[Swyer syndrome with gonadal non-dysgerminoma malignant germ cell tumors: a report of 15 cases in a national medical center].

Objective: To evaluate the incidence, treatment, and survival outcomes of Swyer syndrome with gonadal non-dysgerminoma malignant germ cell tumor (MGCT-NDG). Methods: A retrospective study was performed on Swyer syndrome patients with MGCT-NDG between January 2011 and December 2022 in Peking Union Medical College Hospital to investigate their characteristics and outcomes. Results: A total of 15 patients (4.9%, 15/307) with Swyer syndrome were identified in 307 MGCT-NDG patients. The average age at diagnosis of MGCT-NDG and Swyer syndrome were (16.8±6.7) and (16.7±6.6) years, respectively. Six cases were preoperatively diagnosed as Swyer syndrome, of which 4 cases received bilateral gonadectomy with or without hysterectomy, while the other 2 cases underwent removal of gonadal tumor and unilateral gonadectomy with hysterectomy, respectively. Of the 9 patients postoperatively diagnosed as Swyer syndrome, unilateral gonadectomy, removal of gonadal tumor, and unilateral gonadectomy with hysterectomy were performed in 6 patients, 2 patients, and 1 patient, respectively. Mixed malignant germ cell tumor (MGCT;10 cases), yolk sac tumor (4 cases), and immature teratoma (1 case) were the pathological subtypes, in the descending order. There were International Federation of Gynecology and Obstetrics (FIGO) stage Ⅰ in 6 cases, stage Ⅱ in 3 cases, stage Ⅲ in 5 cases, and stage Ⅳ in 1 case, respectively. Eleven patients received reoperation for residual gonadectomy after a average delay of (7.9±6.2) months, including 8 MGCT-NDG patients and 1 gonadoblastoma patient, no tumor involved was seen in the remaining gonads in the other 2 cases. Ten patients experienced at least one recurrence, with a median event free survival of 9 months (5, 30 months), of which 2 patients received surgery only at the time of initial treatment. All patients with recurrence received surgery and combined with postoperative chemotherapy. After a median follow-up of 25 months (15, 42 months), 10 patients were disease-free, 3 patients died of the tumor, 1 died of side effects of leukemia chemotherapy, and 1 survived with disease. Conclusion: The incidence rate of Swyer syndrome in patients with MGCT-NDG is about 4.9%; timely diagnosis and bilateral gonadectomy should be emphasized to reduce the risk of reoperation and second carcinogenesis in this population.

Elucidating the Cancer Phenotype in Turner Syndrome: A 20-Year Observational Cohort Study.

BACKGROUND/AIM: Turner syndrome confers increased cancer susceptibility; however, large-scale epidemiological evidence is lacking. This study aimed to analyze the incidence and prevalence of various malignancies in patients with Turner syndrome over 20 years of age to inform screening strategies. PATIENTS AND METHODS: We performed a retrospective cohort analysis of 11,502 patients with Turner syndrome from 2000 to 2020 utilizing the TriNetX research network database. The outcomes encompassed the incidence and prevalence of 20 cancers. Stratified analyses were used to evaluate variations in age, sex, and race. RESULTS: Key findings demonstrated markedly elevated risks of breast (1.7%), colon (1.0%), renal (0.4%), gonadoblastoma (0.4%), and other cancers. Significant demographic variations were observed in the incidence of cancers, such as gonadoblastoma, renal, and colon cancer. CONCLUSION: This large real-world study offers novel insights into the spectrum of cancer risk across adulthood in Turner syndrome. Our findings elucidate Turner syndrome's complex cancer phenotype to inform clinical decision-making, prognostication, and tailored screening strategies to ultimately advance patient care.

Gonadoblastoma in Turner syndrome with puberty delay: A case report and literature review.

