Prepubertal XY gonadal dysgenesis

Two children had prepubertal XY gonadal dysgenesis. A 7-year-old girl with clitoral enlargement had a left ovarian tumor that contained a dysgerminoma; the right gonad proved to be a gonadoblastoma. The second child (a 2-year-old girl) showed poor physical development and slight virilization of the genitalia. Her bilateral dysgenetic gonads were removed at exploratory laparotomy. The occurrence of gonadal tumors in XY gonadal dysgenesis is increased. It is probably related to the hypergonadotropinism existing from childhood as well as to genetic predisposition of the cryptorchid testis in the presence of a Y chromosome. Our first patient is one of the youngest who had XY gonadal dysgenesis iwth gonadoblastoma reported. The indication of prophylactic gonadectomy in XY gonadal dysgenesis is emphasized.     

Alopecia congenita universalis,microcephaly, cutis marmorata,short stature and XY gonadal dysgenesis: variable expression of El-Shanti syndrome

Alopecia congenita, laryngomalacia, and XY gonadal dysgenesis has been reported recently as a new syndrome in two unrelated Arab families from Jordan. We report a 4-year-old girl of first cousin Arab parents who had alopecia, microcephaly, cutis marmorata, short stature and borderline cognitive development. Karyotype analysis revealed a male constitution (46,XY) with no deletion of STS or SRY. She showed entirely normal female external genitalia and absence of female internal genitalia. Histological examination of the very small testicles found on laparascopy showed developed spermatic cords and paratesticular tissue with no testicular parenchyma, no Sertoli or Leydig cell development, and no seminiferous tubular development. Hormonal profile was that of a normal female child. Southern blotting and PCR assays showed an intact Y chromosome. Limited sequencing of the SRY gene revealed no mutations. Conclusion: this patient, together with the recently reported consanguineous families, represent a previously unrecognised autosomal recessive trait with pleiotropic effects including XY gonadal dysgenesis.     

Idiopathic male pseudohermaphroditism: variations in presentation and management

Male pseudohermaphroditism (MPH) is the abnormal development of genitalia in an individual with a 46,XY chromosome complement and testicular tissue. The etiology of MPH is unknown in most cases, which are defined as idiopathic. OBJECTIVE: To analyze the data for cases of idiopathic MPH. PATIENTS AND METHODS: A retrospective study of 29 patients with idiopathic MPH and no uterus. Results: Four patients had a family history of abnormal sexual development and five had low birth weight. The initial manifestations were sexual ambiguity (26), microphallus and hypospadias (2), and primary amenorrhea (1). Basal and/or stimulated testosterone concentrations showed insufficient testosterone secretion in three patients. Genitography showed a vagina in 13 patients. Male genitoplasties were performed on 21 out of the 24 patients reared as males and female genitoplasties on five patients. Histological studies of the gonads of these showed streak gonads in one, normal gonads in one and signs of testicular dysgenesis in three others. Molecular studies on the SRY gene (17) showed no mutation. CONCLUSIONS: Idiopathic male pseudohermaphroditism is a heterogeneous condition, even within families with a history of this condition. We propose a set of guidelines for the management of these patients.     

Ullrich-Turner syndrome: relevance of searching for Y chromosome fragments

Forty consecutive patients with Ullrich-Turner syndrome (UTS) were followed-up and investigated for the presence of Y chromosome fragments in their genomes. We used the polymerase chain reaction (PCR) to detect SRY (sex-determining region on the Y chromosome) and the sequence-tagged sites (STS) sY57, sY59, sY85, sY94, sY124 and sY157--which correspond to regions 3C (sY57 and 59), 5C, 5G, 5P, and 6F, respectively, of the Y chromosome--searching for Y fragments that could bear the putative locus (loci) for gonadoblastoma (GBY). It has been shown that the presence of GBY greatly increases the risk of dysgenic gonads to undergo malignant transformation. Among our 40 patients, we found Y-derived sequences--including SRY and the region spanning from sY57 to sY94--in two. These two patients had a marker chromosome detected by conventional cytogenetic analysis (45,X/46,X + mar). Their gonads were excised and found to be streaks. In one of the patients, we found foci of primitive sex cords (amidst the gonadal stroma), oviducts and Wolffian remnants. Fluorescence in situ hybridization (FISH) did not show Y chromosome material in her gonad-derived fibroblasts. The other girl had hyperplastic Leydig cells in the gonadal stroma, oviducts and Wolffian remnants, with signs of epididymal differentiation. PCR assays performed on DNA extracted from paraffin-embedded gonadal tissue were negative for SRY sequences in both patients. These findings show that all UTS patients should be examined for Y chromosome material, and that positive cases should have their dysgenic gonads excised due to the high risk of malignancy.     

