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1.
Reprod Domest Anim ; 54(6): 928-935, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30903716

RESUMO

An 8-month-old female Staffordshire bull terrier was clinically examined because of external sexual organs abnormality-clitoral hypertrophy. As stated by the owner, the female dog had not been in heat yet. Serum profile of testosterone (3.39 ng/ml), as well as an anti-Mullerian hormone (24.0 ng/ml), suggested the presence of testicular tissue. On the contrary, the estimated level of 17ß-oestradiol (24.6 pg/ml) was approximately two times higher when compared with the normal anoestrus values (5-10 pg/ml). A midline laparotomy was performed to detect the cranial parts of the genital system. Gonads resembling testicle or ovotestis (left) and hypoplastic testicle (right) was visible. Cranial portion of gonads was attached to structures indicative of bilateral epididymidis. The next tubular structures-oviducts were resected along with adherent parts of a hypoplastic uterus. Histological evaluation confirmed that the examined gonad samples were testicles with modified interstitial testicular tissue. Hypertrophy of interstitial space was predominantly formed by Leydig cells. Examination of a cross-section through the head of suspected epididymidis confirmed their characteristic structures. In addition, the characteristic configuration of the oviducts was presented. The uterus consisted of three walls, in which the endometrium was hypoplastic with the presence of endometrial glands. No Y chromosome was detected by chromosomal analysis using CFA Y probe and the amplification of SRY-gene coding region (813 bp) indicated genotype 78, XX; SRY-negative. Sequencing of SOX9 gene exons 1-3 did not reveal any differences in exon 1 and 3. On the contrary, a few changes were determined in the SOX9 exon 2 sequences: G instead of A at position 103; C instead of reference T at position 115; GCG instead of reference CGC at position 138-140; T instead of reference C at positions 161, 164 and 167.


Assuntos
Doenças do Cão/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/veterinária , Animais , Hormônio Antimülleriano/sangue , Circuncisão Feminina/veterinária , Doenças do Cão/cirurgia , Cães , Estradiol/sangue , Feminino , Genótipo , Histerectomia/veterinária , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Análise de Sequência de DNA , Testosterona/sangue
2.
Reprod Biomed Online ; 37(1): 107-112, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29673731

RESUMO

RESEARCH QUESTION: The purpose of the present study was to investigate whether ten unrelated SRY-negative individuals with this sex differentiation disorder presented a double dose of SOX9 as the cause of their disease. DESIGN: Ten unrelated SRY-negative 46,XX ovotesticular disorder of sexual development (DSD) subjects were molecularly studied. Multiplex-ligation dependent probe amplification (MLPA) and quantitative real-time PCR analysis (qRT-PCR) for SOX9 were performed. RESULTS: The MLPA analysis demonstrated that one patient presented a heterozygous duplication of the entire SOX9 coding region (above 1.3 value of peak ratio), as well as at least a ~ 483 kb upstream duplication. Moreover, no duplication of other SOX9 probes was observed corresponding to the region between -1007 and -1500 kb upstream. A qRT-PCR analysis showed a duplication of at least -581 kb upstream and ~1.63 kb of the coding region that encompasses exon 3. The limits of the duplication were mapped approximately from ~71539762 to 72122741 of Chr17. No molecular abnormalities were found in the remaining nine patients. CONCLUSION: This study is thought to be the first report regarding a duplication of SOX9 that is associated with the presence of 46,XX ovotesticular DSD, encompassing at least -581 kb upstream, and the almost entire coding region of the gene.


