Yolk sac tumor and dysgerminoma in the left gonad following gonadoblastoma in the right gonad in a 46,XY DSD with a novel SRY missense mutation: a case report.

BACKGROUND: Approximately 10-15% of 46,XY disorders of sex development (DSDs) have an SRY mutation residing in the high mobility group (HMG) domain. Here, we present a case of 46,XY DSD caused by a novel missense mutation in the HMG region of SRY rapidly progressing to germ cell tumors (GCTs). CASE PRESENTATION: An adolescent female (15 years old) exhibiting primary amenorrhea was later diagnosed as a 46,XY female with bilateral gonadal dysplasia on the basis of peripheral lymphocyte karyotype 46,XY and a novel missense mutation in SRY (c.281 T > G, p.L94R). The novel missense mutation (c.281 T > G, p.L94R) and its adjacent region were conserved. Protein structure analysis showed that the mutant site was located in the middle of the HMG domain, and the mutant protein had a diminished ability to bind to DNA. Imaging examination revealed an adolescent female with a naive uterus. Laparoscopy and initial pathological examination revealed left gonadal dysplasia and right gonadal dysplasia with gonadoblastoma (GB). Right gonadectomy by laparoscopy was performed upon consent from the patient's parents. Less than 1 year postoperatively, the left gonadal gland deteriorated as observed by the findings of a mass in the left adnexal region by pelvic MRI and serum AFP > 1000 ng/ml by serological tests, and then total hysterectomy and adnexal and left gonadectomy by laparoscopy were performed. The GCT stage was classified as stage Ic according to FIGO. At this time, pathologic examination showed that the left gonad had progressed to yolk sac tumor and dysgerminoma. The patient underwent chemotherapy post-operatively but developed type III myelosuppression and tumor recurrence several months later. CONCLUSIONS: The patient initially presented with right gonadoblastoma but chose only right gonadectomy by laparoscopy to preserve the female sex characteristics, which resulted in rapid deterioration of the left gonad and poor treatment outcomes. This case demonstrates the importance of early genetic diagnosis and treatment of 46,XY female DSD.

Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours: a report from the Children's Oncology Group.

BACKGROUND: Abnormal DNA methylation may be important in germ cell tumour (GCT) aetiology, as germ cells undergo complete epigenetic reprogramming during development. GCTs show differences in global and promoter methylation patterns by histologic subtype. We conducted an epigenome-wide study to identify methylation differences by GCT histology. METHODS: Using the Illumina HumanMethylation450K array we measured methylation in 154 paediatric GCTs (21 germinomas/seminomas/dysgerminoma, 70 yolk sac tumours [YST], 9 teratomas, and 54 mixed histology tumours). We identified differentially methylated regions (DMRs) between GCT histologies by comparing methylation beta values. RESULTS: We identified 8,481 DMRs (FWER < 0.05). Unsupervised hierarchical clustering of individual probes within DMRs resulted in four high level clusters closely corresponding to tumour histology. Clusters corresponding to age, location, sex and FFPE status were not observed within these DMRs. Germinomas displayed lower levels of methylation across the DMRs relative to the other histologic subtypes. Pathway analysis on the top 10% of genes with differential methylation in germinomas/seminomas/dysgerminoma compared to YST suggested angiogenesis and immune cell-related pathways displayed decreased methylation in germinomas/seminomas/dysgerminoma relative to YST. CONCLUSIONS: Paediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.

Dysgerminoma and gonadoblastoma in the course of Swyer syndrome.

We present a case of a woman with primary amenorrhea. Ultrasound imaging showed a uterus of normal size but bands of connective tissues at the site of ovaries. A genetic test was done which revealed the XY karyotype. Swyer syndrome was diagnosed. The patient did not report for the follow-up visits. Three years later, the woman reported back because of increasing abdominal circumference. The patient underwent an operation. Radical hysterectomy was performed. Histopathological examination showed dysgerminoma and gonadoblastoma on the left gonad and dysgerminoma on the right one. This case report presents the natural history of Swyer syndrome.

Characterization of common marmoset dysgerminoma-like tumor induced by the lentiviral expression of reprogramming factors.

