RESUMO
Ovotesticular disorders of sex development (OT-DSD) are characterized by ovarian follicles and seminiferous tubules in the same individual, with a wide range of atypical genitalia. We report on two sibs with atypical genitalia and SRY-negative 46,XX DSD, OT-DSD was confirmed only in the boy, while the girl had bilateral ovaries. Chromosome microarray analysis (CMA) showed a 737-kb duplication at Xq27.1 including the entire SOX3 gene in both sibs, which was confirmed by quantitative real time PCR. Also, X chromosome inactivation assay showed random inactivation in both sibs. Whole exome sequencing revealed no pathogenic or likely pathogenic variant. CMA of the parents showed normal results for both, suggesting that germline mosaicism could be the reason of recurrence of this duplication in the siblings. Our results support a pathogenic role of SOX3 overexpression in 46,XX subjects leading to variable DSD phenotypes.
Assuntos
Mosaicismo , Transtornos Ovotesticulares do Desenvolvimento Sexual , Masculino , Feminino , Humanos , Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/patologia , Irmãos , Ovário/patologia , Células Germinativas/patologia , Fatores de Transcrição SOXB1/genéticaRESUMO
Background: Differences/disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Objective: The aim of this study is to report the histological characteristics and immunoexpression patterns of gonadal parenchyma in patients with 46,XX testicular and ovotesticular DSD, with a focus on the detection of germ cell malignancies. Design: Inclusion criteria were SRY-negative 46,XX testicular and ovotesticular DSD with available samples from gonadal biopsy or gonadectomy for the review of histological findings. Gonadal histology was assessed on hematoxylin and eosin-stained sections and immunohistochemical analysis. Histopathological criteria from the last World Health Organization classification of urogenital tumors were used to identify undifferentiated gonadal tissue, gonadoblastoma, and dysgerminoma. Results: Median age at first histological evaluation of gonadal samples was 1.46 years (range: 0.16-16 years). Totally 15 patients were classified as ovotesticular and only 1 as testicular DSD. Most individuals had bilateral ovotestes (12/15). No histological alterations were found in the ovarian parenchyma, while signs of dysgenesis were seen in all cases of testicular parenchyma. In 4/15 ovotesticular DSD, a prepubertal biopsy failed to identify ovarian parenchyma. We detected early prepubertal preinvasive and invasive malignancies in this cohort (five patients had undifferentiated gonadal tissue, five gonadoblastoma, and one dysgerminoma). Conclusion: 46,XX disorders of gonadal development are historically considered at a low risk for germ cell cancer, and the need for assessment of gonadal histology has been questioned. The finding of early germ cell malignancies in our cohort brings awareness and needs further research.
Assuntos
Transtornos do Desenvolvimento Sexual , Disgerminoma , Gonadoblastoma , Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Transtornos Ovotesticulares do Desenvolvimento Sexual , Transtornos do Desenvolvimento Sexual/diagnóstico , Disgerminoma/genética , Feminino , Gonadoblastoma/genética , Gonadoblastoma/patologia , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Ovarianas/patologia , Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Transtornos Ovotesticulares do Desenvolvimento Sexual/genéticaRESUMO
INTRODUCTION: Ovotesticular disorder of sex development (OT-DSD) is a rare condition defined by concomitance of testicular tissue and ovarian tissue (containing follicles) in the same individual. In SRY-negative 46,XX OT-DSD, the presence of testicular tissue may be due to variations in NR5A1. Our aims were to search for NR5A1 variants in SRY-negative 46,XX OT-DSD patients and to perform a systematic review on the contribution of NR5A1 variations to 46,XX OT-DSD. METHODS: Sanger sequencing of NR5A1 was performed in seven SRY-negative 46,XX OT-DSD patients: five simplex cases and two with another sibling with a 46,XX DSD. Systematic review of original studies on NR5A1 sequencing of 46,XX OT-DSD patients was performed according to PRISMA-P guideline. Case reports were selected for analysis of clinical features. Individuals with NR5A1-associated testicular DSD were not included. RESULTS: Sanger sequencing of NR5A1 did not reveal pathogenic variants among our patients. Our cohort was included in this systematic review with seven other articles, totalizing fifty-six 46,XX OT-DSD patients investigated by Sanger or whole-exome sequencing. From them, three NR5A1 pathogenic variants were identified (5% of the cases). Clinical analysis of these 3 cases and 5 case reports revealed: predominance of ovotestis (13/16 gonads) and bilateral OT-DSD (5/8 cases). CONCLUSION: The etiology of most 46,XX OT-DSD cases remains elusive, highlighting the importance of a deeper molecular investigation.
