Dysgenetic Gonads Research Articles

Association of Distal Deletion of the Short arm of Chromosome 9 with 46,XY Disorder of Sex Development and Gonadoblastoma

Deletion of the short arm of chromosome 9 is associated with two distinct clinical prototypes. Small telomeric distal 9p deletions have been reported in patients 46,XY with gonadal dysgenesis, this region contains genes required in two copies for normal testis development. Recent studies have narrowed the interval 9p24.3-pter containing the putative autosomal testis-determining gene(s) known as domain DMRT. On the other hand, and depending on the extent of deletion of the short arm, the clinical characteristics of monosomy 9p syndrome may emerge. We present an infant female with complete 46,XY gonadal dysgenesis, who was examined for motor developmental retardation. In the karyotype a chromosomal deletion 9p24.1 was identified by cytogenetic and fluorescence in situ hybridization studies. No SRY deletion or mutation was detected. Ultrasonographic studies showed a normal uterus. Basal luteinizing hormone and follicle stimulating hormone values were high. The patient underwent gonadectomy at 3.2 years of age, and histologic analysis disclosed dysgenetic gonads with gonadoblastoma.

Mixed gonadal dysgenesis in 45,X Turner syndrome with SRY gene.

Turner syndrome is the most common chromosomal disorder in girls. Various phenotypic features show depending upon karyotype from normal female through ambiguous genitalia to male. Usually, Turner girls containing 45,X/46,XY mosaicism, or sex-determining region Y (SRY) gene may have mixed gonadal dysgenesis with various external sexual differentiation. We experienced a short statured 45,X Turner girl with normal external genitalia. Because SRY gene was positive, laparoscopic gonadectomy was performed. The dysgenetic gonads revealed bilateral ovotesticular tissues. The authors report a mixed gonadal dysgenesis case found in clinical 45,X Turner patient with positive SRY gene. Screening for SRY gene should be done even the karyotype is 45,X monosomy and external genitalia is normal.

Swyers Syndrome: primary amenorrohea with gonadal dysgenesis a rare cause

Swyer syndrome is an uncommon form of gonadal dysgenesis, characterised by a 46, XY karyotype (1). In spite of presence of Y chromosome the affected individual has a female phenotype as the dysgenetic gonad produces neither AMH nor androgens. As a result of failure of masculinisation of both internal and external genitalia is that of a female. These cases generally present at puberty with primary amenorrhoea and lack to development of secondary sexual characteristics. With this case report, we aimed to underline the necessity of considering 46, XY complete pure gonadal dysgenesis in the differential diagnosis in every adolescent female patient with primary amenorrhoea and the importance of early gonadectomy in order to avoid the risk for gonadal tumour development.

Oophorectomy versus salpingo-oophorectomy in Turner syndrome patients with Y-chromosome material: clinical experience and current practice patterns assessment

Background/purposeGonadectomy is recommended in Turner syndrome (TS) patients with Y-chromosome material due to high risk of tumor in the dysgenetic gonads. No recommendations exist on whether concurrent salpingectomy should be performed. MethodsA retrospective chart review of surgical procedure and histopathology in TS patients with Y-chromosome enrolled in a TS database was undertaken at Cincinnati Children’s Hospital Medical Center. An electronic survey was sent to members of the International Pediatric Endosurgery Group to assess prevalent practice patterns and attitudes on gonadectomy and concurrent salpingectomy in this population. ResultsIn March 2011, 12/158 (8%) TS girls (mean age 6.6years) enrolled in the database had TS with Y-chromosome. Gonadoblastoma was identified in 4/12 (33%) patients and 2/4 had malignant transformation to dysgerminoma and teratoma. Approach to gonadectomy was varied and 3/12 had concurrent salpingectomy. Fifty-four laparoscopic surgeons responded to the survey with no clear consensus on whether salpingectomy should be concurrently performed. ConclusionsTS patients with Y-chromosome have an increased risk of gonadal tumor development and gonadectomy is recommended. While there is no consensus among pediatric laparoscopic surgeons on concurrent salpingectomy, it is reasonable to consider this combination procedure.

Swyer Syndrome: A Case Report

Swyer syndrome was first identified in 1955 by Doctor Swyer in 2 women with primary amenorrhea, normal female external genitals, vagina and cervix, tall and, a 46.XY karyotype (1). Patients with Swyer syndrome have female phenotype. They usually present with delayed puberty or primary amenorrhea due to absence of functional gonads and reproductive potential. 25% of cases develop gonadoblastoma or dysgerminoma (2). Here, we present a 23-year-old patient with Swyer syndrome who had gonadoblastom in both dysgenetic gonads.

