Successful surgical sperm retrieval from a patient with 45,X/46,XY mosaicism followed by in vitro fertilization pregnancy: A case report.

RATIONALE: Mixed gonadal dysgenesis is a rare disorder of sex development, and typically contains a mosaic 45,X/46,XY karyotype. PATIENT CONCERNS: We reported here a case of a 42-year-old man with infertility for 6 years and inability to ejaculate during intercourse. DIAGNOSIS: Physical examination confirmed that the external genitalia was male. The right testis of this patient was resected and the left testis had intrascrotal calcification. Hormone test showed that the level of follicle-stimulating hormone was 20.14 IU/L (normal range, 1.27-19.26 IU/L). No deletion or mutation was found on the sex-determining region Y. H&E staining revealed seminiferous tubule dysgenesis. The karyotyping in peripheral blood and testicular tissue was 45,X/46,XY and 45,X/47,XYY/46,XY, respectively. Based on these results, the patient was diagnosed with 45,X/46,XY or 45,X/47,XYY/46,XY mosaicism and gonadal dysgenesis. INTERVENTIONS: In vitro fertilization and embryo transfer technology were used to help his wife to achieve pregnancy. OUTCOMES: A normal baby boy was born at 36 weeks of gestation with a karyotype 46, XY. LESSONS: We reported a rare case of a karyotype 45,X/46,XY in blood cells and 45,X/47, XYY/46,XY in testicular tissue. In vitro fertilization and embryo transfer technology can help to achieve pregnancy.

Multiple genomic aberrations in a patient with mental retardation and hypogonadism: 45,X/46,X,psu dic(Y) karyotype, thyroid hormone receptor beta (THRB) mutation and heterozygosity for Wilson disease.

We report on multiple genomic aberrations in a patient with mental retardation. In addition, he had hypogonadism, elevated thyroid hormone levels, hearing loss, delayed speech development and mild dysmorphic features. First, we identified a mosaic karyotype, 45,X/46,X,psu dic(Y). The pseudo-dicentric Y chromosome has three short arm segments. Second, we found a germline mutation (Pro453Thr) of the thyroid hormone receptor beta (THRB) which is associated with resistance to thyroid hormone. Third, he was found to be a carrier of a heterozygous ATP7B mutation (c.2575 + 5G > C), the Wilson disease gene. Even though an array-CGH (with a density of approximately 1 Mb) did not reveal any further genomic gains or losses, we cannot exclude that all contributing factors have been identified. However, this case report shows that with increasing technological possibilities we can find more than one cause for developmental problems in a single patient. The identification of multiple causes in a single patient may complicate explaining the disorder and genetic counseling.

Long term follow-up of a child with ambiguous genitalia, mixed gonadal dysgenesis, and unusual mosaicism.

Mixed gonadal dysgenesis (MGD) is a condition of abnormal and asymmetrical gonadal development. This disorder is typically associated with 45,X/46,XY mosaicism; however, other karyotypes have been rarely reported. The phenotype characterizing MGD is highly variable, although in most cases ambiguous genitalia are found. In addition, many individuals with MGD exhibit stigmata of Turner's syndrome. We describe a patient with MGD, found to have a 45,X/47,XYY karyotype, with the majority of the cell lines being 47,XYY. To our knowledge, our report is the first to describe the long-term follow-up of a patient with ambiguous genitalia diagnosed at birth with 45,X/47,XYY mosaicism.

[Mixed gonadal dysgenesis combined with gonadoblastoma].

Gonadal dysgenesis is defined by incomplete or defect forming of gonads, a result of disturbed process of migration of germ cells or and their correct organization in gonadal ridge. The combination of dysgenetic gonads and Y chromosome is a prerequisite for developing ovarian neoplasma--most frequent gonadoblastoma. We present a case of mixed gonadal dysgenesis at a patient with caryotype 46XY in combination with gonadoblastoma.

The Dilemma of Sex of Rearing: A Case of a 45,X/46,XY Neonate with Hydrocolpos.

