Gonadal dysgenesis is associated with worse outcomes in patients with ovarian nondysgerminomatous tumors: A report of the Children's Oncology Group AGCT 0132 study.

PURPOSE: In this report, we characterize the timing and behavior of malignant ovarian germ cell tumors (GCTs) in pediatric patients with dysgenetic gonads compared to those with normal gonadal development. PATIENTS AND METHODS: Patients from the Children's Oncology Group AGCT0132 with malignant ovarian GCTs were included. Within this population, we sought to identify patients with gonadoblastoma, streak ovaries, or other evidence of gonadal dysgenesis (GD). Patients with malignant GCTs containing one or more of the following histologies-yolk sac tumor, embryonal carcinoma, or choriocarcinoma-were included. Patients were compared with respect to event-free survival (EFS) and overall survival (OS). RESULTS: Nine patients with GD, including seven with gonadoblastoma (mean age, 9.3 years), were compared to 100 non-GD patients (mean age, 12.1 years). The estimated 3-year EFS for patients with GD was 66.7% (95% CI 28.2-87.8%) and for non-GD patients was 88.8% (95% CI 80.2-93.8%). The estimated 3-year OS for patients with GD was 87.5% (95% CI 38.7-98.1%) and for non-GD patients was 97.6% (95% CI of 90.6-99.4%). CONCLUSION: Patients presenting with nongerminomatous malignant ovarian GCTs in the context of GD have a higher rate of events and death than counterparts with normal gonads. These findings emphasize the importance of noting a contralateral streak ovary or gonadoblastoma at histology for any ovarian GCT and support the recommendation for early bilateral gonadectomy in patients known to have GD with Y chromosome material. In contrast to those with pure dysgerminoma, these patients may represent a high-risk group that requires a more aggressive chemotherapy regimen.

New NR5A1 mutations and phenotypic variations of gonadal dysgenesis.

Mutations in NR5A1 have been reported as a frequent cause of 46,XY disorders of sex development (DSD) associated to a broad phenotypic spectrum ranging from infertility, ambiguous genitalia, anorchia to gonadal dygenesis and female genitalia. Here we present the clinical follow up of four 46,XY DSD patients with three novel heterozygous mutations in the NR5A1 gene leading to a p.T40P missense mutation and a p.18DKVSG22del nonframeshift deletion in the DNA-binding domain and a familiar p.Y211Tfs*83 frameshift mutation. Functional analysis of the missense and nonframeshift mutation revealed a deleterious character with loss of DNA-binding and transactivation capacity. Both, the mutations in the DNA-binding domain, as well as the familiar frameshift mutation are associated with highly variable endocrine values and phenotypic appearance. Phenotypes vary from males with spontaneous puberty, substantial testosterone production and possible fertility to females with and without Müllerian structures and primary amenorrhea. Exome sequencing of the sibling's family revealed TBX2 as a possible modifier of gonadal development in patients with NR5A1 mutations.

Primary amenorrhea: diagnosis and management.

Puberty is a defining time of many adolescents' lives. It is a series of events that includes thelarche, pubarche, and menarche. Primary amenorrhea is the absence of menarche. There are numerous etiologies including outflow tract obstructions, gonadal dysgenesis, and anomalies of the hypothalamic axis. This review's aims are to define primary amenorrhea and describe the various causes, their workups, associated comorbidities, and treatment options. At the end, a generalist should be able to perform an assessment of an adolescent who presents with primary amenorrhea and, if warranted, begin initial treatment.

Pure gonadal dysgenesis and spontaneous pregnancy: a case report.

We report a case of pure gonadal dysgenesis with streak gonads in which spontaneous conception occurred 10 years after the diagnosis. Her pregnancy proceeded as normal, and she gave birth to a live baby at term by cesarean section. A lactation period lasting for 1 year and afterwards proceeded as amenorrheic. Gonadotropins measurements in post-lactational period were at the menopausal levels again. To the best of our knowledge, this is the first case of pure gonadal dysgenesis with streak gonads in which spontaneous conception occurred.