Tumor del saco vitelino puro con síndrome de Turner mosaico X0/XY

El síndrome de Turner es una afección genética por falta de un cromosoma X. Algunos casos se presentan con mosaicos XY, aumentando el riesgo de tumores gonadales de comportamiento maligno. Es importante determinar la presencia del cromosoma Y para realizar la extirpación profiláctica de las gónadas disgenésicas. Presentamos el caso de una paciente con síndrome de Turner, mosaico 45,X0/46,XY, asociado a tumor del saco vitelino puro gigante. Esta asociación es un caso extremadamente raro de tumor maligno en una paciente con disgenesia gonadal mixta.Palabras clave: Síndrome de Turner, mosaicismo, disgenesia gonadal, tumor del saco vitelino.

Expression of SALL4 and SF-1 in Gonadoblastoma

Gonadoblastoma is a rare gonadal neoplasm composed of primordial germ cells and sex cord-stromal cells and usually occurs in patients with dysgenetic gonads. When patients with gonadoblastoma develop an invasive germ cell tumor, the invasive germ cell component can take the form of dysgerminoma/seminoma, embryonal carcinoma, or yolk sac tumor. In this study, we performed immunohistochemical analysis for SALL4 and steroidogenic factor-1 (SF-1) on 4 cases of gonadoblastoma to examine the expression patterns of these proteins. All of the patients were phenotypically female. One patient had Swyer syndrome, the rest had Turner syndrome. The primordial germ cell component was histologically similar to cells in dysgerminoma/seminoma in these 4 cases. Two patients showed the invasive component-dysgerminoma. As expected, SALL4 stained the germ cells and SF-1 stained the sex cord-stromal cells. There was a clear distinction between the staining patterns of these 2 cell populations. This study demonstrates the utility of SALL4 and SF-1 in determining whether or not there is an invasion in the primordial germ cell component.

Dysregulation of the mitosis–meiosis switch in testicular carcinoma in situ

Testicular germ cell tumours (TGCT) of young adults arise from the intratubular precursor, carcinoma in situ (CIS). CIS cells are thought to be developmentally arrested and transformed fetal germ cells that survive through childhood and gain invasive capacity after puberty. Given that germ cell neoplasms arise frequently in undervirilized and dysgenetic gonads and the striking physiological difference between meiotic entry in ovaries (fetal life) versus testes (at puberty), this study aimed to investigate whether errors in regulation of meiosis may be implicated in the pathogenesis of CIS or its invasive progression to TGCT. The main focus was on a key sex differentiation and meiosis regulator, DMRT1, which has also been linked to TGCT risk in recent genetic association studies. Expression patterns of DMRT1 and other meiosis regulators (SCP3, DMC1, STRA8, CYP26B1, NANOS2, NANOS3) were investigated in pre- and post-pubertal CIS samples and TGCT by quantitative RT-PCR and immunohistochemistry. The results demonstrated that meiosis markers and meiosis inhibitors were simultaneously expressed in CIS cells, in both pre- and post-pubertal testis samples. DMRT1 was present in a restricted subset of CIS cells, which was relatively greater in pre-pubertal (27%) compared to adult (2.6%) samples. In contrast to the majority of CIS cells, DMRT1-positive CIS cells in adult testes were not proliferating. DMRT1 and most of the other meiosis regulators were absent or expressed at low levels in invasive TGCT, except in spermatocytic seminoma (not derived from CIS). In conclusion, this study indicates that meiosis signalling is dysregulated in CIS cells and that a key regulator of the mitosis-meiosis switch, DMRT1, is expressed in 'early-stage' CIS cells but is down-regulated with further invasive transformation. Whether this mixed meiosis signalling in CIS cells is caused by insufficient virilization of the fetal somatic niche or a partial post-pubertal maturation remains uncertain and requires further study.

Utility of OCT3/4, TSPY andβ-Catenin as Biological Markers for Gonadoblastoma Formation and Malignant Germ Cell Tumor Development in Dysgenetic Gonads

BACKGROUND: Gonadoblastoma (GB) is regarded as an in situ form of germ cell tumor in dysgenetic gonads, and 30% of patients with GB develop a dysgerminoma/seminoma tumor.OBJECTIVE: Determine whether OCT3/4 andβ-catenin are expressed in dysgenetic gonads before GB development and whether TSPY participates in the OCT3/4-β-catenin pathways in the malignant invasive behavior.METHODS: dysgenetic gonads of Disorders of sex differentiation (DSD) patients with mixed gonadal dysgenesis were analyzed by immunohistochemistry and immunofluorescence for comparison with GB and dysgerminoma/seminoma.RESULTS: Our results suggest that the development of GB is secondary to the interaction of OCT3/4 and TSPY, thatβ-catenin does not participate in this process.CONCLUSIONS: The use of this biological markers detects the potential high risk gonads.