Assuntos
Duplicação Gênica , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Fatores de Transcrição SOX9/genética , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Lactente , Masculino
3.
Reprod Domest Anim ; 53(3): 822-825, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29575379

RESUMO

A 1-year-old, previously spayed phenotypic female Poodle/Soft-coated Wheaten Terrier (Whoodle) cross was presented for a suspected ovarian remnant. Serum luteinizing hormone (LH) concentration was below the detection limit (<1 ng/ml Witness® LH), and serum progesterone concentration was elevated in the chemiluminescence immunoassay (CLIA; 20 ng/ml), consistent with dioestrus and presence of ovarian tissue. Transabdominal ultrasound revealed a retroperitoneal soft tissue structure suspected to be a gonad. On exploratory laparotomy, a gonad was removed from the cranial retroperitoneum, cranial to the right kidney, after ligation of its primary blood supply. Histological examination proved the gonad to be an ovotestis. Subsequent cytogenetics revealed a 78 XX karyotype, thus confirming the diagnosis of ectopic ovotestis in a XX ovotesticular, SRY-negative, disorder of sexual development in a dog.


Assuntos
Cães/anormalidades , Transtornos Ovotesticulares do Desenvolvimento Sexual/veterinária , Animais , Feminino , Cariótipo , Hormônio Luteinizante/sangue , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/cirurgia , Progesterona/sangue
4.
Balkan Med J ; 35(3): 272-274, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29219112

RESUMO

Background: Ovotesticular disorder is characterized by the presence of testicular and ovarian tissues in the same individual. Single gene mutations in SRY, SOX9, DMRT1 and DAX1 can lead to ovotesticular disorder of sexual development. Case Report: Herein, we report a 3-month-old phenotypically female baby in whom differentiated tissues of both Müllerian and Wolffian ducts were detected on pathological analysis of laparoscopic biopsy material. Chromosomal analysis observed 46,XY, der(9)t(3;9)(p25;p24) with deletion of 9p24.3p23 including the DMRT gene cluster and duplication of 3p26.3p24.3 on array comparative genomic hybridisation. Conclusion: In support of previous literature, we found that haploinsufficiency of the DMRT gene cluster leads to ovotesticular disorder of sexual development. In addition, we emphasize that array comparative genomic hybridisation is an important technique in the molecular diagnosis of ovotesticular disorder of sexual.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Haploinsuficiência/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Tionucleosídeos/genética , Trifosfato de Adenosina/genética , Feminino , Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal 46 XY/genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Família Multigênica , Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Fatores de Transcrição SOX9 , Testículo
5.
Sex Dev ; 12(1-3): 145-154, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28926831

RESUMO

We report on an adult male initially presenting with gynecomastia and a painless scrotal mass without additional genital anomalies. Hyperpigmentation of the skin following the Blaschko's lines was identified. He underwent gonadectomy because of suspected cancer. Histological analyses revealed an ovotestis with ovulatory activity confirmed by immunohistochemistry with multiple markers. Karyotyping of cultured peripheral blood lymphocytes and a buccal smear revealed a 46,XX/46,XY chimeric constitution with different percentages. Multiple molecular analyses as well as blood typing implied a tetragametic origin. After the unilateral gonadectomy, the patient developed recurrent painful cystic swellings of the remaining gonad. Because of the wish to preserve hormonal activity as well as future fertility, the patient underwent surgical resection of a cystic gonadal area. The removed tissue showed ovulation-related features in addition to both testicular and ovarian tissue, diagnosed as an ovotestis. Testosterone therapy was initiated to suppress the persistently elevated gonadotropins and thereby suppress ovarian activity. During treatment, the recurrent pain complaints and cystic swellings ceased, although gonadotropin levels were not fully suppressed. Based on these observations, the importance of a detailed genetic and pathological diagnosis and the clinical dilemmas including the pros and cons of personalized treatment with gonadal preservative surgery are discussed.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/patologia , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Transtornos Ovotesticulares do Desenvolvimento Sexual/patologia , Ovulação , Transtornos 46, XX do Desenvolvimento Sexual/sangue , Transtornos 46, XX do Desenvolvimento Sexual/genética , Tipagem e Reações Cruzadas Sanguíneas , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Transtorno 46,XY do Desenvolvimento Sexual/genética , Feminino , Gônadas/patologia , Humanos , Masculino , Transtornos Ovotesticulares do Desenvolvimento Sexual/sangue , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
6.
J Med Genet ; 54(10): 705-709, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28483799

