假两性畸形。我院于1990年4月至1994年10月，4年间手术治疗两性畸形8例．其姐妹患同样睾丸女性化综合征1例。8例中真性两性畸形2例，男性及女性候两性畸形各3例。治疗情况报道如下。     

黄体生成素受体基因的激活突变与青春期发育关系的研究进展

黄体生成素受体(LHR)基因突变会影响人类尤其是男性的性发育。本文从黄体生成素受体基因的定位、激活突变的类型、对两性性发育的影响以及可能的致病机制等方面对国外LHR基因激活突变的分子遗传学研究进展进行综述。     

小儿尿道下裂、性发育异常临床常见病因探讨

目的 通过总结和分析1982年4月～2007年5月遗传室男性小儿尿道下裂、性发育异常等临床常见泌尿生殖系统疾病的主要类型和分布,探讨25年来该类疾病发生的相关变化及其发病原因.方法 详细观察就诊者症状体征,病史搜集,资料登记,染色体检查,激素水平,B超,CT,MRI,骨龄检测等.结果 1982年～1997年间,主要以小儿外阴异常,性别模糊,两性畸形等具有综合征性质的中、重度泌尿生殖道畸形多见.1998年～2007年间以出生后及青春期前男性小儿外生殖器发育不良,肥胖等为主要疾病类型,而近年来孕早、中期用药,特别是使用雌孕激素保胎所致小儿尿道下裂病例有较快增长.结论 环境中内分泌干扰物所致男性小儿生殖系统发育不良和孕早、中期使用雌孕激素保胎所致单纯性尿道下裂已成为目前临床常见的小儿泌尿生殖系统疾病类型,此类疾病通过采取措施可以得到较好地预防和加以避免.     

性发育异常患者的细胞分子遗传学分析

目的: 探讨性发育异常患者的细胞分子遗传学特征。方法: 应用多重连接依赖的探针扩增(MLPA)技术对3例染色体核型为46,XX的男性性反转综合征患者及1例女性假两性畸形患者父母进行SRY、CYP21A2、DSS、DAX1、WNT4、SOX9、NR5A1等性别相关基因的拷贝数筛查,并采用细菌人工染色体(BAC)克隆制备探针,以荧光原位杂交技术(FISH)进行基因定位。结果: 3例男性性反转综合征患者经MLPA基因筛查均发现存在单拷贝SRY基因,FISH技术鉴定存在2条X染色体,SRY基因易位于其中1条X染色体的短臂上;女性假两性畸形患者的母亲染色体核型为46,XX,MLPA基因筛查发现其CYP21A2-ex03杂合性缺失,CYP21A1P-ex02杂合性重复;父亲染色体核型为46,XY,MLPA基因筛查发现CYP21A2-ex01和CYP21A2-ex03杂合性缺失,CYP21A1P-ex02和CYP21A1-ex10杂合性重复。结论: 性别决定是以SRY基因为主导、其它多个基因参与的过程,对性发育异常患者进行MLPA基因筛查有利于明确病因。     

30例性发育异常患者的SRY基因研究

目的对30例性发育异常患者进行分子遗传学检查以探讨性别异常的原因。方法用实时荧光定量聚合酶链反应(fluorescence quantitative poiym erace chain reaction,FQ-PCR)的方法检测SRY基因。结果11例46,XY男性尿道下裂,SRY( );2例46,XY睾丸女性化综合症,SRY( );8例46,XX女性假两性畸形,SRY(-);3例46,XX两性畸形,SRY( );1例46,XY尿道下裂,SRY(-);1例46,XX阴蒂肥大,SRY( );1例46,XY阴蒂肥大,SRY( );2例45,X/46,XY男性,其中1例SRY( ),1例SRY(-);1例46,XX/46,XY男性,SRY( )。结论性分化异常患者进行SRY基因检测对诊断和治疗及探讨其发病机制具有十分重要意义。     

假两性畸形临床-细胞遗传学分析

本文经细胞遗传学、内分泌检查、B超、MRI、手术探查及病理检查,诊断4例假两性畸形.其中女性假两性畸形1例,男性假两性畸形3例.根据患者性腺功能情况和外生殖器矫形的可能性,结合患者和(或)家属意愿,确定性别,进行手术矫形及选择性的性腺切除.结合文献对假两性畸形的临床表现及治疗作简要探讨.     