BACKGROUND: A rare disorder of sex development is 45,X/46,XY mosaicism, which is phenotypically very heterogenous, ranging from normal male (or female) to that of genital ambiguity of varying degrees. CASE: We report a case of a neonate with 45,X/46,XY mosaicism and hydrocolpos, and we point out the dilemma and the difficulty in gender assignment. SUMMARY AND CONCLUSION: Gender assignment of cases with frank genital ambiguity is often difficult to be determined, because several factors have to be taken into consideration, such as genital appearance, anticipated urological and sexual function, capacity for future fertility, gonadal malignancy risk, and psychosocial factors. A multidisciplinary approach is definitely needed in the management of such cases.

Participation of OCT3/4 and beta-catenin during dysgenetic gonadal malignant transformation.

Gonadoblastoma (GB) is an in situ tumor consisting of a heterogeneous population of mature and immature germ cells, other cells resembling immature Sertoli/granulosa cells, and Leydig/lutein-like cells, may also be present. GB almost exclusively affects a subset of patients with intersex disorders and in 30% of them overgrowth of the germinal component of the tumor is observed and the lesion is term dysgerminoma/seminoma. Several pathways have been proposed to explain the malignant process, and abnormal OCT3/4 expression is the most robust risk factor for malignant transformation. Some authors have suggested that OCT3/4 and beta-catenin might both be involved in the same oncogenic pathway, as both genes are master regulators of cell differentiation and, overexpression of either gene may result in cancer development. The mechanism by which beta-catenin participates in GB transformation is not completely clear and exploration of the E-cadherin pathway did not conclusively show that this pathway participated in the molecular pathogenesis of GB. Here we analyze seven patients with mixed gonadal dysgenesis and GB, in an effort to elucidate the participation of beta-catenin and E-cadherin, as well as OCT3/4, in the oncogenic pathways involved in the transformation of GB into seminoma/dysgerminoma. We conclude that the proliferation of immature germ cells in GB may be due to an interaction between OCT3/4 and accumulated beta-catenin in the nuclei of the immature germ cells.

Short stature in a phenotypic male caused by mixed gonadal dysgenesis.

BACKGROUND: An 8.5-year-old boy was referred to a pediatric endocrinology clinic for evaluation of short stature. At birth, a chordee without hypospadius, 90-degree penile torsion and an undescended testis on the right had been observed. The boy had undergone surgical repair at 1 year of age and at that time an undescended 'nonfunctional' streak gonad and a horseshoe kidney had been noted. Subsequent karyotype analysis had revealed a 45,X0/46,XY karyotype with mosaicism. Since 4-5 years of age, the patient's height has been below the 3(rd) percentile, whereas his weight has been maintained at approximately the 3(rd) percentile. INVESTIGATIONS: Performance of thyroid function tests, measurement of levels of insulin-like growth factor I and insulin-like growth factor binding protein 3, estimation of bone age, calculation of height and weight percentiles and SD scores based on 2000 normative data from the National Center for Health Statistics, USA. DIAGNOSIS: Mixed gonadal dysgenesis with a 45,X0/46,XY karyotype. MANAGEMENT: The patient's growth was found to be following the 50(th) percentile growth curve on the Turner syndrome growth chart, which was significantly below his mid-parental target height. He was started on growth hormone at a dose of 0.35 mg/kg/week. The patient remains under close follow-up to monitor his linear growth velocity and his pubertal development.

Early development of a gonadal tumor in a patient with mixed gonadal dysgenesis.

A gonadal tumor was diagnosed in the first months of life in a patient with genital ambiguity, a 45,X/46,XY karyotype, and mixed gonadal dysgenesis. Gonadal biopsies at the age of 3 months revealed dysgenetic testes and a gonadoblastoma on the right testis. Even though gonadal tumors are rare in childhood, this case indicates that prophylactic removal of dysgenetic gonads should be performed as early as possible, especially when the female sex is assigned to a patient with a Y-chromosome sequence.

Mixed gonadal dysgenesis and Denys-Drash syndrome: urologists should screen for nephrotic syndrome.