BACKGROUND: Y chromosome material stands as an independent risk determinant for the onset of gonadoblastoma (GB) and subsequent gonadal germ cell tumours in individuals with Turner syndrome (TS). However, the delayed and underestimated identification of Y chromosome material through karyotyping within primary care settings exacerbates the intricacies of managing these patients over the long term. METHODS: We present a case involving TS accompanied by Y chromosome material, wherein puberty delay and GB were identified during prophylactic gonadectomy. Subsequently, we delve into the literature to explore the GB-related malignancy risk in TS patients with Y chromosome material, the incidence of Y chromosome presence in TS patients using methodologies beyond routine chromosomal testing, and the diagnosis and treatment of puberty delay in TS patients, all based on our case. RESULTS: A spectrum of more sensitive molecular techniques, including polymerase chain reaction (PCR) and fluorescence in situ hybridisation, effectively augments the detection of Y chromosome material alongside karyotyping. In addition to gonadectomy, the implementation of appropriate oestrogen therapy and a holistic, multidisciplinary approach to care can enhance the quality of life, while mitigating the long-term morbidity and mortality risks for TS patients harbouring Y chromosome material. CONCLUSIONS: Beyond gonadectomy, adopting a multifaceted approach the Y chromosome material detection, prompt initiation of puberty, tailored oestrogen therapy, and coordinated multidisciplinary management significantly contributes to the comprehensive health oversight of TS patients with Y chromosome material.

A Perplexing Case of a Germ Cell Tumor: A Case Report.

Germ cell tumors (GCTs) are associated with pure gonadal dysgenesis or Swyer syndrome. Swyer syndrome usually presents with primary amenorrhea, streak ovaries, and mixed GCT. However, our patient presented with secondary amenorrhea, normal female external genitalia, and a mixed GCT. Constitutional karyotype was suggestive of 46,XY. Management comprised chemotherapy, followed by surgery. Histopathology was suggestive of dysgerminoma complicating a gonadoblastoma. The purpose of reporting this case is its rarity and the importance of diagnosing an XY karyotype, as the incidence of GCTs is higher in these patients.

Frasier syndrome: A case report / El síndrome de Frasier, caso clínico

Introduction: Frasier syndrome is a genetic disorder produced by a mutation in intron 9 of the WT1 gene, responsible for renal and genital dysfunctions. Clinical findings: It is characterized by discrepancy between the individual karyotype and the individual phenotype and corticosteroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis. Patients usually have a female phenotype with a 46 XY karyotype, which increases the risk of gonadoblastoma in 50% of cases. Kidney disease requires kidney transplantation in adulthood. Cardiovascular and bone-derived comorbidities such as hyperlipidaemia and osteopenia/osteoporosis, respectively, are also common. Main diagnoses: Mutations of the WT1 gene can lead to different clinical entities, most notably Denysh-Drash syndrome, Frasier syndrome, or isolated focal segmental glomerulosclerosis. We present a clinical case of a woman who debuted in childhood with difficult-to-control nephrotic syndrome, the lack of pubertal development, primary amenorrhoea and the absence of ovaries on imaging tests in adolescence, alerted to an underlying genetic problem that, after cytogenetic studies, allowed a diagnosis of Frasier syndrome. Therapeutic interventions: It is recommended to remove the gonads due to increased risk of developing gonadoblastoma. Treatment of associated dyslipidaemia and osteopenia is also necessary. Conclusion: Frasier syndrome is an unusual cause of infertility due to gonadal dysgenesis and is associated with kidney problems.(AU)

Introducción: El síndrome de Frasier es un trastorno genético producido por una mutación en el intrón 9 del gen WT1, responsable de disfunciones a nivel renal y genital. Principales síntomas: Se caracteriza por disgenesia gonadal con discrepancia entre cariotipo-fenotipo y síndrome nefrótico resistente a corticoides debido a glomeruloesclerosis focal y segmentaria. Las pacientes presentan habitualmente fenotipo femenino con cariotipo 46 XY, lo que aumenta el riesgo de gonadoblastoma en un 50% de los casos. La enfermedad renal obliga a trasplante renal en la edad adulta. Son habituales también las comorbilidades derivadas a nivel cardiovascular y óseo como hiperlipidemia y osteopenia/osteoporosis, respectivamente. Diagnósticos principales: Las mutaciones del gen WT1 pueden conducir en distintas entidades clínicas entre las que destaca el síndrome de Denys-Drash, el síndrome de Frasier o la glomeruloesclerosis focal y segmentaria aislada. Se presenta un caso clínico de una mujer que debutó en la infancia con síndrome nefrótico de difícil control y que, durante la adolescencia, ante la falta de desarrollo puberal, la amenorrea primaria y la ausencia de ovarios en las pruebas de imagen alertaron de un problema genético subyacente que, tras estudios citogenéticos, permitió el diagnóstico de síndrome de Frasier. Intervenciones terapéuticas: Se recomienda la exéresis de las gónadas debido al riesgo incrementado de gonadoblastoma. El tratamiento de la dislipemia y la osteopenia asociadas también es necesario. Conclusión: El síndrome de Frasier es una causa inusual de infertilidad debido a una disgenesia gonadal y se asocia con problemas a nivel renal.(AU)