Recent generation of induced pluripotent stem (iPSCs) has made a significant impact on the field of human regenerative medicine. Prior to the clinical application of iPSCs, testing of their safety and usefulness must be carried out using reliable animal models of various diseases. In order to generate iPSCs from common marmoset (CM; Callithrix jacchus), one of the most useful experimental animals, we have lentivirally transduced reprogramming factors, including POU5F1 (also known as OCT3/4), SOX2, KLF4, and c-MYC into CM fibroblasts. The cells formed round colonies expressing embryonic stem cell markers, however, they showed an abnormal karyotype denoted as 46, X, del(4q), +mar, and formed human dysgerminoma-like tumors in SCID mice, indicating that the transduction of reprogramming factors caused unexpected tumorigenesis of CM cells. Moreover, CM dysgerminoma-like tumors were highly sensitive to DNA-damaging agents, irradiation, and fibroblast growth factor receptor inhibitor, and their growth was dependent on c-MYC expression. These results indicate that DNA-damaging agents, irradiation, fibroblast growth factor receptor inhibitor, and c-MYC-targeted therapies might represent effective treatment strategies for unexpected tumors in patients receiving iPSC-based therapy.

Dysgerminoma Probably Due to a Novel SOHLH1-pathogenic Variant Causing Familial Ovarian Dysgenesis.

Pathogenic variants of the SOHLH1 gene are responsible for an autosomal recessive form of ovarian dysgenesis; this gene encodes a transcription factor expressed early in spermatogonia and oocytes and contributes to folliculogenesis. Previously, four affected women from two unrelated families reported homozygous variants in the SOHLH1 gene, but none had a history of gonadal malignancy or a histologic description. We present two sisters and their paternal great-aunt with a history of primary amenorrhea, pubertal delay, and hypergonadotrophism who came from an inbred Mexican family. The proband was the younger sister who was referred for bilateral dysgerminoma. She had a normal blood karyotype, and whole-exome sequencing analysis revealed a novel homozygous missense variant, c.275C>T, in SOHLH1; several family members were also analyzed. In addition to pure dysgerminoma, histopathological analysis revealed an ovarian cortex with fibrosis and almost total absence of follicles. This work confirms the inheritance of ovarian dysgenesis 5, supports the occurrence of cell loss in mouse models, and suggests that affected women should undergo periodic imaging surveillance due to the likely risk of tumor development.

Novel mutation of the sex-determining region on the Y chromosome in a 46,XY female patient with monolateral dysgerminoma: a case report.

Patients with 46,XY complete gonadal dysgenesis (Swyer syndrome) are characterized by the presence of female internal genital tract and bilateral streak gonads in a phenotypic female. These women have a high risk of developing rare type II malignant germ cell tumors. We report a rare case of a 33-year-old 46,XY female patient, who presented with an adnexal mass suspected for dysgerminoma, with a novel mutation of the sex-determining region on the Y chromosome consisting in the variant c.301C> G (p.L101V). Considering that effective screening is not available and the high risk of developing malignant neoplasm, prophylactic gonadectomy is mandatory.

Late Diagnosis of Swyer Syndrome in a Patient with Bilateral Germ Cell Tumor Treated with a Contraceptive Due to Primary Amenorrhea.

Swyer syndrome is a special form of DSD (disorders of sex development), so-called pure gonadal dysgenesis with a karyotype 46, XY and a female phenotype. One of the most important problems in patients with DSD is the risk of gonadal tumors. We present a case of a 26-year-old patient with Swyer syndrome. The patient had primary amenorrhea and no puberty characteristics. In ultrasound imaging in the vicinity of the uterus, there were two homogeneous structures. A genetic diagnosis was also performed, which showed karyotype 46, XY. The patient underwent a bilateral gonadectomy. Histopathological examination revealed the presence of dysgerminoma in both dysgenetic gonads. The follow-up of five years now did not show any changes suspected of invasion. We concluded that the primary amenorrhea, along with the absence of development of sexual characteristics, should prompt an expanded diagnosis for disorders of sex development. Gonadal dysgerminoma should be suspected even in the absence of tumor features on ultrasound and blood laboratory tests. Early prophylactic gonadectomy could protect patients from developing tumors in dysgenetic gonads.

Molecular genetic analysis of bilateral ovarian germ cell tumors.