RESUMO

BACKGROUND: The XX male disorder of sex development (DSD) is a rare condition that is most commonly associated with the presence of the SRY gene on one of the X chromosomes due to unequal crossing-over between sex chromosomes during spermatogenesis. However, in about 20% of the XX male individuals, SRY is missing, although these persons have at least some testis differentiation. The genetic basis of genital ambiguity and the mechanisms triggering testis development in such patients remain unknown. METHODS: The proband with 46,XX SRY-negative testicular DSD was screened for point mutations by whole exome sequencing and CNVs using a high-resolution DSD gene-targeted and whole genome array comparative genomic hybridisation. The identified Xp21.2 genomic alteration was further characterised by direct sequencing of the breakpoint junctions and bioinformatics analysis. RESULTS: A unique, 80 kb microdeletion removing the regulatory sequences and the NR0B1 gene was detected by microarray analysis. This deletion disturbs the human-specific genomic architecture of the Xp21.2 dosage-sensitive sex (DSS) reversal region in the XX patient with male-appearing ambiguous genitalia and ovotestis. CONCLUSIONS: Duplication of the DSS region containing the MAGEB and NR0B1 genes has been implicated in testis repression and sex reversal. Identification of this microdeletion highlights the importance of genomic integrity in the regulation and interaction of sex determining genes during gonadal development.


Assuntos
Transtornos Testiculares 46, XX do Desenvolvimento Sexual/genética , Cromossomos Humanos X/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Deleção de Sequência , Transtornos Testiculares 46, XX do Desenvolvimento Sexual/patologia , Pré-Escolar , Hibridização Genômica Comparativa , Receptor Nuclear Órfão DAX-1/genética , Variações do Número de Cópias de DNA , Feminino , Disgenesia Gonadal/genética , Humanos , Masculino , Ovário/patologia , Transtornos Ovotesticulares do Desenvolvimento Sexual/patologia , Sequências Reguladoras de Ácido Nucleico , Testículo/patologia
7.
Horm Res Paediatr ; 87(5): 307-314, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28376506

RESUMO

OBJECTIVE: To describe the clinical characteristics, biochemistry, histopathology, and long-term outcomes in subjects with ovotesticular (OT) disorder of sex development (DSD). STUDY DESIGN: This is a retrospective subset analysis of 64 cases of histologically confirmed OT DSD. RESULTS: All subjects were South African; 97% (n = 62) were African and 92% (n = 59) were of Zulu ethnicity. The most common karyotype was 46,XX (88%; n = 56), followed by 46,XY (8%), 46,XY/45,X (3%), and 46,XX/46,XY (1%). The median age at presentation was 7 months (0.5 months to 5.1 years). Sixty-one of the subjects (95%) presented with DSD. The ovotestis was the most frequent gonad (56%), followed by the ovary (23%) and the testis (16%). Testes were more commonly located on the right and ovaries on the left (p < 0.0001). The male gender was the predominant sex of rearing in two-thirds of the subjects. Gender dysphoria was noted in 8 subjects (11%) at a median of 6.4 (4.3-9.3) years. Long-term follow-up (n = 14) revealed spontaneous puberty in 5 subjects, gender dysphoria in 2 subjects, and neuropsychiatric disorders in 4 subjects. CONCLUSION: OT DSD is an important differential diagnosis in Black South Africans with 46,XX DSD.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual , Grupo com Ancestrais do Continente Africano , Transtorno 46,XY do Desenvolvimento Sexual , Transtornos Ovotesticulares do Desenvolvimento Sexual , Transtornos 46, XX do Desenvolvimento Sexual/epidemiologia , Transtornos 46, XX do Desenvolvimento Sexual/etnologia , Transtornos 46, XX do Desenvolvimento Sexual/genética , Transtornos 46, XX do Desenvolvimento Sexual/patologia , Grupo com Ancestrais do Continente Africano/etnologia , Grupo com Ancestrais do Continente Africano/genética , Criança , Pré-Escolar , Transtorno 46,XY do Desenvolvimento Sexual/epidemiologia , Transtorno 46,XY do Desenvolvimento Sexual/etnologia , Transtorno 46,XY do Desenvolvimento Sexual/genética , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Feminino , Humanos , Lactente , Masculino , Transtornos Ovotesticulares do Desenvolvimento Sexual/epidemiologia , Transtornos Ovotesticulares do Desenvolvimento Sexual/etnologia , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/patologia , África do Sul/epidemiologia , África do Sul/etnologia
8.
Horm Res Paediatr ; 87(3): 205-212, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28253506