真两性畸形1例尸体解剖报道

真性两性畸形是人类性分化畸形中最少见和复杂的一种 ,占两性畸形的 2 0 %。国内对真两性畸形的临床报道较多见 ,但对真两性畸形的尸体解剖国内外文献尚少见报道。我们收集到的一具无名真两性畸形尸体的解剖结果报道如下 :死者因车祸致下肢大出血而亡 ,年龄在 3 0岁左右 ,社会性别、婚姻和家族史无从考证。体形和面部特征如女性 ,皮肤较细嫩 ,但四肢尚粗大 ,身高 166cm ,上半身 90cm ,下半身 76cm。无喉结和胡须 ,有少许腋毛 ,阴毛稀少。乳房发育差。外阴呈现两性 (图 1) ,阴茎短小 ,长 3cm ,直径 1.5cm ,有龟头 ,龟头上可见尿道口 ,阴茎向…     

性发育异常患者的SRY基因分析

应用PCR扩增及PCR产物直接测序对12例性发育异常患者进行SRY基因检测,12例患者中,5例患者的社会性别与染色体性别不相符。2例性反转患者SRY结果与洒色体性别不一致,其他10例SRY基因与染色体性别均一致,即存在Y染色体的患者,SRY为阳性,无Y染色体的患者,SRY为阴生。4例确诊为性反转;2例为假两性畸形,其中1例为肾上腺增生综合症,4例为要亡命民SRY基因未见异常但伴有性器官发育不良。上述,兴类的民中能是SRY基因为主导,一系列基因参与协调的调控串模式,而性别的分化则可能是由SRY决定性别后,在由其他因素参与共同完成的。SRY基因检测是诊断性另发育异常患者的重要手段。     

性腺发育及生育功能异常的染色体分析CSCD

【摘要】目的分析性腺发育及生育功能异常患者的染色体核型。方法对因原发闭经、性腺发育异常、卵巢功能早衰、不孕不育等原因就诊的患者进行染色体核型分析。结果在1386例患者中,共114例存在染色体异常,异常率为8．2％。性染色体异常52例,占异常核型的45．6％。其中特纳综合征24例,占性染色体异常的46．2％;克氏综合征18例,占34．6％;47,XYY3例、47,XXX3例、性反转2例、两性畸形2例,比率分别为5．8％、5．8％、3．8％、3．8％。结论性染色体异常是导致原发闭经、性腺发育异常、卵巢功能早衰、不孕不育等疾病的重要原因之一,对该类患者应做到早诊断、早治疗。     

Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA

The distal region on the short arm of chromosome 9 is of special interest for scientists interested in sex development as well as in the clinical phenotype of patients with the 9p deletion syndrome, characterized by mental retardation, trigonocephaly and other dysmorphic features. Specific genes responsible for different aspects of the phenotype have not been identified. Distal 9p deletions have also been reported in patients with 46,XY sex reversal, with or without 9p deletion syndrome. Within this region the strongest candidates for the gonadal dysgenesis phenotype are the DMRT genes; however, the genetic mechanism is not clear yet. Multiple ligation-dependent probe amplification represents a useful technique to evaluate submicroscopic interstitial or distal deletions that would help the definition of the minimal sex reversal region on 9p and could lead to the identification of gene(s) responsible of the 46,XY gonadal disorders of sex development (DSD). We designed a synthetic probe set that targets genes within the 9p23-9p24.3 region and analyzed a group of XY patients with impaired gonadal development. We characterized a deletion distal to the DMRT genes in a patient with isolated 46,XY gonadal DSD and narrowed down the breakpoint in a patient with a 46,XY del(9)(p23) karyotype with gonadal DSD and mild symptoms of 9p deletion syndrome. The results are compared with other patients described in the literature, and new aspects of sex reversal and the 9p deletion syndrome candidate regions are discussed.     

Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development

Arboleda VA, Lee H, Sánchez FJ, Délot EC, Sandberg DE, Grody WW, Nelson SF, Vilain E. Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development. Disorders of sex development (DSD) are rare disorders in which there is discordance between chromosomal, gonadal, and phenotypic sex. Only a minority of patients clinically diagnosed with DSD obtains a molecular diagnosis, leaving a large gap in our understanding of the prevalence, management, and outcomes in affected patients. We created a novel DSD‐genetic diagnostic tool, in which sex development genes are captured using RNA probes and undergo massively parallel sequencing. In the pilot group of 14 patients, we determined sex chromosome dosage, copy number variation, and gene mutations. In the patients with a known genetic diagnosis (obtained either on a clinical or research basis), this test identified the molecular cause in 100% (7/7) of patients. In patients in whom no molecular diagnosis had been made, this tool identified a genetic diagnosis in two of seven patients. Targeted sequencing of genes representing a specific spectrum of disorders can result in a higher rate of genetic diagnoses than current diagnostic approaches. Our DSD diagnostic tool provides for first time, in a single blood test, a comprehensive genetic diagnosis in patients presenting with a wide range of urogenital anomalies.     

