FRI446 A Case Of 46 XX Testicular Disorder Of Sex Development Presenting As Hypogonadism And Infertility
Authors: Balachandar Neeraja , Agarwal Shubham , Soe Kyaw Kyaw 
Published: October 2023

Disclosure: N. Balachandar: None. S. Agarwal: None. K.K. Soe: None.

Introduction: Hypergonadotropic hypogonadism in males can be due to genetic, acquired or developmental causes. Common etiologies of testicular failure include trauma, systemic illnesses, radiotherapy, gonadotoxic drugs, and viral orchitis; in addition, genetic causes should be considered. Here, we present a case of primary hypogonadism and infertility due to 46 XX testicular disorder of sex development (DSD).

Case Report: A male in his early fifties with history of obesity presented with fatigue to his PCP. A total testosterone level was 1.8 ng/mL (normal: 1.7 - 7.6 ng/mL) with a repeat value confirming the finding. Bioavailable testosterone was low at 85.1 ng/dL (normal: 110-575 ng/dL). FSH was elevated at 39.9 mIU/mL (normal: 1.3 - 19.3 mIU/mL), and LH was elevated at 16.6 mIU/mL (normal: 1.2 - 8.6 mIU/mL). In endocrinology clinic, he reported a year of fatigue, erectile dysfunction despite normal libido, and an inability to conceive despite three years of regular unprotected intercourse. He noted loss of muscle mass, bilateral breast tissue development, and reduction in testicular size. Physical exam revealed normal phallus, diffusely sparse body hair with atypical male distribution, bilateral gynecomastia, and bilateral reduction in testicular volume (right: 5 mL; left: 8 mL). Chromosomal analysis showed a mosaic pattern of 45 XO in 6% of cells and 46 XX in 94% of cells. Fluorescence in situ hybridization (FISH) analysis confirmed the presence of the sex-determining region (SRY) gene in 96% of cells. Metaphase FISH showed cryptic insertion of the SRY gene into the p arm of the X chromosome. Semen analysis showed azoospermia. He was diagnosed with 46 XX testicular DSD with abnormal mosaicism. He was prescribed testosterone gel and counseled on fertility options resulting in improvement of testosterone levels, sexual function, and subjective well-being.

Discussion: The SRY gene, normally located on the p arm of the Y Chromosome, is responsible for development of primitive gonads into testicles during embryogenesis. Homologous recombination occurs between chromosomes during gametogenesis. It is hypothesized that in patients with 46 XX DSD, the SRY gene is translocated to the X chromosome, as demonstrated in this case. Its expression helps with selection of male sex in a growing fetus. Thus, in a 46 XX SRY positive male, the phenotypic presentation is male. Since the AZF gene on the q arm of the Y chromosome which is essential for spermatogenesis is not translocated, 46 XX males are infertile and undiagnosed until adulthood when azoospermia is noted during infertility workup. 46 XX SRY negative males develop ambiguous genitalia leading to earlier diagnosis. Eighty-percent of 46 XX males are SRY positive and twenty-percent are SRY negative. Thus, in adult males presenting with infertility and hypogonadism, genetic causes such as 46 XX DSD with SRY translocation should be considered.

Presentation: Friday, June 16, 2023