RESUMO

AIMS: To evaluate gonadal function in a newborn with suspected ovotesticular disorder of sex development (DSD). METHODS: Gonadal function was evaluated at baseline and after gonadotropin-releasing hormone agonist (GnRHag) stimulation testing. RESULTS: A full-term 46,XX neonate with genital ambiguity produced serum testosterone and anti-Müllerian hormone (AMH) levels appropriate for males within days, while serum estradiol remained prepubertal, both spontaneously and in response to GnRHag stimulation testing. Ovotesticular DSD was diagnosed at laparoscopy: the left gonad was an ovotestis and the right gonad an ovary arrested at the primordial follicle stage of development. Mosaicism for an isochromosome of the Y short arm in 6-18% of gonadal cells was demonstrated. After ovotestis removal at 3 weeks of age, serum AMH became low within a month, but the elevated testosterone was slow to resolve, apparently from ovarian androgenic hyperfunction coincident with ovarian estrogenic hyperfunction and an adult degree of ovarian development. Ovarian morphology and function gradually normalized as neonatal minipuberty waned. CONCLUSIONS: In a neonate with genital ambiguity due to ovotesticular DSD, testicular AMH and testosterone production respectively appear to account for the initial arrest of ovarian development and subsequent rapid hyperfunction of the contralateral ovary after ovotestis removal.
.


Assuntos
Hormônio Antimülleriano/sangue , Estradiol/sangue , Transtornos Ovotesticulares do Desenvolvimento Sexual/sangue , Transtornos Ovotesticulares do Desenvolvimento Sexual/cirurgia , Testosterona/sangue , Adulto , Cromossomos Humanos Y/genética , Feminino , Humanos , Recém-Nascido , Masculino , Mosaicismo , Ovário/metabolismo , Ovário/cirurgia , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Testículo/metabolismo , Testículo/cirurgia
9.
BMC Urol ; 17(1): 21, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28351396

RESUMO

BACKGROUND: The aim of this study is to review and present the clinical features and process of evaluation and treatment for OT-DSD in a single center in recent years in China. METHODS: Sixteen patients with OT-DSD during the past 4 years underwent the evaluation and treatment in a single center. The clinical characteristics and outcomes of surgery were analyzed. RESULTS: The surgical age ranged from 17 months to 66 months with a mean age of 20 months, and the mean follow-up was 30 months (4 months to 56 months). The presentation in 11 patients was ambiguous genitalia, and the rest 5 patients were suspected to have DSD in preoperative examination before hypospadias repair. The karyotypes were 46, XX in 11 patients, 46, XX/46, XY in 3, 46, XX/47, XXY in 1, and 46, XY in 1. Initial reared sex was male in 14 patients, female in 1, and undetermined in 1. After surgery, genders were reassigned in 3 patients, while 15 patients were raised as male with testicular tissue left. Only 1 patient with ovarian tissue left was raised as female. Repair was completed in 11 males and 1 female, and stage I urethroplasty was done in 4 males. No further surgery to remove the gonads was needed for inconsonance of gender assignment. No gonadal tumors were detected. CONCLUSIONS: OT-DSD is a rare and complex deformity with few systematic reports in China. It's important to establish a regular algorithm for evaluation and treatment of OT-DSD.


