RESUMO
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.
Assuntos
Disgenesia Gonadal/mortalidade , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Ovarianas/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/patologia , Disgenesia Gonadal/terapia , Humanos , Lactente , Recém-Nascido , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Taxa de SobrevidaRESUMO
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.
Assuntos
Disgenesia Gonadal/genética , Disgenesia Gonadal/fisiopatologia , Mutação , Fator Esteroidogênico 1/genética , Adolescente , Criança , Feminino , Seguimentos , Disgenesia Gonadal/terapia , Células HeLa , Humanos , Masculino , Fenótipo , Fator Esteroidogênico 1/metabolismo , Proteínas com Domínio T/genéticaRESUMO
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.
Assuntos
Amenorreia/etiologia , Amenorreia/terapia , Genitália Feminina/anormalidades , Disgenesia Gonadal/complicações , Ovário/anormalidades , Doenças da Hipófise/complicações , Adeno-Hipófise , Adolescente , Amenorreia/diagnóstico , Feminino , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/terapia , Humanos , Doenças da Hipófise/diagnóstico , Doenças da Hipófise/terapia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/terapiaRESUMO
Antecedentes: Son muchos los genes que se han implicado en la diferenciación testicular, cuyas alteraciones dan cuadros de trastornos de la diferenciación sexual y cariotipo 46XY. Caso clínico: Recién nacido con hipospadias interescrotal, gónadas palpables y pene hipoplásico. Cariotipo 46XY. Ecografía abdominal: testes y sin restos müllerianos. Buena respuesta al test corto de gonadotropinas. Al año presenta retraso psicomotor, hipotonía. Resonancia magnética con atrofia de sustancia blanca frontotemporal y disminución del cuerpo calloso. Biopsia testicular compatible con disgenesia gonadal. Dada la situación intersexual al nacimiento, el retraso psicomotor y la presencia de dismorfias faciales se solicita cariotipo de alta resolución: deleción 46, XY, del(9p)(p23-pter).ish tel (9p-). Comentarios: Son muchos los genes implicados en la diferenciación testicular, algunos de ellos también influyen sobre el desarrollo de otros tejidos. En el brazo corto del cromosoma 9 se encuentran dos genes, DMRT1 y DMRT2, implicados en la diferenciación sexual, cuyas alteraciones también han sido descritas como causantes de retraso mental. En la evaluación de los trastornos de la diferenciación sexual son muy importantes los signos acompañantes para poder orientar el estudio genético (AU)
Background: Many genes are involved in testicular differentiation. The alterations of these genes are responsible for sexual differentiation disorders with 46 XY karyotype. Case: We report the case of a newborn who had an interscrotal hypospadias, palpable gonads and hypoplastic penis. Karyotype 46 XY. Abdominal ultrasound revealed testes and absence of Müllerian remnants. There was a good response to the short gonadotrophin test. At one year he had signs of psychomotor retardation and hypotonia. The magnetic resonance revealed frontal-temporal atrophy and a decrease in the corpus callosum. Testicular biopsy was compatible with gonadal dysgenesis. A preoperative cystography showed a vaginal remnant. Due to the presence of a sexual differentiation disorder, psychomotor retardation and facial dysmorphism, we requested a high-resolution karyotype: deletion 46, XY, del (9p) (p23-pter). Ish tel (9p-). Discussion: Many genes are involved in testicular differentiation, some of which also affect the development of other tissues. In the short arm of chromosome 9, two genes, DMRT1 and DMRT2, are involved in sexual differentiation. Their alterations have also been described as causing mental retardation. In the evaluation of 46,XY disorders of sex differentiation, the accompanying signs are very important for guiding the genetic study (AU)
Assuntos
Humanos , Masculino , Recém-Nascido , Disgenesia Gonadal/complicações , Disgenesia Gonadal/diagnóstico , Deficiência Intelectual/complicações , Corpo Caloso/anormalidades , Corpo Caloso/patologia , Diferenciação Sexual , Hipospadia/complicações , Disgenesia Gonadal/terapia , Disgenesia Gonadal/genética , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/genética , AbdomeRESUMO
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.
Assuntos
Amenorreia/fisiopatologia , Disgenesia Gonadal/fisiopatologia , Amenorreia/terapia , Feminino , Disgenesia Gonadal/terapia , Terapia de Reposição Hormonal/métodos , Humanos , Gravidez , Adulto JovemRESUMO
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.
Assuntos
Cromossomos Artificiais Bacterianos/genética , Disgenesia Gonadal/genética , Hibridização in Situ Fluorescente/métodos , Adolescente , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/patologia , Disgenesia Gonadal/terapia , Humanos , Cariotipagem , Masculino , Aberrações dos Cromossomos SexuaisRESUMO
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.
Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/terapia , Criança , Técnicas de Laboratório Clínico , Diagnóstico Diferencial , Identidade de Gênero , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/terapia , HumanosRESUMO
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.
