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.

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.

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.

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.

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.

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.

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.

Phenotypic spectrum of 45,X/46,XY males with a ring Y chromosome and bilaterally descended testes.

OBJECTIVE: To characterize the phenotypic spectrum of males with bilaterally descended testes and a 45,X/46,X,(r)Y karyotype. DESIGN: Retrospective review of patient records; cytogenetic and molecular analysis. SETTING: Tertiary medical center setting. PARTICIPANT(S): Five males, two prepubertal and three postpubertal, with a 45,X/46,X(r)Y karyotype and bilaterally descended testes. INTERVENTION(S): Linear growth evaluation, testicular endocrine and exocrine studies, cytogenetic and molecular analysis on each patient. MAIN OUTCOME MEASURE(S): Clinical phenotype versus genotype. RESULT(S): Both prepubertal males had short stature and low testosterone. All three adults had normal puberty and normal testosterone levels. Two of the adults (one with short stature and one with normal stature) had elevated gonadotropins and azoospermia. The third adult had normal stature, severe oligospermia, normal gonadotropins, and normal serum testosterone. CONCLUSION(S): The phenotypic spectrum of males with a 45,X/46,X(r)Y karyotype and bilaterally descended testes varies greatly from males with short stature and spermatogenic failure to males without short stature and less severely affected spermatogenesis. This broad spectrum of phenotypic findings needs to be taken into account when the clinical geneticist encounters a prenatal diagnosis of a 45,X/46,X(r)Y karyotype. This information will also be helpful for pediatric and reproductive endocrinologists in counseling males with bilaterally descended testes and a 45,X/46,X(r)Y karyotype.

[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.

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.

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.

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.

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.

Bilateral seminomas in a 45X/46XY mosaic with Turner's phenotype: an unusual case of mixed gonadal dysgenesis.

A wide spectrum of phenotypic manifestations are seen in cases with 45X/46XY mosaicism. We present a case with 45X/46XY having female phenotype with Turner's stigmata. Prophylactic laparoscopic gonadectomy was performed and the patient was found to have mixed gonadal dysgenesis with bilateral gonadoblastomas. Microinvasive seminomas were also detected in both gonadoblastomas. The presence of Y cell line in karyotype prompted early and prophylactic gonadectomy, a procedure which is life-saving for these individuals.

Mixed gonadal dysgenesis and precocious puberty.

A girl aged 5 years and 6 months presented with premature thelarche in our outpatient clinic. During long-term observation, we recorded growth acceleration, advanced bone age, and elevated oestradiol levels which together were taken to confirm the diagnosis of precocious puberty. The patient was successfully treated with a gonadotropin-releasing hormone agonist, but in view of the poor growth prognosis, recombinant human growth hormone was administered concurrently. At the age of 9 years and 6 months a mild clitoris enlargement and conspicuous muscle development without any further signs of virilization were noticed. Laboratory findings showed high values for testosterone and normal basal values for 17-hydroxyprogesterone and dehydroepinadrosterone sulphate. Explorative laparotomy revealed a gonadoblastoma arising from testicular structures on the left, a female streak gonad on the right side, and normal uterus and fallopian tubes. The karyotype was 46,XY/45,X. These findings confirmed the diagnosis of mixed gonadal dysgenesis with testosterone-producing gonadoblastoma.

Penoscrotal hypospadias and coarctation of the aorta with mixed gonadal dysgenesis.

A 45,X/46,Xidic(Y)(q11.2) mosaicism was found in a 4-year-old boy. The clinical appearance was characterized by bilateral cryptorchidism, penoscrotal hypospadias, short penis, and coarctation of the aorta. The latter is the only abnormality also seen in Turner syndrome. A biopsy of the gonads revealed normal prepubertal testicular tissue. A chromosome analysis in all boys with penoscrotal, scrotal, or perineal hypospadias and a thorough examination of the heart in children with 45,X/46,XY mosaicism are recommended.

A novel missense mutation in the HMG box region of the SRY gene in a Japanese patient with an XY sex reversal.

The sex-determining region of the Y chromosome, the SRY gene, located on the short arm of the Y chromosome, is appreciated as one of the genes that is responsible for directing the process of sex differentiation. To date, 34 different mutations, including 29 missense and nonsense mutations in the SRY gene, have been described in XY female patients. We investigated the molecular basis of the sex reversal in one Japanese XY female patient by determining the nucleotide sequence of the SRY gene, using polymerase chain reaction and direct sequencing. We identified a novel mutation, of the substitution of Tyr for Asn at nucleotide position 87 (N87Y). This Asn residue is located within the DNA-binding high-mobility-group (HMG) motif, which is considered to be the main functional domain of the SRY protein. Further, this amino acid, Asn, is a conserved residue among mammalian SRY genes. These findings indicate that this amino acid substitution may be responsible for the sex reversal in this patient.