Utility of OCT3/4, TSPY and β-catenin as biological markers for gonadoblastoma formation and malignant germ cell tumor development in dysgenetic gonads.

BACKGROUND: Gonadoblastoma (GB) is regarded as an in situ form of germ cell tumor in dysgenetic gonads, and 30% of patients with GB develop a dysgerminoma/seminoma tumor.OBJECTIVE: Determine whether OCT3/4 and β-catenin are expressed in dysgenetic gonads before GB development and whether TSPY participates in the OCT3/4-β-catenin pathways in the malignant invasive behavior.METHODS: dysgenetic gonads of Disorders of sex differentiation (DSD) patients with mixed gonadal dysgenesis were analyzed by immunohistochemistry and immunofluorescence for comparison with GB and dysgerminoma/seminoma.RESULTS: Our results suggest that the development of GB is secondary to the interaction of OCT3/4 and TSPY, that β-catenin does not participate in this process.CONCLUSIONS: The use of this biological markers detects the potential high risk gonads.

Gonadoblastoma: Case report of two young patients with isochromosome 12p found in the dysgerminoma overgrowth component in one case

Gonadoblastomas are unusual neoplasias that frequently appear in the dysgenetic gonads of women with chromosome Y anomaly. We present two cases of gonadoblastoma associated with complete gonadal dysgenesis and Turner syndrome, respectively, with dysgerminoma overgrowth found in one case. We were interested in the DNA ploidy, the presence of Y chromosome DNA sequence and the status of chromosome 12p arm among the tumor cells. We performed cytophotometry to analyze the DNA content and fluorescence in situ hybridization (FISH) to identify the Y chromosome and the isochromosome 12p within the tumor cells. The cytophotometric result showed diploid DNA content in gonadoblastoma, whereas dysgerminoma revealed aneuploid DNA. The FISH result revealed Y chromosome DNA sequence within gonadoblastoma and dysgerminoma. Isochromosome 12p was identified in dysgerminoma, but not in gonadoblastoma. We conclude that gonadoblastoma and dysgerminoma have a strong association with the Y chromosome, and dysgerminoma overgrowth is due to further chromosomal aberrations, such as isochromosome 12p. Histological, immunohistocheimcal and molecular studies should render the correct diagnosis. Identifying dysgerminoma overgrowth is crucial since it is associated with adverse prognosis and requires additional therapy.

Absence of inactivating mutations and deletions in the DMRT1 and FGF9 genes in a large cohort of 46,XY patients with gonadal dysgenesis

Despite advances in our understanding of the mechanisms involved in sex determination and differentiation, the specific roles of many genes in these processes are not completely understood in humans. Both DMRT1 and FGF9 are among this group of genes. Dmrt1 controls germ cell differentiation, proliferation, migration and pluripotency and Sertoli cell proliferation and differentiation. Fgf9 has been considered a critical factor in early testicular development and germ cell survival in mice. We screened for the presence of DMRT1 and FGF9 mutations in 33 patients with 46,XY gonadal dysgenesis. No deletions in either DMRT1 or FGF9 were identified using the MLPA technique. Eight allelic variants of DMRT1 were identified, and in silico analysis suggested that the novel c.968-15insTTCTCTCT variant and the c.774G>C (rs146975077) variant could have potentially deleterious effects on the DMRT1 protein. Nine previously described FGF9 allelic variants and six different alleles of the 3’ UTR microsatellite were identified. However, none of these DMRT1 or FGF9 variants was associated with increased 46,XY gonadal dysgenesis. In conclusion, our study suggests that neither DMRT1 nor FGF9 abnormalities are frequently involved in dysgenetic male gonad development in patients with non-syndromic 46,XY disorder of sex development.