Undetectable anti-Mullerian hormone and inhibin B do not preclude the presence of germ cell tumours in 45,X/46,XY or 46,XY gonadal dysgenesis.

OBJECTIVE: Individuals with 45,X/46,XY or 46,XY gonadal dysgenesis are at increased risk of germ cell malignancies. Therefore, prophylactic bilateral gonadectomy is advised in girls and considered in boys with atypical genitalia for undescended, macroscopically abnormal gonads. However, severely dysgenetic gonads may not contain germ cells rendering gonadectomy unnecessary. Therefore, we investigate if undetectable preoperative serum anti-Müllerian hormone (AMH) and inhibin B can predict the absence of germ cells, (pre)malignant or otherwise. DESIGN, PATIENTS AND MEASUREMENTS: Individuals who had undergone bilateral gonadal biopsy and/or gonadectomy because of suspected gonadal dysgenesis in 1999-2019 were included in this retrospective study if preoperative AMH and/or inhibin B were available. Histological material was reviewed by an experienced pathologist. Haematoxylin and eosin and immunohistochemical stainings for SOX9, OCT4, TSPY and SCF (KITL) were used. RESULTS: Thirteen males and 16 females were included, 20 with 46,XY and 9 with 45,X/46,XY DSD. Three females had dysgerminoma alongside gonadoblastoma; two gonadoblastoma, one germ cell neoplasia in situ (GCNIS) and three males had pre-GCNIS and/or pre-gonadoblastoma. Gonadoblastoma and/or dysgerminoma were present in 3/11 individuals with undetectable AMH and inhibin B, one of whom also had non-(pre)malignant germ cells. Of the other 18, in whom AMH and/or inhibin B were detectable, only one had no germ cells. CONCLUSIONS: Undetectable serum AMH and inhibin B cannot reliably predict the absence of germ cells and germ cell tumours in individuals with 45,X/46,XY or 46,XY gonadal dysgenesis. This information should help in counselling about prophylactic gonadectomy, taking into account both the germ cell cancer risk and potential for gonadal function.

Deferring gonadectomy in patients with turner syndrome with a genetic Y component is not a safe practice.

INTRODUCTION: Patients with Turner syndrome who harbor Y chromosome material are known to be at increased risk of developing germ cell neoplasms. The optimal timing to perform gonadectomy to reduce the risk of cancer development in these patients is not well defined. We present outcomes of Turner with a Y component (TSY) patients who underwent gonadectomy at our institution. HYPOTHESIS/OBJECTIVE: We hypothesized that tumors could occur in a significant portion of TSY patients at any age and gonadectomy can be safely performed at diagnosis rather than deferred. STUDY DESIGN: We performed an IRB-approved retrospective single center study in which we queried our institutions electronic health record to identify all patients with TSY who underwent gonadectomy at our institution from 2012 to 2021. RESULTS: In our series of 18 consecutive TSY patients, a tumor was identified in 6 patients (33.3%): 4 (22.2%) with dysgerminoma (DG) [Fig. 1] and 2 (11.1%) with gonadoblastoma (GB). DISCUSSION: Our cohort of 18 consecutive TSY who underwent gonadectomy over a 9-year period is the largest published single site cohort to date. Additionally, our patient who was found to have GB at 40 days is to our knowledge the youngest TSY patient to be diagnosed with GB in the literature. This patient's remarkably early incidence of tumor occurrence illustrates the urgency of protective gonadectomy. Given the high incidence of tumor formation in this population and the minimal morbidity associated with gonadectomy, we do not recommend delaying gonadectomy in this population for any reason. Our study is vulnerable to selection bias and confounding innate to any retrospective study. There was variation with respect to the frequency and timing of pre-operative imaging as a strict preoperative imaging protocol with sequential studies was not in place at our institution. Additionally, we do not have a comparison cohort of patients who are being followed without operative intervention as all TSY patients at our institution have undergone gonadectomy. CONCLUSION: TSY patients cannot be safely observed for tumor formation based on clinical factors such as imaging or age. Gonadectomy is safe with a low complication rate and without tumor recurrence during three-year follow-up. We continue to recommend bilateral gonadectomy in this patient population at the time of diagnosis.