Assuntos
Transtornos Ovotesticulares do Desenvolvimento Sexual , Pré-Escolar , China , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/cirurgia , Feminino , Humanos , Hipospadia/genética , Hipospadia/cirurgia , Lactente , Cariótipo , Masculino , Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/cirurgia , Consentimento dos Pais/ética
10.
Horm Res Paediatr ; 87(3): 191-195, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27855412

RESUMO

BACKGROUND: A variant in steroidogenic factor-1 (SF-1, encoded by the gene NR5A1), p.Arg92Trp, has recently been reported in multiple families with 46,XX ovotesticular or testicular disorders of sex development (DSD). This amino acid change impacts the DNA-binding domain and perturbs gonadal differentiation pathways. METHODS: Whole-exome sequencing was performed on a 46,XX subject with ovotesticular DSD. RESULTS: Exome results identified a heterozygous NR5A1 variant, p.Arg92Gln, in the 46,XX ovotesticular DSD proband. This arginine-to-glutamine change has been previously reported in the homozygous state in a 46,XY patient with gonadal and adrenal dysgenesis, though 46,XY and 46,XX heterozygous carriers of this variant have not been previously reported to have any clinical phenotype. CONCLUSIONS: The NR5A1 p.Arg92Gln variant, which has thus far only been seen in a family with 46,XY DSD, most likely contributes to the ovotesticular DSD in this case. In light of the recent reports of unrelated 46,XX subjects with testicular or ovotesticular DSD with the NR5A1 variant p.Arg92Trp, it appears that other mutations in the DNA binding domain have the potential to impact the factors determining testicular and ovarian differentiation. This case demonstrates the variability of phenotypes with the same genotype and broadens our understanding of the role of SF-1 in gonadal differentiation.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Mutação de Sentido Incorreto , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Fator Esteroidogênico 1/genética , Transtornos 46, XX do Desenvolvimento Sexual/patologia , Substituição de Aminoácidos , Pré-Escolar , Feminino , Humanos , Transtornos Ovotesticulares do Desenvolvimento Sexual/patologia , Domínios Proteicos
11.
Genet Med ; 19(4): 367-376, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27490115

RESUMO

PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD). METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. RESULTS: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed. CONCLUSIONS: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad.Genet Med 19 4, 367-376.


Assuntos
Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica/métodos , Proteínas Nucleares/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Análise de Sequência de RNA/métodos , Fator Esteroidogênico 1/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma/métodos , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto , Ovário/metabolismo , Transtornos Ovotesticulares do Desenvolvimento Sexual/metabolismo , Linhagem , Polimorfismo de Nucleotídeo Único , Fator Esteroidogênico 1/química , Fator Esteroidogênico 1/metabolismo , Testículo/metabolismo , Regulação para Cima , Adulto Jovem
12.
Dev Period Med ; 20(3): 178-180, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27941186

RESUMO

Mixed gonadal dysgenesis is a rare disorder of sex development associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. It is characterized by a unilateral non-palpable (usually intra-abdominal) testis, a contralateral streak gonad and persistent mullerian structures. The clinical presentation can vary from a typical male to female phenotype including all degrees of cryptorchidism, labial fusion, clitoromegaly, epispadias and hypospadias. It is the second most common cause of ambiguous genitalia in the neonatal period. We report a case of Mixed Gonadal Dysgenesis with an inverted Y chromosome.


Assuntos
Cromossomos Humanos Y/genética , Disgenesia Gonadal Mista/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Pré-Escolar , Humanos , Masculino , Aberrações dos Cromossomos Sexuais
13.
Sex Dev ; 10(4): 185-190, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27649576

RESUMO

Individuals with a 46,XX/46,XY karyotype are categorized as ovotesticular disorder of sexual development (ODSD) and have gonads with either an ovary on one side and a testis on the other side or a mixed ovotestis. To examine the distribution of 46,XX and 46,XY cells in gonads of 3 patients with ODSD, FISH for X and Y chromosomes and immunohistochemistry for SOX9 and FOXL2 were carried out. FISH analysis showed that XX signals were present in Sertoli cells in the seminiferous tubules, while cells containing Y signals were seen in epithelia of ovarian follicles. The immunolabeling of SOX9 and FOXL2 in the seminiferous tubules and ovarian follicles was mutually exclusive, irrespective of the presence of reversed sex chromosomes. We therefore suggest that the fate of individual gonadal epithelial cells is determined not only by the sex chromosomes but also by local environmental factors.


