RESUMEN
In mammals, the development of male or female gonads from fetal bipotential gonads depends on intricate genetic networks. Changes in dosage or temporal expression of sex-determining genes can lead to differences of gonadal development. Two rare conditions are associated with disruptions in ovarian determination, including 46,XX testicular differences in sex development (DSD), in which the 46,XX gonads differentiate into testes, and 46,XX ovotesticular DSD, characterized by the coexistence of ovarian and testicular tissue in the same individual. Several mechanisms have been identified that may contribute to the development of testicular tissue in XX gonads. This includes translocation of SRY to the X chromosome or an autosome. In the absence of SRY, other genes associated with testis development may be overexpressed or there may be a reduction in the activity of pro-ovarian/antitesticular factors. However, it is important to note that a significant number of patients with these DSD conditions have not yet recognized a genetic diagnosis. This finding suggests that there are additional genetic pathways or epigenetic mechanisms that have yet to be identified. The text will provide an overview of the current understanding of the genetic factors contributing to 46,XX DSD, specifically focusing on testicular and ovotesticular DSD conditions. It will summarize the existing knowledge regarding the genetic causes of these differences. Furthermore, it will explore the potential involvement of other factors, such as epigenetic mechanisms, in developing these conditions.
Asunto(s)
Testículo , Humanos , Masculino , Testículo/patología , Testículo/metabolismo , Animales , Femenino , Trastornos del Desarrollo Sexual 46, XX/genética , Trastornos del Desarrollo Sexual 46, XX/patología , Diferenciación Sexual/genética , Trastornos del Desarrollo Sexual/genética , Trastornos del Desarrollo Sexual/patologíaRESUMEN
In most cases, male sexual differentiation occurs with SRY gene mediation. However, exceptional genotypes have been identified, as shown in this paper. This was a male adult patient seen at the Servicio de Paternidades, Instituto de Genética, Universidad Nacional de Colombia. The following procedures were carried out: Amelogenin gene and short tandem repeat analyses using human identification commercial kits, conventional karyotype, SRY fluorescent in situ hybridization, PCR analysis for Y chromosome microdeletions, clinical evaluation, and genetic counseling. We present an adult male with unambiguous genitalia, karyotype 46,XX, and an SRY negative and ZFY positive molecular profile. The diagnosis of nonsyndromic 46,XX testicular disorder of sex development (DSD) -a rare genetic condition- was established. Only 20 % of similarly diagnosed patients are SRY negative and exhibit diverse molecular profiles. Until now, available evidence seems to indicate that, even in the absence of SRY, the ZFY factor is involved in male sexual differentiation.
En la mayoría de los casos, la diferenciación sexual masculina ocurre con la participación del gen SRY. Sin embargo, se pueden presentar otros genotipos excepcionales, como en el caso que se presenta en este reporte. Se trata de un paciente adulto de sexo masculino atendido en el Servicio de Paternidades del Instituto de Genética de la Universidad Nacional de Colombia. Se le hicieron los análisis del gen de la amelogenina y de repeticiones cortas en tándem (Short Tandem Repeat, STR) específicas para el gen SRY con estuches comerciales de identificación humana, así como los de cariotipo convencional e hibridación in situ fluorescente del SRY, y el estudio de microdeleciones del cromosoma Y mediante reacción en cadena de la polimerasa (PCR). Se le hizo la evaluación clínica y se le brindó asesoramiento genético. El paciente no presentaba ambigüedad genital, su cariotipo era 46 XX, y el perfil molecular era negativo para el gen SRY y positivo para el ZFY. Se le diagnosticó un trastorno de diferenciación sexual 46 XX testicular no sindrómico, una rara condición genética. Solo el 20 % de los pacientes con este diagnóstico son negativos para SRY y exhiben perfiles moleculares diversos. La información disponible parece indicar que el ZFY está relacionado con la diferenciación sexual masculina, aún en ausencia del gen SRY.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Trastornos del Desarrollo Sexual 46, XX/genética , Genes sry , Genitales Masculinos/anatomía & histología , Adulto , Amelogenina/análisis , Deleción Cromosómica , Cromosomas Humanos Y/genética , Electroforesis Capilar , Genotipo , Humanos , Hibridación Fluorescente in Situ , Infertilidad Masculina/diagnóstico , Infertilidad Masculina/genética , Cariotipificación , Factores de Transcripción de Tipo Kruppel/análisis , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Repeticiones de Microsatélite , Técnicas de Amplificación de Ácido Nucleico , Linaje , Reacción en Cadena de la Polimerasa/métodos , Aberraciones Cromosómicas Sexuales , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/diagnóstico , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/genéticaRESUMEN
Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Patología Molecular , Enfermedades Testiculares/diagnóstico , Proteínas WT1/genética , Trastornos del Desarrollo Sexual 46, XX/genética , Trastornos del Desarrollo Sexual 46, XX/patología , Niño , Proteínas de Unión al ADN/genética , Femenino , Heterocigoto , Humanos , Lactante , Masculino , Mutación , Fenotipo , Desarrollo Sexual/genética , Enfermedades Testiculares/genética , Enfermedades Testiculares/patología , Testículo/patologíaRESUMEN
Genetic tools such as microarray and next-generation sequencing have initiated a new era for the diagnosis and management of patients with disorders of sex development (DSDs). These tools supplement the traditional approach to the evaluation and care of infants, children, and adolescents with DSDs. These tests can detect genetic variations known to be associated with DSDs, discover novel genetic variants, and elucidate novel mechanisms of gene regulation. Herein, we discuss these tests and their role in the management of patients with DSDs.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Trastornos del Desarrollo Sexual 46, XX/genética , Competencia Clínica , Trastorno del Desarrollo Sexual 46,XY/diagnóstico , Trastorno del Desarrollo Sexual 46,XY/genética , Trastornos del Desarrollo Sexual/genética , Variación Genética/fisiología , Trastornos del Desarrollo Sexual 46, XX/psicología , Adolescente , Niño , Trastorno del Desarrollo Sexual 46,XY/psicología , Femenino , Identidad de Género , Pruebas Genéticas , Humanos , Recién Nacido , Masculino , Padres/educación , Padres/psicología , Educación del Paciente como Asunto , Mutación Puntual , Guías de Práctica Clínica como Asunto , Desarrollo SexualRESUMEN
Virilisation of the XX foetus is the result of androgen excess, resulting most frequently from congenital adrenal hyperplasia in individuals with typical ovarian differentiation. In rare cases, 46,XX gonads may differentiate into testes, a condition known as 46,XX testicular disorders of sex development (DSD), or give rise to the coexistence of ovarian and testicular tissue, a condition known as 46,XX ovotesticular DSD. Testicular tissue differentiation may be due to the translocation of SRY to the X chromosome or an autosome. In the absence of SRY, overexpression of other pro-testis genes, e.g. SOX family genes, or failure of pro-ovarian/anti-testis genes, such as WNT4 and RSPO1, may underlie the development of testicular tissue. Recent experimental and clinical evidence giving insight into SRY-negative 46,XX testicular or ovotesticular DSD is discussed.