Swyer Syndrome : A Case Report with Literature Review

Gonadoblastomas are known to develop in dysgenetic gonads, especially so, if Y chromosome material is present. A 20-years-old girl who noticed breast development since the age of 12 years presented with primary amenorhoea, distension of lower abdomen and intermittent pain for two months. She had breakthrough bleeding with six months of estrogen replacement. Tanner breast stage was five and pubic hair stage was also five. Examination revealed a mass in the lower abdomen extending into hypogastrium, umbilical and lumbar regions. Her gonadotropin levels were grossly elevated. Karyotyping showed 46XY. CT scan of abdomen showed a 17X11 cm mass in the pelvis without visible gonads. Surgical excision of the mass along with bilateral salpingophorectomy was performed. Histopathology revealed the mass to be a dysgerminoma, while the right gonad lodged gonadoblastoma. She was diagnosed as a rare case of Swyer syndrome.

Dysgenetic male pseudohermaphroditism

The authors report a case of a dysgenetic male pseudohermaphroditism with a 45,X/46,XY karyotype in a mosaic form, which was diagnosed in an infant. The one-week-old infant was evaluated because of proximal hypospadias and retention of the right testis. The results of hormonal tests were the followings: serum FSH 5.2 mU/ml; LH: 2.0 mU/ml; testosterone: 144.3 ng/dl; androstendione: 0.42 µg/l; 17-hydroxyprogesterone: 1.12 ng/ml. Chromosomal analysis revealed 45,X/46,XY karyotype. Fluorescent in vitro hybridization showed that 51% of the lymphocytes had the Y chromosome and the SRY gene. Analysis of the SRY showed no deletion in the AZF a,b,c regions. Pelvic magnetic resonance imaging indicated the presence of vagina between the bladder and the rectum, and it showed a mass measuring 15×8 mm in the right inguinal canal as well as an oval gonadal mass with a size of 13×7 mm in the left scrotum. During surgical intervention, performed at the age of one, the right gonad was removed and biopsy of the scrotal testis was performed. Histological examination revealed dysgenetic testis in both sides. The authors emphasize the necessity of cytogenetic and endocrinological investigations of newborns with perineoscrotal hypospadia and bilateral or unilateral maldescent testes immediately after birth. Surgical removal of the dysgenetic testicular tissue located in the abdominal cavity and its histological evaluation provides separation of mixed gonadal dysgenesis, dysgenetic male pseudohermaphroditism, bilateral gonadal dysgenesis and ovotestis in the 45,X/46,XY mosaic cases. An accurate evaluation is necessary for a correct sex assignment and for surgical intervention to prevent neoplastic degeneration of the dysgenetic gonad.

Clinical and gonadal features and early surgical management of 45,X/46,XY and 45,X/47,XYY chromosomal mosaicism presenting with genital anomalies

ObjectiveThe 45,X/46,XY and 45,X/47,XYY group of patients includes some of those previously diagnosed with ‘mixed gonadal dysgenesis’. Our aim was to establish the clinical and gonadal spectrum, and early surgical management, of patients with chromosomal mosaicism presenting with genital anomalies. Patients and methodsWe performed a retrospective review of patients with 45,X/46,XY or 45,X/47,XYY mosaicism presenting with genital ambiguity between 1988 and 2009. At least one gonadal biopsy or gonadectomy specimen was available for each patient. Gonadal histology was re-evaluated by a paediatric pathologist. ResultsOf 31 patients with 45,X/46,XY (n = 28) or 45,X/47,XYY (n = 3) mosaicism and genital anomalies, 19 (61%) were raised male. Histology of 46 gonads was available from patients who had undergone a gonadectomy or gonadal biopsy, at a median age of 9.5 months. 18 gonads were palpable at presentation, including 5 (28%) histologically unremarkable testes, 2 streak gonads, and 1 dysgenetic gonad with distinct areas of testicular and ovarian stroma but no oocytes. All intra-abdominal gonads were found to be dysgenetic testes (of which 2 were noted to have pre-malignant changes) or streaks, apart from 1 histologically unremarkable testis. 15 (48%) patients had other anomalies, most commonly cardiac and renal; 4 (13%) had a Turner phenotype. ConclusionThe anatomy and gonadal histology of 45,X/46,XY and 45,X/47,XYY individuals with genital ambiguity do not conform to a set pattern, and hence management of each patient should be individualized according to detailed anatomical and histological assessment.