Assuntos
Gônadas/metabolismo , Transtornos Ovotesticulares do Desenvolvimento Sexual/metabolismo , Transtornos Ovotesticulares do Desenvolvimento Sexual/fisiopatologia , Testículo/metabolismo , Pré-Escolar , Feminino , Proteína Forkhead Box L2/genética , Proteína Forkhead Box L2/metabolismo , Gônadas/fisiologia , Humanos , Imuno-Histoquímica , Lactente , Cariótipo , Masculino , Folículo Ovariano/metabolismo , Folículo Ovariano/fisiologia , Ovário/metabolismo , Ovário/fisiologia , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Fatores de Transcrição SOX9/metabolismo , Túbulos Seminíferos/metabolismo , Túbulos Seminíferos/fisiologia , Testículo/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
J Clin Res Pediatr Endocrinol ; 8(3): 351-5, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27087521

RESUMO

Ovotesticular disorder of sexual development (DSD), formerly known as true hermaphroditism, is a rare form of DSD in which both testicular and ovarian tissues are present in the same individual either in a single gonad (ovotestis) or in opposite gonads with a testis and an ovary on each side. The diagnosis of ovotesticular DSD is based solely on the presence of ovarian and testicular tissue in the gonad and not on the characteristics of the internal and external genitalia, even if ambiguous. Herein, we report two patients with ovotesticular DSD-one presenting with ambiguous genitalia on the third day after birth and the other with short stature and primary amenorrhea in adolescence. Clinical and histopathological investigation revealed a sex-determining region on the Y chromosome (SRY)-positive 46,XX karyotype and bilateral ovotestes in case 1 and a 46,XY karyotype with hypergonadotropic hypogonadism and a streak gonad in one ovotestis with dysgerminoma, gonadoblastoma, and papillary tubal hyperplasia in the contralateral ovotestis in case 2. Laparoscopic examination and gonadal biopsy for histopathological diagnosis remain the cornerstones for a diagnosis of ovotesticular DSD. Moreover, SRY positivity in a 46,XX patient, a 46,XY karyotype, an intra-abdominal gonad, and the age of patient at the time of diagnosis are predictive risk factors for the development of gonadoblastoma and/or dysgerminoma in ovotesticular DSD.


Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Tubas Uterinas/patologia , Gonadoblastoma/diagnóstico , Neoplasias Ovarianas/diagnóstico , Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Adolescente , Transtornos do Desenvolvimento Sexual/complicações , Transtornos do Desenvolvimento Sexual/genética , Feminino , Gonadoblastoma/complicações , Humanos , Hiperplasia , Recém-Nascido , Cariótipo , Masculino , Neoplasias Ovarianas/complicações , Transtornos Ovotesticulares do Desenvolvimento Sexual/complicações , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética
16.
J Vet Med Sci ; 77(12): 1587-98, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26194606