Molecular genetics of hypospadias and cryptorchidism recent developments

During the last decade, a tremendous amount of work has been devoted to the study of the molecular genetics of isolated hypospadias and cryptorchidism, two minor forms of disorders of sex development (DSD). Beyond the genes involved in gonadal determination and sex differentiation, including those underlying androgen biosynthesis and signaling, new genes have been identified through genome-wide association study and familial clustering. Even if no single genetic defect can explain the whole spectrum of DSD, these recent studies reinforce the strong role of the genetic background in the occurrence of these defects. The timing of signaling disruption may explain the different phenotypes.     

A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant

Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.     

COG6-CDG: Expanding the phenotype with emphasis on glycosylation defects involved in the causation of male disorders of sex development

COG6-congenital disorder of glycosylation (COG6-CDG) is caused by biallelic mutations in COG6. To-date, 12 variants causing COG6-CDG in less than 20 patients have been reported. Using whole exome sequencing we identified two siblings with a novel homozygous deletion of 26 bp in COG6, creating a splicing variant (c.518_540 + 3del) and a shift in the reading frame. The phenotype of COG6-CDG includes growth and developmental retardation, microcephaly, liver and gastrointestinal disease, hypohydrosis and recurrent infections. We report two patients with novel phenotypic features including bowel malrotation and ambiguous genitalia, directing attention to the role of glycoprotein metabolism in the causation of disorders of sex development (DSD). Searching the glycomic literature, we identified 14 CDGs including males with DSD, a feature not previously accentuated. This study broadens the genetic and phenotypic spectrum of COG6-CDG and calls for increasing awareness to the central role of glycosylation processes in development of human sex and genitalia.     

Gonadoblastoma and selected other aspects of gonadal pathology in young patients with disorders of sex development

Some patients with disorders of sex development (DSDs), previously known as intersex disorders, have abnormal gonadal development and an increased risk of germ cell tumors. Because of their relative rarity, however, many pathologists are unfamiliar with the morphological findings in the gonads of DSD patients and their clinical significance. This review concentrates on some of the most common DSDs where gonadal specimens may come to the attention of pathologists. It highlights the findings in gonadal dysgenesis, a DSD with a spectrum of clinical, pathologic, and molecular features but with the shared attributes of having both Y chromosomal material (even if in very limited amounts) in the gonad and also having mutations or deletions in genes necessary for normal gonadal development, mostly in those upstream of the SOX9 gene. This situation results in testicular tissue lacking normal Sertoli cells, which are now considered an essential element for the normal maturation of the primordial germ cells that migrate to the gonad from the embryonic yolk sac. Germ cells with delayed maturation mimic neoplastic germ cells, but there are both morphological and immunohistochemical differences. If the gonad having germ cells with delayed maturation also harbors the TSPY gene on the GBY locus of the Y chromosome, the cells may undergo neoplastic transformation and result in the distinctive gonadoblastoma, whose pathologic features are explored at length herein, including its potential for variant morphologies, such as a “dissecting” pattern. Another important DSD, the androgen insensitivity syndrome (AIS), is discussed at length, including the varied appearances of the testis and its distinctive lesions—hamartomas and Sertoli cell adenomas. The potential for germ cell neoplasia in the partial AIS is also discussed and contrasted with that of the complete AIS. A third major topic is ovotesticular DSD (true hermaphroditism). The clinical features and morphology of this condition are reviewed, including the arrangements of the tissue components in an ovotestis. Several other DSDs with distinctive gonadal findings are also considered, including Klinefelter syndrome, 5α-reductase deficiency, 17β-hydroxysteroid dehydrogenase deficiency, and female adrenogenital syndrome.     

Mammalian sex determination—insights from humans and mice

Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models.     

Gene dosage imbalances in patients with 46,XY gonadal DSD detected by an in-house-designed synthetic probe set for multiplex ligation-dependent probe amplification analysis

The development of a testis requires the proper spatiotemporal expression of the SRY gene and other genes that act in a dosage-sensitive manner. Mutations in the SRY gene account for only 10–15% of patients with 46,XY gonadal disorder of sex development (DSD). To enable the diagnostics of deletions and duplications of genes known to be involved in different forms of DSD, we developed a synthetic probe set for multiplex ligation-dependent probe amplification (MLPA) analysis. Here, we report the results from the analysis of 22 patients with 46,XY gonadal DSD. The analysis with the DSD probe set has led to the identification of two copy number variations, an 800-kb NR0B1 ( DAX1 ) locus duplication on Xp21 in a patient with isolated partial gonadal dysgenesis and a duplication of the SRD5A2 gene that represents a rare normal variant. The described MLPA kit represents an optimal complement to DNA sequence analysis in patients with DSD, enabling screening for deletions and duplications of several genes simultaneously. Furthermore, the second identification of an NR0B1 locus duplication in a patient with isolated gonadal dysgenesis, without dysmorphic features and/or mental retardation, highlights the importance of evaluating NR0B1 duplication in patients with gonadal dysgenesis.