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.

WAGR, Sex Reversal, Bilateral Gonadoblastomas, and Intralobar Nephrogenic Rests: Uncertainties of Pre-Biopsy Chemotherapy in a High Risk Syndrome for Nephroblastoma.

Background: WT1 deletions are associated with nephroblastomas, WT mutations are associated with 46, XY sex reversal. It is unclear why only a few WT1 deletions are associated with sex reversal. Case report. This 46, XY female had a 15.2 MB interstitial deletion of 11p14.1p11.2, which included WT1 and FSHB. No pathogenic abnormalities were identified in 156 other genes associated with disorders of sexual development. Bilateral gonadoblastomas were incidentally diagnosed at 17 months of age at the time of prophylactic gonadectomies. She was treated without biopsy for bilateral nephroblastomas radiologically identified at 18 months of age. Bilateral partial nephrectomies contained treated intralobular nephrogenic rests. Conclusion: It is unclear why WT1 deletions are less associated with 46, XY sex reversal than WT1 mutations. Treating suspected nephroblastomas without biopsy, even in patients with syndromes associated with bilateral nephroblastomas, may still lead to diagnostic and therapeutic uncertainties.

[Gonadoblastoma: Clinicopathological study and literature review of 3 cases].

OBJECTIVE: To investigate the clinical feature, pathological morphology, special histopathological subtype and immunohistochemical characteristic of gonadoblastoma. METHODS: Three patients of gonadoblastoma treated from 2014 to 2020 were enrolled, and the clinical characteristics, histological morphology and immunophenotype were analyzed, and the literatures were also reviewed. RESULT: Three phenotypical females were 14,17 and 27 years old. Case 1 was 46,XX with normal gonadal development. Case 2 was 46,XY and case 3 was chromosomal chimeric type (46, XY 90%/45,X 10%), both with dysgenetic gonads. Microscopically, the morphology of classic type was observed in all cases more or less, manifesting small nests of primitive germ cells and surrounding clustered sex cord-like cells, usually with Call-Exner like bodies and calcification. In additon, the morphology of special subtype can be seen in case 1,exhibiting cord-like tumor cells, which was segmentated by cellular fibrous stroma. Cases 2 and 3 were accompanied by dysgerminoma components. Immunohistochemically,all the primal germ cells were positive for OCT3/4, PLAP and CDll7 , and sexcord-like cells were positive for inhibin, SF-1, SOX9 and FOXL2 . Patients were followed up for 10 years, 6 years and 4 years respectively without recurrence. CONCLUSION: Gonadoblastoma is a rare germ cell-sex cord stromal tumor, which is usually accompanied by gonadal hypoplasia. As a special subtype, dissecting gonadoblastoma will be easily confused with dysgerminoma/seminoma, but the prognosis is better. So we should improve the understanding of this subtype and avoid overdiagnosis.

[Human chorionic gonadotropin-secreting gonadoblastomas in a girl of 45, X Turner syndrome: a case report and literature review].