BACKGROUND: Ovarian germ cell tumors (oGCTs) are rare and highly heterogeneous with regard to their clinical and histologic appearance. The risk of tumor development is higher in children with aberrant sexual differentiation. Development of gonadoblastomas is seen in young women with 46,XY gonadal dysgenesis. At least 50 % of gonadoblastomas may develop into malignant oGCTs, mostly dysgerminomas. In this study, we evaluated bilateral oGCTs in clinically inapparent patients for sex chromosomal aberrations. PATIENTS AND METHODS: We analyzed tumor samples of 15 patients with synchronous bilateral oGCTs enrolled onto the consecutive MAKEI trials for non-testicular GCTs. Paraffin embedded samples from the Kiel German Childhood Tumor Registry were evaluated for the presence of Y-chromosomal sequences. Molecular genetic techniques included comparative genomic hybridization, polymerase chain reaction, and fluorescence in situ hybridization. RESULTS: Among 15 patients with bilateral oGCTs, Y-chromosomal DNA sequences were detected in 6 tumors. Both mature teratomas were negative for Y-chromosomal DNA. Thus, 5 of 12 malignant oGCTs and 1 immature teratoma (with elevated AFP) showed Y-chromosomal material. A 45(X,0) karyotype could not be demonstrated. CONCLUSIONS: These investigations provide additional insight into the development of oGCTs: mature teratomas, which develop from postmeiotic germ cells, are not associated with gonadal dysgenesis. Bilateral immature teratomas, dysgerminomas and mixed malignant oGCTs may frequently show Y-chromosomal DNA, indicating underlying but clinically inapparent gonadal dysgenesis. Thus, the presence of aberrant Y-chromosomal sequences appears to be involved in tumor development in about half of these patients.

Ovarian gonadoblastoma with dysgerminoma in a girl with 46,XX karyotype 17a-hydroxylase/17, 20-lyase deficiency: A case report and literature review.

17α-hydroxylase/17,20-lyase deficiency (17-OHD), caused by mutations in the gene of the cytochrome P450 family 17 subfamily A member 1 (CYP17A1), is a rare type of congenital adrenal hyperplasia (CAH), usually characterized by cortisol and sex steroid deficiency combined with excessive mineralocorticoid. Gonadoblastoma is a relatively rare ovarian tumor that is frequently seen among patients with 46,XY gonadal dysgenesis. Rarely have they been reported in female patients with normal 46,XX karyotype. Here, we report an interesting case of an 11-year-old Chinese girl who presented acute abdominal pain that was later attributed to tumor rupture of right ovarian gonadoblastoma with dysgerminoma. Further evaluations revealed hypertension and hypokalemia. Hormonal findings showed increased progesterone, hypergonadotropic hypogonadism, and low cortisol levels. Her chromosome karyotype was 46,XX without Y chromosome material detected. Genetic analysis revealed that the patient had a homozygous pathogenic variant c.985_987delTACinsAA (p.Y329Kfs*90) in exon 6 of the CYP17A1 gene and that her parents were all heterozygous carriers of this pathogenic variant. Due to the variable clinical manifestations of 17-OHD, meticulous assessment including genetic analysis is necessary. Further study is warranted to unravel the mechanism of gonadoblastoma in a patient with normal karyotypes.

Gonadal tumor development in 46,XX disorders of gonadal development.

Background: Differences/disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Objective: The aim of this study is to report the histological characteristics and immunoexpression patterns of gonadal parenchyma in patients with 46,XX testicular and ovotesticular DSD, with a focus on the detection of germ cell malignancies. Design: Inclusion criteria were SRY-negative 46,XX testicular and ovotesticular DSD with available samples from gonadal biopsy or gonadectomy for the review of histological findings. Gonadal histology was assessed on hematoxylin and eosin-stained sections and immunohistochemical analysis. Histopathological criteria from the last World Health Organization classification of urogenital tumors were used to identify undifferentiated gonadal tissue, gonadoblastoma, and dysgerminoma. Results: Median age at first histological evaluation of gonadal samples was 1.46 years (range: 0.16-16 years). Totally 15 patients were classified as ovotesticular and only 1 as testicular DSD. Most individuals had bilateral ovotestes (12/15). No histological alterations were found in the ovarian parenchyma, while signs of dysgenesis were seen in all cases of testicular parenchyma. In 4/15 ovotesticular DSD, a prepubertal biopsy failed to identify ovarian parenchyma. We detected early prepubertal preinvasive and invasive malignancies in this cohort (five patients had undifferentiated gonadal tissue, five gonadoblastoma, and one dysgerminoma). Conclusion: 46,XX disorders of gonadal development are historically considered at a low risk for germ cell cancer, and the need for assessment of gonadal histology has been questioned. The finding of early germ cell malignancies in our cohort brings awareness and needs further research.