RESUMO

Mammalian sexual fate is determined by the presence or absence of sex determining region of the Y chromosome (Sry) in the "bipotential" gonads. Recent studies have demonstrated that both male and female sexual development are induced by distinct and active genetic pathways. Breeding the Y chromosome from Mus m. domesticus poschiavinus (POS) strains into C57BL/6J (B6J) mice (B6J-XY(POS)) has been shown to induce sex reversal (75%: bilateral ovary, 25%: true hermaphrodites). However, our B6N-XY(POS) mice, which were generated by backcrossing of B6J-XY(POS) on an inbred B6N-XX, develop as males (36%: bilateral testis with fertility as well as bilateral ovary (34%), and the remainder develop as true hermaphrodites. Here, we investigated in detail the expressions of essential sex-related genes and histological features in B6N-XY(POS) mice from the fetal period to adulthood. The onsets of both Sry and SRY-box 9 (Sox9) expressions as determined spatiotemporally by whole-mount immunohistochemistry in the B6N-XY(POS) gonads occurred 2-3 tail somites later than those in B6N-XY(B6) gonads, but earlier than those in B6J-XY(POS), respectively. It is possible that such a small difference in timing of the Sry expression underlies testicular development in our B6N-XY(POS). Our study is the first to histologically show the expression and ectopic localization of a female-related gene in the XY(POS) testes and a male-related gene in the XY(POS) ovaries. The results from these and previous experiments indicate that the interplay between genome variants, epigenetics and developmental gene regulation is crucial for testis development.


Assuntos
Ovário/crescimento & desenvolvimento , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Processos de Determinação Sexual/fisiologia , Testículo/crescimento & desenvolvimento , Cromossomo X/genética , Cromossomo Y/genética , Alelos , Animais , Cromossomos de Mamíferos/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Processos de Determinação Sexual/genética , Proteína da Região Y Determinante do Sexo/genética , Proteína da Região Y Determinante do Sexo/metabolismo
17.
Sci Rep ; 5: 14696, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26423656

RESUMO

Although the disorder of sex development in dogs with female karyotype (XX DSD) is quite common, its molecular basis is still unclear. Among mutations underlying XX DSD in mammals are duplication of a long sequence upstream of the SOX9 gene (RevSex) and duplication of the SOX9 gene (also observed in dogs). We performed a comparative analysis of 16 XX DSD and 30 control female dogs, using FISH and MLPA approaches. Our study was focused on a region harboring SOX9 and a region orthologous to the human RevSex (CanRevSex), which was located by in silico analysis downstream of SOX9. Two highly polymorphic copy number variable regions (CNVRs): CNVR1 upstream of SOX9 and CNVR2 encompassing CanRevSex were identified. Although none of the detected copy number variants were specific to either affected or control animals, we observed that the average number of copies in CNVR1 was higher in XX DSD. No copy variation of SOX9 was observed. Our extensive studies have excluded duplication of SOX9 as the common cause of XX DSD in analyzed samples. However, it remains possible that the causative mutation is hidden in highly polymorphic CNVR1.


Assuntos
Doenças do Cão/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/veterinária , Fatores de Transcrição SOX9/genética , Animais , Células Cultivadas , Variações do Número de Cópias de DNA , Cães , Feminino , Duplicação Gênica , Estudos de Associação Genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Polimorfismo Genético , Cromossomo X/genética
18.
Endocr Pract ; 21(7): 770-6, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25786559

RESUMO

OBJECTIVE: Ovotesticular disorder of sex development (OT DSD) is a rare disorder of sex development characterized by the presence in the same individual of both histologically proven testis and ovary. There are scant data from the Indian subcontinent regarding this disorder. The aim of this study was to describe the clinical, biochemical, imaging, cytogenetic, surgical, and histopathologic findings and outcomes of patients with OT DSD from Western India. METHODS: The records of patients referred to our center for disorders of sex development between 2005 and 2013 were reviewed, and 7 patients were found to have histologically proven OT DSD. RESULTS: The median age at presentation was 8 years (range, 2 months to 25 years). Clinical presentation varied from genital ambiguity and inguinal swelling at birth to gynecomastia and cyclical hematuria after puberty. Karyotype was 46, XX in 6 patients and 46, XY in 1 patient. All patients underwent pelvic ultrasonography, laparoscopy, and surgery for removal of gonads not congruous with the chosen sex of rearing. Gender assignment for all the patients was done by the parents at birth, which was mainly influenced by the external genitalia and sociocultural influences, with 5 out of the 7 patients being reared as males. There was no evidence of gonadal tumors in our study. CONCLUSION: OT DSD should be considered as one of the differential diagnoses in cases of ambiguous genitalia with nonpalpable or asymmetrical gonads, pubertal gynecomastia, and cyclical hematuria, irrespective of the karyotype or internal genitalia.


