Two adult 46,XY sisters with female-like phenotype due to a novel homozygous LHCGR splice-site variant

Abstract The luteinizing hormone/choriogonadotropin receptor (LHCGR) is essential for Leydig cell function, gonadal steroidogenesis, and male sexual differentiation. Loss-of-function variants in LHCGR are a rare cause of 46,XY differences of sex development (DSD). We report 2 46,XY adult sisters born to consanguineous parents, who presented with primary amenorrhea and absent secondary sexual characteristics. Both exhibited tall stature, female external genitalia, hypergonadotropic hypogonadism with very low testosterone levels. Imaging revealed bilateral cryptorchid testes and absence of Müllerian structures. Both sisters underwent bilateral gonadectomy, and histopathological findings provide strong morphological support for Leydig cell hypoplasia. Genetic testing identified a novel homozygous splice-site variant (c.384-2A>G) in LHCGR, predicted to cause aberrant splicing and a loss of receptor function. These findings expand the mutational spectrum of LHCGR-related DSD, a rare cause of 46,XY DSD.