Assuntos
Transtornos do Desenvolvimento Sexual , Transtornos Ovotesticulares do Desenvolvimento Sexual , Fator Esteroidogênico 1 , Humanos , Masculino , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/patologia , Gônadas , Metanálise como Assunto , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/patologia , Fator Esteroidogênico 1/genética , Testículo/patologiaAssuntos
Duplicação Gênica/genética , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Fatores de Transcrição SOXB1/genética , Proteína da Região Y Determinante do Sexo , Transtornos Testiculares 46, XX do Desenvolvimento Sexual/sangue , Transtornos Testiculares 46, XX do Desenvolvimento Sexual/genética , Transtornos Testiculares 46, XX do Desenvolvimento Sexual/patologia , Pré-Escolar , Criptorquidismo/genética , Criptorquidismo/patologia , Humanos , Hipospadia/genética , Masculino , Transtornos Ovotesticulares do Desenvolvimento Sexual/sangue , Transtornos Ovotesticulares do Desenvolvimento Sexual/patologiaRESUMO
OBJECTIVE: To describe genetic evaluation and response to surgery and letrozole therapy of a 46,XX/SRY-negative true hermaphrodite. DESIGN: Case report. SETTING: University Medical Center. PATIENT(S): Nineteen-year-old male with penile hypospadias, micropenis, and crytorchidism at the time of birth. INTERVENTION(S): Unilateral gonadectomy, and contralateral conservative gonadal surgery, followed by therapy with letrozole. MAIN OUTCOME MEASURE(S): Histopathologic, genetic and hormonal studies. RESULT(S): Genetic analysis showed that the subject was 46,XX/SRY-negative. Gonadectomy of the left gonad was performed at 16 years. The gonad resected was an ovotestes. The patient's estradiol was high (492±25 pmol/L), whereas the testosterone was low (4.2±0.5 nmol/L). Nineteen months later, conservative gonadal surgery of the contralateral gonad was performed to resect ovarian tissue, and treatment with letrozole was started. During letrozole treatment, testosterone was significantly increased (8±0.7 nmol/L), but estradiol was not changed (323±118 pmol/L). After letrozole withdrawal, testosterone did not decreased significantly (6.9±0.4 nmol/L), estradiol showed an oscillating pattern and a gonadal ultrasound showed an ovoid structure, which appeared to correspond to a follicle. At that time, estradiol was elevated (393 pmol/L). CONCLUSION(S): We present the case of a 46,XX/SRY-negative phenotypic male with bilateral ovotestes. Conservative gonadal surgery should be performed only when all ovarian tissue can be resected. Our results suggest that letrozole is not an adequate treatment for 46,XX true hermaphrodite males with ovotestes.
Assuntos
Transtornos Ovotesticulares do Desenvolvimento Sexual/diagnóstico , Transtornos Ovotesticulares do Desenvolvimento Sexual/terapia , Inibidores da Aromatase/uso terapêutico , Castração/métodos , Cromossomos Humanos , Deleção de Genes , Humanos , Letrozol , Masculino , Nitrilas/uso terapêutico , Transtornos Ovotesticulares do Desenvolvimento Sexual/sangue , Transtornos Ovotesticulares do Desenvolvimento Sexual/genética , Proteína da Região Y Determinante do Sexo/genética , Triazóis/uso terapêutico , Adulto JovemRESUMO
CONTEXT: Differentiation of testicular tissue in 46,XX individuals is seen either in XX males, the majority of them with SRY gene, or in individuals, usually SRY(-), with ovotesticular disorder of sex development (OT-DSD). Although they are sporadic cases, there are some reports on familial recurrence, including coexistence of XX maleness and OT-DSD in the same family. OBJECTIVE: We report on a case of SRY(-) 46,XX monozygotic twins with genital ambiguity. METHODS: Hormonal evaluation included testosterone, FSH, and LH measurements. SRY gene was investigated by PCR and two-step PCR in peripheral leukocytes and gonadal tissues, respectively. Direct DNA sequencing of the DAX-1 coding sequence was performed. Real-time PCR for SOX9 region on chromosome 17 was obtained. RESULTS: Both twins had a 46,XX karyotype. Twin A had a 1-cm phallus with chordee, penoscrotal hypospadias, and palpable gonads. Serum levels of FSH (2.34 mIU/ml), LH (8.8 mIU/ml), and testosterone (1.6 ng/ml) were normal, and biopsies revealed bilateral testes. Twin B had a 0.5-cm phallus, perineal hypospadias, no palpable gonad on the right, and a left inguinal hernia. Hormonal evaluation revealed high FSH (8.2 mIU/ml) and LH (15 mIU/ml) and low testosterone (0.12 ng/ml). Upon herniotomy, a right testis (crossed ectopia) and a small left ovotestis were found. SRY gene was absent in both peripheral leukocytes and gonadal tissue samples. Neither DAX-1 mutations nor SOX9 duplication was identified. CONCLUSIONS: This case provides evidence that both XX maleness and XX OT-DSD are different manifestations of the same disorder of gonadal development.