OBJECTIVE: We present a child with Denys-Drash syndrome recognized after surgery for mixed gonadal dysgenesis, and discuss screening procedures the urologist should consider in similar circumstances. CASE REPORT: A 1-year-old child with XY gonadal dysgenesis underwent genital reconstruction. The postoperative period was complicated by incisional drainage, which led to the recognition of a nephrotic syndrome. Molecular analysis of the WT-1 gene confirmed a mutation associated with the Denys-Drash syndrome. CONCLUSION: The Denys-Drash syndrome should be suspected in children with XY gonadal dysgenesis. The presence of urine protein should be sought in such children, and if present, consultation with genetic and nephrology specialists is warranted.

External genital abnormalities associated with Wilms tumor.

The records of 170 patients with unilateral and 18 patients with bilateral Wilms tumor and 6 patients with congenital mesoblastic nephroma were reviewed for abnormalities of the external genitalia. There were 4 patients with cryptorchism, 1 with hypospadias, 1 with mixed gonadal dysgenesis, and 3 with male pseudohermaphroditism. Of the group, these 9 patients had earlier symptoms; 6 of them were under two years old. Five patients (27.7%) with bilateral Wilms tumors had external genital anomalies in contrast to only 4 (2.3%) of those with unilateral tumors. One of the 9 children with genital anomalies had unilateral congenital mesoblastic nephroma; the others had Wilms tumor. In all cases the histologic subtypes were unusual. These observations substantiate the previously reported association between external genital abnormalities and Wilms tumor and also represent a somewhat higher than expected incidence. The children with this association are remarkable for the high frequency of a particular histologic type of tumor and for the high incidence of bilaterality. The high incidence of Wilms tumors in the male pseudohermaphrodite population presented suggests that such patients should be monitored for development of renal tumors.

Bilateral gonadoblastomas in a dog with mixed gonadal dysgenesis.

Gonadoblastomas are rare mixed germ cell neoplasms, which are frequently diagnosed in testes excised for other reasons. In human patients these tumours are usually associated with undescended testes or dysgenetic gonads. This report describes a 10-year-old male dog with mixed gonadal dysgenesis ("streak testis" on the right side and testis on the left side) and bilateral gonadoblastomas. Immunohistochemical analysis revealed an atypical and mitotically active germ cell population which co-expressed placental alkaline phosphatase and c-kit oncogene, admixed with inhibin- and S-100 protein-positive sex cord cells. The findings were generally consistent with previous reports of the dual population of neoplastic cells in gonadoblastomas affecting human patients, and closely resembled the findings in the only other case reported in dogs. Moreover, the findings further support the proposal that gonadoblastomas should be considered a special form of in-situ germ cell neoplasia.

Clear cell adenocarcinoma of the cervix and vagina in a woman with mixed gonadal dysgenesis. A case report.

Clear cell adenocarcinoma of the cervix and vagina occurred in a woman with 45,X/46,XY gonadal dysgenesis. The patient had no known exposure to synthetic estrogen prenatally and did not receive exogenous estrogen at any time.

[Association of mixed gonadal dysgenesis and non-classic 21-hydroxylase deficiency]. / Association d'une dysgénésie gonadique mixte et d'une forme non classique de bloc de la 21-hydroxylase.

BACKGROUND: The rare association of mixed gonadal dysgenesis and non classical congenital hyperplasia by 21-hydroxylase deficiency poses the problem of their respective responsibility in the development of sexual ambiguity. CASE REPORT: In a newborn with ambiguous genitalia, blood 17-OH progesterone was moderately elevated (3.9 to 14.1 ng/mL) leading to the diagnosis of non-classical 21 hydroxylase deficiency, Molecular studies later confirmed this diagnosis. However, the presence of a palpable gonad and the karyotype (45 X/46 XY mosaicism) indicated a mixed gonadal dysgenesis as the cause of sexual ambiguity. Histological examination revealed the presence of a testis and a streak gonad. CONCLUSION: This observation emphasizes the need for a complete clinical and biological analysis in all newborns with sexual ambiguity.

[Mixed gonadal dysgenesis with seminoma: a case report].