SRY基因检测在儿童性发育疾病诊断中的应用

目的：应用SRY基因直接测序检测技术和外周血染色体核型分析技术对外生殖器模糊的幼儿及青春期儿童进行检查以明确诊断。方法：采用常规G显带方法分析20例外生殖器模糊的患儿染色体核型,用PCR技术扩增其SRY基因,进行基因测序,分析是否存在SRY基因及SRY基因是否存在突变情况。结果：20例患儿中SRY基因阳性的有17例,阴性3例。直接测序结果显示所有SRY基因阳性患者该基因均未发生突变。染色体核型分析中检出4例特殊核型为：46, XY, del (Y) (q12)/45, X、46, XY, add (Y) (p11)、46, XY, r (9)及46, XY, 9 qh+。结论：SRY基因检测有助于明确儿童性发育疾病的分型,具有快速检测的优越性,与常规G显带相结合分析有助于儿童性发育疾病的初步诊断。     

Global gene profiling and comprehensive bioinformatics analysis of a 46,XY female with pericentric inversion of the Y chromosome

XY females are rare individuals who carry a Y chromosome but are phenotypically female. In approximately 80–90% of these cases, there are no mutations in the SRY gene, a testis-determining gene on the short arm of the Y chromosome, and the pathophysiology of XY females without SRY mutation remains unclear. In the present study, we used a molecular data mining technique to analyze the pathophysiology of an XY female with functional SRY and pericentric inversion of the Y chromosome, and compared the results with those of a normal male. Interestingly, upregulations of numerous genes included in the development category of the Biological Process ontology, including genes associated with sex determination and organ morphogenesis, were seen in the patient. Additionally, the transforming growth factor-β (TGF-β) signaling pathway and Wnt signaling pathway, in which most cell–cell interactions during embryonic development are involved, were altered. Alterations in the expression of numerous genes at the developmental stage, including alterations at both the gene and pathway levels, may persist as a vestige of anomalies of sex differentiation that presumably began in the fetal period. The present study indicates that a data mining technique using bioinformatics contributes to identification of not only genes responsible for birth defects, but also disorders of sex development (DSD)-specific pathways, and that this kind of analysis is an important tool for clarifying the pathophysiology of human idiopathic XY gonadal dysgenesis. Our findings could serve as one of the basic datasets which will be used for future follow-up investigations.     

Mixed gonadal dysgenesis. Apropos of a series of 21 cases

Twenty-one cases of mixed gonadal dysgenesis referred at age 1 to 16 years are studied. External genitalia were in most cases of types III-IV, with a small penis and posterior hypospadias, asymmetrical genital folds containing an externalized testis on one side. The internal genitalia varied according to the degree of dysgenesis of the gonads, and included an uterus and/or a vagina in 18 among the 21 cases. A chromosomal mosaicism XO/XY or XX/XY was found in 11 patients, the other 10 having a normal 46 XY caryotype. Pubertal follow-up was obtained in 10 cases, and showed always a male sexual development, without possibility to exactly evaluate the function of the testis. Choosing the sex assignment is relatively easy in newborns or infants with mixed gonadal dysgenesis. It relies more on anatomy (size of corpora cavernosa, feasibility of urethroplasty or vaginoplasty) than on the results of hormonal measurements. The presence of an Y chromosome is not by itself an argument to choose the male sex. In most cases, the choice of the female sex is the easiest and relies on strong clinical arguments, but it leads unavoidably to suppress both the testis and the dysgenetic gonad.     

A sex reversal infant with XX karyotype and complete male external genitalia

The unusual case of a Japanese newborn XX male is presented. Examination of chromosomes in amniotic fluid cells had shown a normal female karyotype (46,XX), but ultrasonography revealed a penis and a scrotum. The neonate had normal male external genitalia, and serum levels of luteinizing hormone follicle stimulating hormone, and testosterone were all within the normal range. High resonance chromosome analysis revealed an excess portion on the short arm of one of the X chromosoms. We examined his genomic DNA by polymerase chain reaction (PCR) and detected two Y specific regions in his genomic DNA, the sex-determining region Y (SRY) and pseudoautosomal boundary Y. Nucleotide sequencing of the PCR products of SRY indicated no mutation. These findings suggested that the translocation or insertion of an SRY region on the X chromosome led to the development of testicles and a male phenotype.     