[Molecular and cytogenetic study on 5 cases with gonadal dysgenesis: clinical applications of fluorescence in situ hybridization(FISH) and BAC-FISH].

OBJECTIVE: To explore the applications of fluorescence in situ hybridization (FISH) in the diagnosis for the patients with gonadal dysgenesis. METHODS: After routine gynecologic examination, ultrasonography and endocrine examination, 5 cases of gonadal dysgenesis and hypogonadism were analyzed by using chromosomal diagnoses including G-banding, Q-banding, multiplex FISH and BAC-FISH analyses. RESULTS: Among the 5 cases of gonad agenesis patients, 2 were pure gonadal dysgenesis with 46, XY karyotype, 3 were mixed gonadal dysgenesis with mos 45, X/47, XXX; 45, X/46, XY or 46, X, der(Y) karyotype. CONCLUSION: Sex chromosomal abnormalities resulted in gonadal dysgenesis symptoms. Applications of FISH and BAC-FISH analyses can correctly diagnose the sex chromosomal abnormalities for patients with gonad agenesis and provide accurate medical genetic data for clinical diagnosis and therapy.

Disorders of sexual development.

In human sexual development, the female phenotype represents the default pathway. Therefore, a failure of testis determination results in the development of the female phenotype, while genetic alterations resulting in partial testicular development can give rise to a wide spectrum of masculinization. In addition to defects in peptide hormones and their receptors, timing of hormonal exposure is also critical to appropriate development. Although much work remains to be done, recent advances in our knowledge have begun to unravel the molecular basis of disorders of sexual development. Consensus statements from investigators have recommended changes in the nomenclature, and further investigations have examined the role of the female and male psyche in patients with these disorders. This review focuses on the diagnosis and management of conditions related to disorders of sexual development.

[Quality of life in the patients with disorders of sexual development and with Y chromosome in karyotype]. / Kvalita zivota pacientu s poruchou sexuálního vyvoje a s Y chromozómem v karyotypu.

New nomenclature of disorders of sexual development is provided. Contemporary the management and the quality of life in the patients with pure gonadal dysgenesis and mixed gonadal dysgenesis is assessed.

[Modern concepts in the treatment of intersexuality]. / Zum aktuellen Stand der Intersextherapie.

Treatment of intersexuality is demanding and requires experience and interdisciplinary cooperation. Preconditions for normal development and clear gender identification are correct (not emergency) diagnosis and gender assignment and adequate hormonal and surgical treatment. Surgery should be done early (6th to 15th month) as atraumatically as possible with cosmetically and functionally satisfying results. These preconditions are not met consistently, resulting in a 20-25% rate of mistakes in diagnosis and treatment. In experienced centers, feminizing genitoplasty, even of the severest forms, is carried out through a perineal one-stage approach. Masculinization corresponds to surgery for severe hypospadias. The high risk of malignant degeneration requires removal of all inadequate structures such as streak gonads, uterus, and tubes. In 5-alpha deficiency, early gonadectomy and feminization are not recommended since gyneophile behavior can be expected. Late or non-correction is rejected by the majority of psychiatrists. Many problems remain unclear and controversial due to lack of knowledge. In the future they can only be solved through cooperation, documentation, and observation of these individuals over their lifetime.

A case of mistaken identity. A rare presentation of gonadal dysgenesis.

BACKGROUND: The incidence of gonadal dysgenesis (hermaphroditism) is recognised to be low. Rarer still is an initial late presentation in the general practice setting. OBJECTIVE: To present a case study of a 35 year old man diagnosed as a hermaphrodite after routine investigations in general practice for lower abdominal pain. He has normal male external genitalia, a fully formed uterus and vagina, with no identifiable gonads. DISCUSSION: This incidental finding in general practice is supported by a 46,X,i(Yp)/45,X karyotype and mosaicism for an isochromosome of the short arm of the Y. It is not unusual that with normal male genitalia, such patients are likely to survive undiagnosed or incorrectly diagnosed into adulthood.