Objective: To summarize the experience in diagnosis and treatment of 45, X Turner syndrome (TS) with gonadal Y chromosome mosaicism and bilateral gonadoblastoma (Gb) secreting human chorionic gonadotrophin(HCG). Methods: A female patient aged 5 years and 3 months was admitted to the hospital with a complaint of "enlarged breasts for 27 months, and elevated blood ß-HCG for 8 months". The clinical data were summarized, and related literature up to March 2022 with the key words"Turner syndrome" "Gonadoblastoma" "Y chromosome" "human chorionic gonadotropin" "precocious" in PubMed, CNKI and Wanfang databases were reviewed. Results: The girl went to the local hospital for 2-month breast development at age of 3 years, and was found with a heart murmur diagnosed with "pulmonary venous malformation and atrial septal defect (secondary foramen type)". Surgical correction was performed. She experienced the progressive breast development, rapid linear growth and markedly advanced skeletal age, which cannot be explained by partial activation in the hypothalamic-pituitary-gonadal axis determined at the age of 3 years and 7 months in local hospital. Then whole-exome sequencing revealed chromosome number abnormality 45, X, which was confirmed by Karyotyping. At the age of 4 years and 6 months, serum ß-HCG was found to be elevated (24.9 U/L) with no lesion found at the local hospital. On physical examination, she was found with breast development, pubic hair development and clitoromegaly with elevated serum testosterone (1.96 µg/L) and ß-HCG (32.3 U/L). Sex determining region Y(SRY) gene was negative in peripheral blood sample. Thoracic and abdominal CT, head and pelvic magnetic resonance imaging were normal. Exploratory laparotomy confirmed the presence of a left adnexal tumor and a right fibrous streak gonad. During surgery, simultaneous samples of bilateral gonadal and peripheral venous blood were obtained and serum ß-HCG, estradiol and testosteron concentrations was higher to lower from left gonadal venous blood, right gonadal venous blood, to peripheral venous blood. Bilateral gonadectomy was performed. Histopathology revealed bilateral gonadoblastomas. SRY was positive in bilateral gonadal tissues. After surgery, serum E2, testerone and ß-HCG returned to normal. So far 4 cases of HCG-secreting gonadoblastoma had been reported worldwide. The phenotypes of the 4 cases were all female, with virilization or amenorrhea, and the preoperative peripheral blood ß-HCG concentrations were 74.4, 5.0, 40 456.0, and 42.4 U/L, respectively. Conclusions: There is a high risk of Gb in TS with Y chromosome components. Gb is infrequently presented with breast development, and Gb associated with HCG secretion is rare. Karyotyping should be performed in a phenotypic female with masculinization, and virilization in TS indicates the presence of Y chromosome material with concurrent androgen secreting tumors.

Prevalence and characteristics of gonadoblastoma in a retrospective multi-center study with follow-up investigations of 70 patients with Turner syndrome and a 45,X/46,XY karyotype.

Introduction: A gonadectomy is currently recommended in patients with Turner syndrome (TS) and a 45,X/46,XY karyotype, due to a potential risk of gonadoblastoma (GB). However, the quality of evidence behind this recommendation is low. Objective: This study aimed to evaluate the prevalence of GB, its characteristics, as well as its risk factors, according to the type of Y chromosomal material in the karyotype. Methods: Our study within French rare disease centers included patients with TS and a 45,X/46,XY karyotype, without ambiguity of external genitalia. Clinical characteristics of the patients, their age at gonadectomy, and gonadal histology were recorded. The regions of the Y chromosome, the presence of TSPY regions, and the percentage of 45,X/46,XY mosaicism were evaluated. Results: A total of 70 patients were recruited, with a median age of 29.5 years (21.0-36.0) at the end of follow-up. Fifty-eight patients had a gonadectomy, at a mean age of 15 ± 8 years. GB was present in nine cases. Two were malignant, which were discovered at the age of 14 and 32 years, without metastases. Neither the percentage of XY cells within the 45,X/46,XY mosaicism nor the number of TSPY copies was statistically different in patients with or without GB (P = 0.37). However, the entire Y chromosome was frequent in patients with GB (6/9). Conclusions: In our study, including a large number of patients with 45,X/46,XY TS, the prevalence of gonadoblastoma is 12.8%. An entire Y chromosome appears as the main risk factor of GB and should favor early gonadectomy. Significant statement: About 10% of patients with TS have a karyotype containing Y chromosomal material: 45,X/46,XY. Its presence is related to the risk of GB. Therefore, a prophylactic gonadectomy is currently recommended in such patients. However, the quality of evidence is low. Our objective was to evaluate the prevalence of GB according to the type of Y-chromosomal material. We found a prevalence of GB of 12.8% in a cohort of 70 TS patients. No sign of hyperandrogenism was observed. The entire Y chromosome was the most frequent type of Y-material in patients with GB. As the prognosis of these tumors was good, a delay of surgery might be discussed.