Undifferentiated Gonadal Tissue, Y Chromosome Instability, and Tumors in XY Gonadal Dysgenesis

Patients with XY gonadal dysgenesis are at increased risk of developing gonadal tumors. The etiology of several cases of XY gonadal dysgenesis remains unknown, but X/XY gonadal mosaicism has been hypothesized to play a role. At the histologic level, the presence of persistent primitive sex cords containing immature germ cells in dysgenetic gonads (an entity called undifferentiated gonadal tissue, or UGT) was recently described, and these immature germ cells are thought to be at risk of neoplastic transformation. To further investigate both these aspects, we retrospectively studied the gonads from 30 patients with pure (22) and mixed (8) gonadal dysgenesis. Cytogenetic analyses performed on 35 gonads revealed that structurally abnormal Y chromosomes were lost in a majority of cells from the gonads, explaining the gonadal dysgenesis of patients bearing a rearranged Y chromosome. On the other hand, normal Y chromosomes were less often lost in gonads of patients with gonadal dysgenesis. At the histologic level, 43 of the 51 gonads presented areas characteristic of a streak; 13 of these streak gonads also presented areas of UGT. Structures resembling sex cords but without germ cells were found in many of the streaks not containing UGT, suggesting that UGT was initially present. Of the 13 gonads containing both UGT and a streak, 9 developed a tumor. The proximity of UGT with the tumors as well as the immunostaining patterns (PLAP+, OCT3/4+, and CD117/KIT+) suggests that germ cells found in UGT are a risk factor for gonadal tumors.

Abnormal streak gonads in 46,XY complete gonadal dysgenesis

To describe the surgical findings in two adolescents with 46,XY complete gonadal dysgenesis. Report of two cases. University teaching hospital. Two adolescents with 46,XY complete gonadal dysgenesis who underwent laparoscopic bilateral gonadectomy. Laparoscopic bilateral gonadectomy. Removal of dysgenetic gonads. One benign fibrothecoma and one gonadoblastoma were identified upon pathologic evaluation of the streak gonads. Individuals with 46,XY complete gonadal dysgenesis are at risk for malignant transformation of the dysgenetic gonads. Because the risk of malignancy is approximately 30%, prompt gonadectomy should be performed after diagnosis of 46,XY complete gonadal dysgenesis.

Dysgerminoma in a case of 46, XY pure gonadal dysgenesis (swyer syndrome): a case report

Simple 46, XY gonadal dysgenesis syndrome, also called Swyer syndrome, is known as pure gonadal dysgenesis. Individuals with the syndrome are characterized by 46, XY karyotype and phenotypically female with female genital appearance, normal Müllerian structures and absent testicular tissue. The condition usually first becomes apparent in adolescence with delayed puberty and primary amenorrhea due to the gonads have no hormonal or reproductive potential. Herein, we report a case of dysgerminoma diagnosed in a dysgenetic gonad of a 21-year-old patient with Swyer syndrome.

FOXL2 and SOX9 Distinguish the Lineage of the Sex Cord–Stromal Cells in Gonadoblastomas

Gonadoblastomas are mixed germ cell sex cord-stromal tumors that arise in dysgenetic gonads and are composed of immature germ cells and sex cord-stromal cells of indeterminate differentiation. FOXL2 is one of the first genes expressed in female gonad development, and it is required for proper granulosa cell differentiation during folliculogenesis. SOX9 , a downstream target of SRY , the gene in the Y chromosomal sex-determining region, is required for testicular development and for the formation and maintenance of (pre-)Sertoli cells. This study characterized the sex cord-stromal cells of gonadoblastoma by evaluating the expression of these counteracting transcription factors. Archival paraffin-embedded material of 7 gonadoblastomas, 5 of which were overgrown by dysgerminoma, was examined by immunohistochemistry for expression and localization of FOXL2 and SOX9. The sex cord-stromal cells revealed strong nuclear staining for FOXL2 and were negative for SOX9 expression. Germ cells in the gonadoblastoma and dysgerminoma components showed no FOXL2 and SOX9 expression. Areas of transition between gonadoblastoma and dysgerminoma revealed nests with a gradual reduction of FOXL2 expression. Our results support the hypothesis that the sex cord-stromal cell component of gonadoblastomas is of granulosa cell origin. In addition, FOXL2 appears to be a useful marker for the evaluation of overgrowth by dysgerminomas and for the identification of the transition zone of "dysgerminoma in situ." As FOXL2 and SOX9 are differentially expressed, they also should be useful for distinguishing gonadoblastomas from intratubular germ cell neoplasias and can help to differentiate those with a Sertoli cell component from gonadoblastoma with a granulosa cell component.

Malignant ovarian germ cell tumours in gonadal Y chromosome mosaicism

AimsPrevious studies have shown that two partially overlapping mechanisms are responsible for the development of malignant ovarian germ cell tumours (MOGCT): either spontaneous mutations, mostly in KIT gene, or the...