Bone morphogenetic protein signalling activity distinguishes histological subsets of paediatric germ cell tumours.

Germ cell tumours (GCTs) are cancers of the testis, ovary or extragonadal sites that occur in infants, children and adults. Testicular GCT is the most common cancer in young men aged 15-40 years. Abnormalities in developmental signalling pathways such as wnt/ß-catenin, TGF-ß/BMP and Hedgehog have been described in many childhood tumours. To date, however, the status of BMP signalling in GCTs has not been described. Herein, we examine BMP-SMAD signalling in a set of clinically-annotated paediatric GCTs. We find that BMP signalling activity is absent in undifferentiated tumours such as seminomas and dysgerminomas, but robustly present in most yolk sac tumours, a differentiated tumour type. Gene expression profiling of TGF-ß/BMP pathway genes in germinomas and yolk sac tumours reveals a set of genes that distinguish the two tumour types. There is significant intertumoural heterogeneity between tumours of the same histological subclass, implying that the BMP pathway can be differentially regulated in individual tumours. Finally, through miRNA expression profiling, we identify differential regulation of a set of miRNAs predicted to target the TGF-ß/BMP pathway at multiple sites. Taken together, these results suggest that the BMP signalling pathway may represent a new therapeutical target for childhood GCTs.

Malignant germ cell tumors associated with Swyer syndrome.

Swyer syndrome is characterized by a higher risk of developing genital malignancies. In this disorder, the most common is gonadoblastoma and dysgerminoma but also, in rare cases, choriocarcinoma. The prognosis in choriocarcinoma is poor. The early diagnosis of dysgenetic gonads is necessary in view of the risk of malignancies. It can be difficult due to its different clinical masks. When the neoplasm precedes the diagnosis of gonadal dysgenesis, adequate oncological treatment should be introduced with parallel gonadectomy. We present a case of 14-year-old female with 46, XY karyotype with choriocarcinoma in one gonad and dysgerminoma in the second one.

Bilateral ovarian gonadoblastoma with coexisting dysgerminoma in a girl with 46, XX karyotype.

Gonadoblastoma is a rare gonadal tumor with tumor cells arranged in nests surrounded by ovarian stroma containing Leydig or lutein-type cells. In 50% of the cases, there is an overgrowth of germ cells with progression to dysgerminoma. A case of gonadoblastoma with coexisting dysgerminoma developing in both ovaries of a 20-year-old girl who had increased abdominal girth is presented here. A pelvic mass measuring 20 x 14 cm was detected by pelvic ultrasonography. Bilateral salphingo-oophorectomy was performed. The histopathological report revealed bilateral gonadoblastoma with coexisting dysgerminoma. After surgery the patient received radiation and chemotherapy (BEP: bleomycin, etoposide, cisplatin) and was started on hormone replacement therapy. Five years and eight months after treatment, the patient is well and free of recurrence.

Dysgerminoma in a Prepubertal Girl with Complete 46XY Gonadal Dysgenesis: Case Report and Review of the Literature.

BACKGROUND: Complete 46XY gonadal dysgenesis (Swyer syndrome) is a rare and challenging diagnosis among prepubertal girls, as estrogen insufficiency becomes evident only during adolescence, with nonspecific symptoms such as primary amenorrhea and/or delayed puberty. Unfortunately, girls with Swyer syndrome are at high risk for malignancies in the dysgenetic gonads, which can be prevented only by performing prophylactic bilateral gonadectomy. CASE: We present a 9-year-old patient with Swyer syndrome diagnosed with dysgerminoma in the right gonad and gonadoblastoma in the left gonad after prophylactic bilateral gonadectomy. SUMMARY AND CONCLUSION: Concerning the high risk of early gonadoblastoma and its malignant transformation, we recommend performing prophylactic bilateral gonadectomy at the time of diagnosis, even if the patient is prepubertal.

XY Gonadal Dysgenesis in a Phenotypic Female Identified by Direct-to-Consumer Genetic Testing.

We report a 16-year-old phenotypic female with 46,XY complete gonadal dysgenesis and metastatic dysgerminoma, unexpectedly discovered through direct-to-consumer (DTC) commercial genetic testing. This case underscores the importance of timely interdisciplinary care, including psychosocial intervention and consideration of gonadectomy, to optimize outcomes for individuals with differences of sex development. Her unique presentation highlights the implications of DTC genetic testing in a new diagnostic era and informs general pediatricians as well as specialists of nongenetic services about the value, capabilities, and limitations of DTC testing.