Assuntos
Disgenesia Gonadal/genética , Adulto , Pré-Escolar , Cromossomos Humanos Y , Feminino , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/terapia , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/genética , Disgenesia Gonadal 46 XY/terapia , Humanos , Cariotipagem , Qualidade de VidaAssuntos
Disgenesia Gonadal , Diagnóstico Diferencial , Feminino , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/etiologia , Disgenesia Gonadal/fisiopatologia , Disgenesia Gonadal/terapia , Humanos , Masculino , Prognóstico , Testosterona/administração & dosagem , Procedimentos Cirúrgicos UrogenitaisAssuntos
Disgenesia Gonadal , Amenorreia/diagnóstico , Amenorreia/etiologia , Amenorreia/fisiopatologia , Amenorreia/terapia , Diagnóstico Diferencial , Feminino , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/etiologia , Disgenesia Gonadal/fisiopatologia , Disgenesia Gonadal/terapia , Humanos , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/etiologia , Insuficiência Ovariana Primária/fisiopatologia , Insuficiência Ovariana Primária/terapia , Prognóstico , Aberrações dos Cromossomos Sexuais , SíndromeAssuntos
Disgenesia Gonadal , Testículo/anormalidades , Diagnóstico Diferencial , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/etiologia , Disgenesia Gonadal/fisiopatologia , Disgenesia Gonadal/terapia , Hormônios Esteroides Gonadais/uso terapêutico , Humanos , Masculino , Prognóstico , Síndrome , Testículo/embriologia , Testosterona/deficiência , Testosterona/fisiologia , Procedimentos Cirúrgicos Urológicos MasculinosAssuntos
Anormalidades Múltiplas , Disgenesia Gonadal , Útero/anormalidades , Vagina/anormalidades , Amenorreia , Diagnóstico Diferencial , Feminino , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/etiologia , Disgenesia Gonadal/fisiopatologia , Disgenesia Gonadal/terapia , Procedimentos Cirúrgicos em Ginecologia/métodos , Humanos , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/embriologia , Mutação , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Técnicas de Reprodução Assistida/tendências , Síndrome , Proteínas Wnt/genética , Proteínas Wnt/fisiologia , Proteína Wnt4Assuntos
Transtornos do Desenvolvimento Sexual/terapia , Identidade de Gênero , Disgenesia Gonadal/terapia , Planejamento de Assistência ao Paciente , Transexualidade/terapia , Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/psicologia , Feminino , Genitália/cirurgia , Disgenesia Gonadal/complicações , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/psicologia , Humanos , Lactente , Recém-Nascido , Masculino , Notificação aos Pais , Satisfação do Paciente , Comportamento Sexual/fisiologia , Transexualidade/complicações , Transexualidade/diagnóstico , Transexualidade/psicologiaRESUMO
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.
Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/cirurgia , Feminização/diagnóstico , Feminização/cirurgia , Hipospadia/diagnóstico , Hipospadia/cirurgia , Administração dos Cuidados ao Paciente/métodos , Pré-Seleção do Sexo/métodos , Adolescente , Criança , Pré-Escolar , Transtornos do Desenvolvimento Sexual/terapia , Feminino , Feminização/terapia , Genitália/cirurgia , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/cirurgia , Disgenesia Gonadal/terapia , Humanos , Hipospadia/terapia , Lactente , Recém-Nascido , Masculino , Administração dos Cuidados ao Paciente/organização & administração , Procedimentos Cirúrgicos Urogenitais/métodosRESUMO
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.
Assuntos
Disgenesia Gonadal/diagnóstico , Dor Abdominal/etiologia , Adulto , Seguimentos , Identidade de Gênero , Disgenesia Gonadal/complicações , Disgenesia Gonadal/terapia , Humanos , Crise de Identidade , Imageamento por Ressonância Magnética , MasculinoRESUMO
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
Assuntos
Humanos , Feminino , Amenorreia/etiologia , Genitália/anormalidades , Disgenesia Gonadal/complicações , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/terapia , Estudos ProspectivosAssuntos
Humanos , Masculino , Feminino , Disgenesia Gonadal Mista , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/etiologia , Disgenesia Gonadal/genética , Disgenesia Gonadal/fisiopatologia , Disgenesia Gonadal/terapia , Aberrações dos Cromossomos Sexuais , Disgenesia Gonadal 46 XY , Síndrome de Noonan , Cromossomos Sexuais , Síndrome de Turner , UltrassonografiaRESUMO
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.
Assuntos
Densidade Óssea , Disgenesia Gonadal/metabolismo , Hipogonadismo/metabolismo , Adolescente , Adulto , Colágeno/análise , Colágeno Tipo I , Feminino , Disgenesia Gonadal/terapia , Humanos , Hipogonadismo/terapia , Osteocalcina/sangue , Peptídeos/análise , PuberdadeRESUMO
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.
Assuntos
Disgenesia Gonadal/patologia , Adolescente , Adulto , Biópsia , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Criança , Criptorquidismo/genética , Criptorquidismo/patologia , Disgenesia Gonadal/genética , Disgenesia Gonadal/terapia , Humanos , Lactente , Cariotipagem , Masculino , Células de Sertoli/patologia , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologiaRESUMO
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.