Disgenesias gonadais: estudo de 84 pacientes / Gonadal dysgenesis: study of 84 patients

OBJETIVOS: Este estudo pretende avaliar as pacientes portadoras de disgenesia gonadal atendidas no período de janeiro de 1970 a maio 1999 no Serviço de Ginecologia do Departamento de Tocoginecologia do Hospital de Clínicas da Universidade Federal do Paraná. CASUISTICA E MÉTODOS: Realizouse estudo retrospectivo das 84 pacientes com disgenesia gonadal atendidas no ambulátorio de Ginecologia Endócrina deste serviço. RESULTADOS: Das 84 pacientes estudadas, 39 (46,43 por cento) tiveram o diagnóstico de disgenesia gônado-somática (grupo I); 41 delas (48,81 por cento) tiveram o diagnóstico de disgenesia gonadal pura (grupo II) e em quatro (4,76 por cento), o diagnóstico foi de disgenesia gonadal mista (grupo III). CONCLUSÕES: O presente estudo analisou e concluiu que conveniente observaçäo clínica e laboratorial é importante para a orientaçäo e prognóstico das pacientes portadoras de disgenesias gonadais. Discute-se a orientaçäo medicamentosa e cirúrgica nesta entidade

A concomitant decrease in cortical and trabecular bone mass in isolated hypogonadotropic hypogonadism and gonadal dysgenesis.

To assess the impact of hypogonadism on bone mineral density, we performed a cross-sectional study of 70 amenorrheic women, comprising 22 cases of gonadal dysgenesis and 48 cases of isolated hypogonadotropic hypogonadism (IHH). Bone mineral density was measured by DEXA at four sites: the femur neck, Ward's triangle, trochanter, and lumbar spine (L2-4). The results were compared to those of a control group consisting of 60 age-matched, normal-cycling women. Bone mineral densities around age 20 were already significantly lower at all four sites in patients with IHH and gonadal dysgenesis when compared with controls, suggesting that these patients failed to achieve peak bone mass during pubertal development. In patients with IHH, the initial BMD around age 18-20 were significantly lower at all four sites and the decrease in bone density continued rapidly during the early twenties up to age 25, and then it slowed markedly thereafter. Bone biochemical marker, ICTP and osteocalcin were significantly negatively correlated with age and remained increased until age 40, which was reminiscent of menopausal bone loss pattern such as high bone turn-over in the early twenties, followed by slow bone loss in the late twenties. In patients with gonadal dysgenesis, bone biochemical marker, ICTP and osteocalcin were also significantly negative correlated with age and remained increased until age 40, but no significant changes in BMD were noted as a function of age, which may be attributed to the small sample size and slow bone loss. These findings suggest that the initiation of prompt and timely therapeutic intervention as early as possible in the menarchal period and throughout the remainder of life, particularly during the period associated with rapid bone loss.

Management of males with 45,X/46,XY gonadal dysgenesis.

Males with the 45,X/46,XY karyotype and malformations of the external genitalia carry an increased risk of developing germ cell neoplasia of the gonads. We have studied gonadal tissue from 10 individuals, 0.3-17 years of age, with a male phenotype and either hypospadias and/or cryptorchidism. Four patients, 0.3-15 years of age, had carcinoma in situ, 1 boy had Sertoli-cell-only pattern and the remainder prepubertal histology. Gonadoblastoma or invasive carcinoma was not found. On the basis of our current knowledge we propose a strategy for management and follow-up of these boys in order to detect possible premalignant histological changes early and prevent development of a gonadal tumour.

[Gonadal dysgenesis: diagnosis and therapeutic perspectives]. / Disgenesia gonadal: diagnóstico y perspectivas terapéuticas.

Ovarian dysgenesis is the endstage of a process of follicular atresia, Turner syndrome (45,X) being the most common cause, with an incidence of 1 in 2500 female births. In addition to ovarian failure, these patients have short stature and a number of primary and derived somatic anomalies. Tertiary preventive measures are considered and treatment of short stature, estrogen deficiency and of infertility is discussed.