Medical and psychosexual outcome in women affected by complete gonadal dysgenesis

BACKGROUND: Prenatal exposure to testicular hormones influences the development of brain structures and behavior in many non-human mammalian species. Less understood is the role of possessing a Y chromosome, independent of testicular hormones, on psychosexual differentiation. HYPOTHESIS: Phenotypic women affected by complete gonadal dysgenesis possess a 46,XY chromosome complement and streak gonads. This population is suitable to test the influence of an absence of androgens and Müllerian inhibiting substance on psychosexual development in genetic males. PATIENTS: Three 46,XY women diagnosed with complete gonadal dysgenesis participated. METHODS: Psychosexual development, medical outcome and knowledge of medical condition were assessed with a written questionnaire and a physical examination. RESULTS: All participants were healthy, compliant with their hormone therapy, and exhibited female-typical psychosexual development. However, participants were poorly informed about their condition and the fertility treatment options available to them. CONCLUSIONS: These data indicate no obvious role for genes on the Y chromosome, outside of its pseudoautosomal region and SRY, on psychosexual differentiation in genetic males who do not produce testicular hormones. Greater efforts need to be made to educate affected women about their pregnancy options.     

Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature

The main factor influencing the sex determination of an embryo is the genetic sex determined by the presence or absence of the Y chromosome. However, some individuals carry a Y chromosome but are phenotypically female (46,XY females) or have a female karyotype but are phenotypically male (46,XX males). 46,XX maleness is a rare sex reversal syndrome affecting 1 in 20,000 newborn males. Molecular analysis of sex-reversed patients led to the discovery of the SRY gene (sex-determining region on Y). The presence of SRY causes the bipotential gonad to develop into a testis. The majority of 46, SRY-positive XX males have normal genitalia; in contrast SRY-negative XX males usually have genital ambiguity. A small number of SRY-positive XX males also present with ambiguous genitalia. Phenotypic variability observed in 46,XX sex reversed patients cannot be explained only by the presence or absence of SRY despite the fact that SRY is considered to be the major regulatory factor for testis determination. There must be some other genes either in the Y or other autosomal chromosomes involved in the definition of phenotype. In this article, we evaluate four patients with 46,XX male syndrome with various phenotypes. Two of these cases are among the first reported to be diagnosed prenatally.     

Y chromosome sequences in Turner's syndrome: association with virilization and gonadoblastoma

The presence of Y chromosome fragments in patients with Turner's syndrome is known to increase the risk of gonadoblastoma and virilization. Y chromosome material is detected in up to 6% of patients with Turner's syndrome by karyotype. By DNA analysis, Y chromosome sequences have been reported in 0-60% of patients. The putative gonadoblastoma gene has been mapped to the pericentromeric region of the Y chromosome increasing the interest in studying these sequences. AIMS: 1. To determine the frequency of occult Y chromosome sequences in patients with Turner's syndrome. 2. To analyze the clinical implications of Y sequences detected by karyotype and occult Y sequences. STUDY DESIGN: Cross-sectional study of 58 patients with Turner's syndrome (30 45,X; two with structural anomalies; 26 mosaic [two of whom were 45,X/46,XY]). SRY, TSPY and DYZ3 sequences were amplified by PCR using genomic DNA from peripheral blood. RESULTS: All three Y chromosome sequences were found in one out of 56 patients whose karyotype was not suggestive of having Y chromosome material and in one patient with 45,X/46,Xr(X) karyotype. The patients with the ring chromosome and 45,X/46,XY karyotype underwent surgery and were found to have a gonadoblastoma and dysgerminoma. The four patients with Y chromosome material had non-virilized female genitalia. CONCLUSIONS: Analysis by PCR was more sensitive in detecting Y chromosome sequences than conventional karyotype. The presence of Y material was not associated with virilization. We confirmed the association of Y fragments and gonadoblastoma at an early age.     