Assuntos
Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Índia/epidemiologia , Lactente , Masculino , Transtornos Ovotesticulares do Desenvolvimento Sexual/epidemiologia , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/cirurgia , Adulto Jovem
19.
J Pediatr Endocrinol Metab ; 28(5-6): 677-80, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25514326

RESUMO

BACKGROUND: Ovotesticular disorder of sex development (OT-DSD) (true hermaphroditism) is an anatomopathological diagnosis based on the findings of testicular and ovarian tissues in the same subject, in the same gonad (ovotestis), or in separate gonads. OT-DSD is a rare cause of sex ambiguity, and the most common karyotype is 46,XX; mosaics and chimeras are found only in 10%-20%. AIM: To report a case of an OT-DSD patient with a rare karyotype constitution. CASE REPORT: A 2-month-old child with male sex assignment was referred to our clinic for investigation of sex ambiguity. He was the second child of healthy unrelated parents; pregnancy and labor were uneventful. On physical examination, he had a 2.3-cm phallus and perineal hypospadias (Prader grade III); the right gonad was in the labioscrotal fold and the left was found in the inguinal channel. Karyotype was 46,XX/47,XXY/48,XXYY. Anatomopathological examination of gonads revealed right testis and left ovotestis. The male sex assignment was maintained; the child underwent left gonadectomy, removal of Mullerian structures and urethroplasty. CONCLUSION: A thorough revision of literature revealed a single case of OT-DSD with the same chromosome constitution. Gonadal biopsy is necessary to establish diagnosis in cases of sex chromosome mosaicism.


Assuntos
Cariótipo , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Feminino , Humanos , Recém-Nascido , Masculino
20.
J Pediatr Adolesc Gynecol ; 28(1): 6-11, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25444050

RESUMO

STUDY OBJECTIVE: The aim of our study was to determine the etiologic distribution of 46,XX disorder of sexual development (DSD) according to the new DSD classification system and to evaluate the clinical features of this DSD subgroup in our patient cohort. PARTICIPANTS: The evaluation criteria and clinical findings of 95 46,XX patients were described by clinical presentation, gonadal morphology, genital anatomy, associated dysmorphic features, presence during prenatal period with/without postnatal virilization, hormonal characteristics, and presence or absence of steroidogenic defects among 319 patients with DSD. RESULTS: Types and ratios of each presentation of our 95 patients with 46,XX DSD were as follows: 82 had androgen excess (86.3%): (74 had classical congenital adrenal hyperplasia, 2 had CAH variant possibility of P450-oxidoreductase gene defect), 6 had disorders of ovarian development (6.3%): (1 patient had gonadal dysgenesis with virilization at birth with bilateral streak gonad, 4 patients had complete gonadal dysgenesis, and 1 patient had ovotesticular DSD) and 7 had other 46,XX DSD. Two sisters, who had 46,XX complete gonadal dysgenesis,were diagnosed with Perrault Syndrome with ovarian failure due to streak gonads and associated with sensorineural deafness. CONCLUSION: 46,XX DSD are usually derived from intrauterine virilization and CAH is the most common cause of 46,XX DSD due to fetal androgen exposure.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/etiologia , Hiperplasia Suprarrenal Congênita/complicações , Disgenesia Gonadal/complicações , Transtornos 46, XX do Desenvolvimento Sexual/classificação , Adolescente , Hiperplasia Suprarrenal Congênita/genética , Chicago , Criança , Pré-Escolar , Feminino , Genitália/anormalidades , Disgenesia Gonadal/genética , Humanos , Lactente , Recém-Nascido , Transtornos Ovotesticulares do Desenvolvimento Sexual/complicações , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Estudos Retrospectivos , Adulto Jovem
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