The tumor suppressor gene TRC8/RNF139 is disrupted by a constitutional balanced translocation t(8;22)(q24.13;q11.21) in a young girl with dysgerminoma.

BACKGROUND: RNF139/TRC8 is a potential tumor suppressor gene with similarity to PTCH, a tumor suppressor implicated in basal cell carcinomas and glioblastomas. TRC8 has the potential to act in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control and has been identified in families with hereditary renal (RCC) and thyroid cancers. Haploinsufficiency of TRC8 may facilitate development of clear cell-RCC in association with VHL mutations, and may increase risk for other tumor types. We report a paternally inherited balanced translocation t(8;22) in a proposita with dysgerminoma. METHODS: The translocation was characterized by FISH and the breakpoints cloned, sequenced, and compared. DNA isolated from normal and tumor cells was checked for abnormalities by array-CGH. Expression of genes TRC8 and TSN was tested both on dysgerminoma and in the proposita and her father. RESULTS: The breakpoints of the translocation are located within the LCR-B low copy repeat on chromosome 22q11.21, containing the palindromic AT-rich repeat (PATRR) involved in recurrent and non-recurrent translocations, and in an AT-rich sequence inside intron 1 of the TRC8 tumor-suppressor gene at 8q24.13. TRC8 was strongly underexpressed in the dysgerminoma. Translin is underexpressed in the dysgerminoma compared to normal ovary.TRC8 is a target of Translin (TSN), a posttranscriptional regulator of genes transcribed by the transcription factor CREM-tau in postmeiotic male germ cells. CONCLUSION: A role for TRC8 in dysgerminoma may relate to its interaction with Translin. We propose a model in which one copy of TRC8 is disrupted by a palindrome-mediated translocation followed by complete loss of expression through suppression, possibly mediated by miRNA.

Bilateral gonadoblastoma with dysgerminoma and pilocytic astrocytoma with WT1 GT-IVS9 mutation: A 46 XY phenotypic female with Frasier syndrome.

Frasier syndrome is characterized by a 46 XY disorder of sex development, nephropathy, and increased risk for gonadoblastoma due to Wilms tumor 1(WT1) mutation in the donor splice site of intron-9, resulting in the splice form +KTS. Germ cell tumors and gonadoblastomas have been reported previously in Frasier syndrome. We present the clinical, radiological, and genetic (WT1 mutation analysis) of a 46 XY phenotypic female with Frasier syndrome with bilateral gonadoblastoma with dysgerminoma who developed pilocytic astrocytoma.

Dysgerminoma in a 10-Year Old with 45X/46XY Turner Syndrome Mosaicism.

BACKGROUND: Turner syndrome is a genetic disorder resulting from the absence of or structural abnormality of one X chromosome. The presence of Y chromosome material in girls with Turner syndrome confers an increased risk of benign and malignant germ cell tumor and prophylactic bilateral gonadectomy is recommended. CASE: A 10-year-old Turner mosaic syndrome (45X/46XY) patient underwent prophylactic gonadectomy after unremarkable preoperative pelvic imaging. Histopathology showed a streak right gonad, and left gonad with gonadoblastoma with limited degree of infiltrating germinoma. SUMMARYAND CONCLUSION: Gonadoblastoma and dysgerminoma have been reported in girls with Turner mosaic who carry Y chromosome material. Prophylactic gonadectomy should be considered in these girls without delay.

Gonadoblastoma-Associated Mixed Gonadal Germ Cell Tumor with Dysgerminoma and Hepatoid Yolk Sac Tumor Components in 46XY Gonadal Dysgenesis.

BACKGROUND: Disorders of sex development are congenital conditions with atypical chromosomal, gonadal, or anatomical sex development. Gonadal dysgenesis in patients containing a Y chromosome have a high risk of developing germ cell tumors with potential for malignant transformation. CASE: We present the case of a 17-year-old phenotypic female with primary amenorrhea and 46,XY complete gonadal dysgenesis. Pelvic ultrasound showed a solid cystic lesion in the right gonad. Pathology showed a gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid yolk sac tumor. SUMMARY AND CONCLUSION: To our knowledge, this mixed neoplasm association has not been previously reported and this case illustrates the challenges for the diagnosis of gonadal dysgenesis-associated tumors, emphasizing its recognition and prognostic implications.