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。     

Familial male pseudohermaphroditism

Familial male pseudohermaphroditism (MPH) due to 17, 20-desmolase deficiency is rare. Here we present two siblings with MPH possibly due to 17, 20-desmolase deficiency. The first patient presented with unambiguous female external genitalia and hypergonadotrophic hypogonadism. Chromosomal analysis revealed 46 XY. Ultrasound evaluation of pelvis revealed gonads in the inguinal canal, and no uterus. These findings were confirmed on laparotomy. Histology revealed the gonads to be testes. The second patient had ambiguous genitalia (perineoscrotal hypospadias, bifid scrotum with palpable gonads) with a 46 XY chromosomal pattern. Both patients had high plasma 17-hydroxy progestrone (17 OHP), low normal dehydro epiandrosterone sulphate (DHEAS) and low plasma testosterone. Plasma testosterone and DHEAS showed no response to ACTH or HCG. These features are compatible with the diagnosis of 17, 20-desmolase deficiency.     

Video-assisted gonadectomy in children with Ullrich Turner syndrome or 46,XY gonadal dysgenesis.

Patients with dysgenetic gonads carry a high risk for the development of gonadal neoplasia. The aim of the study is to evaluate indications and feasibility of laparoscopy and video-assisted prophylactic gonadectomy in children with Ullrich Turner syndrome (UTS) or 46,XY gonadal dysgenesis (GoDy). Between 1996 and December 2002 five girls with UTS and nine patients with 46,XY GoDy (female gender role) were explored by laparoscopy. Video-assisted salpingo-oophorectomy or gonadectomy was performed using a three-port technique. Prophylactic salpingo-oophorectomy was exclusively performed in UTS patients with proven presence of translocated parts of the Y chromosome. In three patients with 46,XY GoDy laparoscopy was followed by surgical revision of the groin and open gonadectomy in four patients. In two cases with UTS the removed streak gonads contained small unilateral tumours stage pT1a, and in four cases of 46, XY GoDy histopathological investigation revealed bilateral neoplasms stage pT1b. We found the following tumour types: gonadoblastoma, dysgerminoma, testicular intraepithelial neoplasia, and mature teratoma. In conclusion, investigative laparoscopy gives a good image of the internal genital structures and allows the safe removal of the dysgenetic gonads during the same operation. The high rate of gonadal tumours underlines the indication for early gonadectomy in these patients.     

Association of Turner's syndrome and Swyer's syndrome in the same family

We report two phenotypically and genetically different diseases in the same family. One patient presented with Turner phenotype as a result of chromosomal mosaicism 45,X/46,X, inv(X)(q21;q24) (30%/70%). Her father's sister showed 46,XY female gonadal dysgenesis (Swyer's syndrome) as a result of a point mutation in the SRY gene on her Y chromosome. DNA sequencing revealed a G-->C transversion (nucleotide position 693) resulting in a change from glycine95 to arginine (G95R). Here we report for the first time an association of Turner's syndrome and Swyer's syndrome in the same family.     

Central and gonadal hypogonadism in X-linked lissencephaly

OBJECTIVE: To directly test gonadal function in a patient with X-linked lissencephaly with ambiguous genitalia (XLAG) in light of lack of previous functional data. STUDY DESIGN AND RESULTS: We studied an infant who failed to increase testosterone levels in response to hCG stimulation. CONCLUSION: In XLAG, the gonads are not only structurally dysgenetic but also functionally abnormal.     

A del(X)(p11) carrying SRY sequences in an infant with ambiguous genitalia

Background  

SRY (sex-determining region, Y) is the gene responsible of gonadal differentiation in the male and it is essential for the regular development of male genitalia. Translocations involving the human sex chromosomes are rarely reported, however here we are reporting a very rare translocation of SRY gene to the q -arm of a deleted X chromosome. This finding was confirmed by cytogenetic, fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR).     

Sertoli cell tumor and intratubular germ cell neoplasia located in separate gonads in an adolescent patient with complete androgen insensitivity: a case report and review of literature

Complete androgen insensitivity syndrome (AIS) is an X-linked disorder of sex development. Surgical management entails timely gonadectomy given the risk of malignant transformation. Our patient presented at age 15 years with primary amenorrhea. Initial laboratory testing showed elevated testosterone, luteinizing hormone, anti-Müllerian hormone levels, and 46,XY karyotype. Imaging studies showed no uterus, ovaries, and identified two candidate gonads. She underwent bilateral gonadectomy. Pathology reports revealed Sertoli cell and intratubular germ cell tumors located in separate gonads. Our case is the first report of the youngest patient with AIS with bilateral gonadal tumors derived from different histological origins. We also review literature for reports of AIS patients with gonadal tumors. Currently, there is no consensus for the timing of gonadectomy in AIS patients. However, given the varying potential for malignant transformation of gonads in AIS patients with different phenotypes, development of a standardized treatment guideline is indicated.