Asunto(s)
Trastornos Ovotesticulares del Desarrollo Sexual/metabolismo , Testículo/metabolismo , Trastornos del Desarrollo Sexual 46, XX/genética , Trastornos del Desarrollo Sexual 46, XX/metabolismo , Trastornos del Desarrollo Sexual 46, XX/fisiopatología , Femenino , Humanos , Masculino , Trastornos Ovotesticulares del Desarrollo Sexual/fisiopatología , Factores de Transcripción SOXE/genética , Factores de Transcripción SOXE/metabolismo , Desarrollo Sexual/genética , Desarrollo Sexual/fisiología , Testículo/crecimiento & desarrolloRESUMEN
OBJECTIVE: To perform a clinical, biochemical, and molecular evaluation of patients with CYP17A1 defects, including ovarian imaging. DESIGN: Retrospective study. SETTING: Tertiary care center. PATIENT(S): Sixteen patients with congenital adrenal hyperplasia due to CYP17A1 defects with a median chronological age of 20 years and belonging to 10 unrelated families. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical and biochemical parameters, molecular diagnosis, ovarian imaging, and therapeutic management. RESULT(S): Seventy-one percent of patients presented with primary amenorrhea, 50% had no breast development, and pubic hair was absent or sparse in all patients; 88% had high blood pressure at diagnosis. Basal LH and P levels were high, and androgen levels were low in all patients. Ultrasound revealed ovarian enlargement in 68.7% and ovarian macrocysts in 62.5% of patients before treatment; three patients had a previous surgical correction of ovarian torsion or rupture. Molecular analysis revealed inactivating CYP17A1 mutations in all patients. The most prevalent mutation was p.W406R, and one patient bore a novel p.G478S/p.I223Nfs*10 compound heterozygous mutation. Treatment with dexamethasone, estrogen, and P resulted in reduction of ovarian volume. CONCLUSION(S): Amenorrhea, absent/sparse pubic hair, hypertension, and ovarian macrocysts, whichincrease the risk of ovarian torsion, are important elements in the diagnosis of 46,XX patients with CYP17A1 defects. High basal P levels in patients with hypergonadotropic hypogonadism point to the diagnosis of CYP17A1 defects. Fertility can be achieved in these patients with novel reproductive techniques.
Asunto(s)
Trastornos del Desarrollo Sexual 46, XX/genética , Corticoesteroides , Hiperplasia Suprarrenal Congénita/genética , Enfermedades del Ovario/genética , Esteroide 17-alfa-Hidroxilasa/genética , Trastornos del Desarrollo Sexual 46, XX/sangre , Trastornos del Desarrollo Sexual 46, XX/diagnóstico , Adolescente , Corticoesteroides/sangre , Hiperplasia Suprarrenal Congénita/sangre , Hiperplasia Suprarrenal Congénita/diagnóstico , Adulto , Niño , Femenino , Humanos , Enfermedades del Ovario/sangre , Enfermedades del Ovario/diagnóstico , Linaje , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Three novel heterozygous SF-1 gene mutations affecting multiple members of two unrelated families with a history of 46,XY disorders of sex development (DSD) and 46,XX ovarian insufficiency are described. METHODS: clinical and mutational analysis of the SF-1 gene in 9 subjects of two families. RESULTS: family 1 had 2 affected 46,XY DSD subjects. One, born with severe perineal hypospadias, was raised as a male, and presented normal adolescence. The other, born with ambiguous genitalia, uterus, and mild testicular dysgenesis, was raised as a female. A W279X heterozygous mutation and an intronic deletion (g3314-3317delTCTC (IVS 4 + 8) was found in the SF-1 gene. In family 2, 4/6 affected siblings had 46,XY DSD or hypospadias. An affected 46,XX sister had normal sexual development but increased FSH levels. The 37-year-old affected mother had entered menopause. An Y183X heterozygous mutation was detected. CONCLUSION: an extreme within-family phenotypic variability, ranging from severe prenatal undervirilization to normal pubertal development, was observed in 46,XY-affected siblings, indicating that other unknown factors might be involved in the phenotype. Low ovarian reserve and preserved fertility in 46,XX subjects can be observed in heterozygous SF-1 gene mutations.