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.

Bilateral Gonadoblastoma in a 6-Year-old Girl With Frasier Syndrome: Need for Early Preventive Gonadectomy.

Frasier syndrome (FS) is a rare condition, caused by splice-site mutations of intron 9 in the Wilms' tumor suppressor gene 1 (WT1 gene). The WT1 protein is essential for urogenital development and patients with 46XY karyotype present with female (FS type 1) or male phenotype, gonadal dysgenesis, progressive glomerulopathy, and high risk of gonadoblastoma. We describe a female patient with an IVS9+4C>T donor splice-site mutation, who underwent a preventive gonadectomy at the age of 6 years due to imaging findings of dysplastic gonads. The biopsy revealed bilateral gonadoblastoma, emphasizing the need for early gonadectomy in 46XY FS patients.

Sex chromosome DSD individuals with mosaic 45,X0 and aberrant Y chromosomes in 46,XY cells: distinct gender phenotypes and germ cell tumour risks§.

"Differences of Sexual Development (DSD)," individuals with rearranged Y chromosome breaks in their 46,XY cells are reported with male and female gender phenotypes and differences in germ cell tumour (GCT) risk. This raised the question of whether male or female gender and GCT risk depends on the site of the break and/or rearrangement of the individual´s Y chromosome. In this paper, we report molecular mapping of the breakpoint on the aberrant Y chromosome of 22 DSD individuals with a 45,X/46,XY karyotype reared with a different gender. Their Y chromosome breaks are found at different sites on the long and short Y arms. Our data indicate that gender rearing is, neither dependent on the site of Y breakage, nor on the amount of 45,X0 cells in the individuals' leukocytes. Most prominent are secondary rearrangements of the Y chromosome breaks forming di-centric Y-structures ("dic-Y"). Duplications of the short Y arm and the proximal part of the long Y arm are the results. A putative GCT risk has been analysed with immunohistochemical experiments on some dysgenetic gonadal tissue sections. With specific antibodies for OCT3/4 expression, we marked the pluripotent germ cell fraction being potential tumour precursor cells. With specific antibodies for DDX3Y, TSPY, and UTY we analyzed their putative Gonadoblastoma Y (GBY) tumour susceptibility function in the same specimen. We conclude GBY expression is only diagnostic for GCT development in the aberrant germ cells of these DSD individuals when strong OCT3/4 expression has marked their pluripotency.

Adnexal Torsion Due to Borderline Mucinous Tumor of the Gonad in a Prepubertal Girl with Mixed Gonadal Dysgenesis (45,X/46,XY) and a Turner Phenotype.

BACKGROUND: Turner syndrome (TS) is a sex chromosome condition characterized by complete or partial loss of the X chromosome. Patients with mixed gonadal dysgenesis (45,X/46,XY) and a Turner phenotype are predisposed to gonadoblastoma with malignant transformation. CASE: We present the case of a TS patient with 45,X/46,XY with 2 episodes of left adnexal torsion (AT). Biopsies during detorsion showed benign mucinous cystadenoma. Pathology following bilateral gonadectomy revealed a left gonad with mucinous borderline tumor and right gonad with gonadoblastoma, both of which have malignant potential. SUMMARY AND CONCLUSION: Gonadectomy is recommended in XY gonadal dysgenesis to decrease risk of malignant transformation from gonadoblastoma. Although rare in pediatric patients, ovarian malignancies have been identified among AT cases. To our knowledge, we present the first case of AT due to borderline ovarian mucinous tumor of the ovary and contralateral gonadoblastoma in a patient with mixed gonadal dysgenesis (45,X/46,XY) and a Turner phenotype.

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.