46,XX testicular disorder of sexual development with SRY-negative caused by some unidentified mechanisms: a case report and review of the literature

Abstract

Background: 46,XX testicular disorder of sex development is a rare genetic syndrome, characterized by a complete or partial mismatch between genetic sex and phenotypic sex, which results in infertility because of the absence of the azoospermia factor region in the long arm of Y chromosome. Case presentation: We report a case of a 14-year-old male with microorchidism and mild bilateral gynecomastia who referred to our hospital because of abnormal gender characteristics. The patient was treated for congenital scrotal type hypospadias at the age of 4 years. Semen analysis indicated azoospermia by centrifugation of ejaculate. Levels of follicle-stimulating hormone and luteinizing hormone were elevated, while that of testosterone was low and those of estradiol and prolactin were normal. The results of gonadal biopsy showed hyalinization of the seminiferous tubules, but there was no evidence of spermatogenic cells. Karyotype analysis of the patient confirmed 46,XX karyotype and fluorescent in situ hybridization analysis of the sex-determining region Y (SRY) gene was negative. Molecular analysis revealed that the SRY gene and the AZFa, AZFb and AZFc regions were absent. No mutation was detected in the coding region and exon/intron boundaries of the RSPO1, DAX1, SOX9, SOX3, SOX10, ROCK1, and DMRT genes, and no copy number variation in the whole genome sequence was found. Conclusion: This study adds a new case of SRY-negative 46,XX testicular disorder of sex development and further verifies the view that the absence of major regions from the Y chromosome leads to an incomplete masculine phenotype, abnormal hormone levels and infertility. To date, the mechanisms for induction of testicular tissue in 46, XX SRY-negative patients remain unknown, although other genetic or environmental factors play a significant role in the regulation of sex determination and differentiation.

Methylation Patterns of <b><i>SOX3, SOX9</i></b>, and <b><i>WNT4</i></b> Genes in Gonads of Dogs with XX (<b><i>SRY</i></b>-Negative) Disorder of Sexual Development

“…On the contrary, Sox3 KO males had a lower testis weight (approximately 42%). These findings suggest that Sox3 plays an important role in gonad development but not in their embryonic differentiation and accord with reports that XX DSD human patients lack mutations in the SOX3 coding region [Lim et al, 2000;Li et al, 2014].…”

Molecular cytogenetic analysis and genetic counseling: a case report of eight 46,XX males and a literature review

“…The clinical manifestations are mainly characterized by a normal phenotype in newborns, but delayed puberty, gynecomastia, or infertility in adolescents. In addition, hypospadias, cryptorchidism, and severely ambiguous genitalia can also be observed [14]. The majority of XX males were found to be SRY -positive, presenting sterility with normal male genitalia and SRY translocation to the X chromosome or autosomes.…”

“…However, the mechanism in SRY -negative 46,XX males has remained unclear. Several possibilities were proposed to explain these cases: mosaicism for SRY in hidden gonads, the inhibition of male pathways resulting from mutations of autosomal or X-linked genes, and mutations of other sex-determining genes downstream of SRY [14, 15].…”

Two-Stage Urethroplasty with Buccal Mucosa for Penoscrotal Hypospadias Reconstruction in a Male with a 46,XX Karyotype

“…A fetus conceived from a sperm cell with an X chromosome bearing the SRY gene will develop as a male, despite not having a Y chromosome. This form is called SRY-positive 46,XX testicular disorder of sex development 1, 2…”