A case of mixed gonadal dysgenesis with anaplastic seminoma is reported. A 43-year-old, female, who was brought up as a female, was admitted to our hospital for swelling of left inguinal region. The physical examination revealed a short stature, ambiguous external genitalia but no Turner's stigmata. A child's head-sized tumor was noticed in the left inguinal region by CT scan. The histopathological diagnosis of this tumor was anaplastic seminoma. The right gonad was removed at laparotomy with lymph node dissection in the pelvis. Histological examination of right gonad revealed streak gonad and immature uterine with fallopian tube. In the Japanese literature, 7 cases including our case of mixed gonadal dysgenesis with gonadal tumor have been reported.

[Mixed gonadal dysgenesis with plasty in males].

A 13-year-old Korean boy is reported here as a case of mixed gonadal dysgenesis. The patient presented with perineal hypospadia. He had scrotal testis, epididymis, vas deferens on right side, and abdominal streak gonad, Fallopian tube on left side. He had also uterus and vagina. His chromosome was 46XY type. Among 59 reported cases in Japan, 12 had undergone plasty into male. All of them had hypospadia. In 51 cases, 17 had testes in scrotum. None of them had a testicular tumor. So we decided to do plasty in male, and to follow up his testis quite carefully.

[Mixed gonadal dysgenesis and gonadal tumor--growth of seminoma after 27 years of an exploratory laparotomy].

A case of mixed gonadal dysgenesis with anaplastic seminoma is herein reported. A 38-years-old man was admitted to our hospital with the chief complaint of a painful mass, 19.0 cm in long diameter in his lower abdomen. At 11, 13 and 14 years old he had the history of treatment for an ambiguous external genitalia and defect of both scrotal contents. In the concrete, laparotomy, chordectomy and urethroplasty were performed at those times and the laparotomy revealed a right immature abdominal testis and Müllerian structures. Laboratory examination revealed elevated levels of serum lactic dehydrogenase and HCG. The karyotype from the cultured lymphocyte was that of a normal male. Because the histological finding of biopsied abdominal tumor was shown to be an anaplastic seminoma, firstly two courses of chemotherapy using cisplatin vinblastine and bleomycin were induced, and that after an extensive resection for the tumor and Müllerian structure including some portions of surrounding tissue was performed. We reviewed 40 cases of mixed gonadal dysgenesis reported previously in the Japanese literature and 8 cases of that with a gonadal tumor.

Early development of a gonadal tumor in a patient with mixed gonadal dysgenesis

SUMMARY A gonadal tumor was diagnosed in the first months of life in a patient with genital ambiguity, a 45,X/46,XY karyotype, and mixed gonadal dysgenesis. Gonadal biopsies at the age of 3 months revealed dysgenetic testes and a gonadoblastoma on the right testis. Even though gonadal tumors are rare in childhood, this case indicates that prophylactic removal of dysgenetic gonads should be performed as early as possible, especially when the female sex is assigned to a patient with a Y-chromosome sequence.

Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys.

CONTEXT: Gender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys. OBJECTIVE: The purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys. METHODS: This is a multicenter retrospective study. RESULTS: Mean age at study was 25.6±2.4 years. Eighty-five percent of the patients presented a 'classical' mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of <80 mm. Mean adult height is 156.9±2 cm, regardless of GH treatment. CONCLUSIONS: In summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients.

Atypical presentation and management dilemma of mixed gonadal dysgenesis.

OBJECTIVE: To describe a case of 45,X/46,XY mixed gonadal dysgenesis complicated by malignancy with possible metastasis. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 15-year-old female with primary amenorrhea, short stature, and a vaginal septum. INTERVENTION(S): Resection of transverse vaginal septum and laparoscopic bilateral gonadectomy. RESULT(S): The patient had dysgerminoma arising from gonadoblastoma in the left gonad and gonadoblastoma in the right gonad. No normal gonadal tissue could be identified. Postoperative computed tomography scan results were suspicious for lung metastases, but the patient opted for conservative management without chemotherapy. CONCLUSION(S): Mixed gonadal dysgenesis involves inherent malignancy risk and complex psychosocial issues, which necessitate a multidisciplinary approach to diagnosis and treatment.