MON-140 - Congenital Hypogonadotropic Hypogonadism in Siblings with A Homozygous GNRHR C.113G >A (P.Arg38Gln) Variant: Expanding Evidence for A Likely Pathogenic Role

Background:
Congenital hypogonadotropic hypogonadism (CHH) is characterized by impaired secretion or action of gonadotropin-releasing hormone (GnRH) and commonly presents with delayed puberty, primary amenorrhea, or infertility. Genetic mutations affecting the GnRH signaling pathway are well-recognized causes, among other etiologies. We report two siblings, a sister with primary amenorrhea and a brother with infertility, both carrying a homozygous GNRHR variant, c.113G>A (p.Arg38Gln). This report adds to the limited data on this variant and may support its future reclassification from a Variant of Uncertain Significance (VUS) to likely pathogenic.

Case Presentation:
A 17-year-old Saudi female presented with primary amenorrhea. Her past medical history was otherwise unremarkable, and a previous trial of combined hormonal therapy failed to induce menstruation.
Laboratory evaluation revealed low luteinizing hormone (LH) < 0.12 IU/L, follicle-stimulating hormone (FSH) < 0.22 IU/L, and estrogen levels < 88 pmol/L, while testosterone was within normal 0.93 nmol/L (female reference range 0.25 – 2.75). Other pituitary axes were intact. Pituitary magnetic resonance imaging (MRI) was normal. Pelvic imaging using transabdominal ultrasound and MRI demonstrated uterine hypoplasia, a hypoplastic vagina, and bilateral ovaries.
On physical examination, breast development corresponded to Tanner stage III. The patient declined genital examination; however, using graphical illustrations, she reported pubic hair development consistent with Tanner stage IV.

Investigations and Diagnosis:
The patient underwent genetic evaluation. Karyotyping revealed a 46,XX genotype. Targeted genetic testing identified a homozygous GNRHR gene variant, c.113G>A (p.Arg38Gln). Family history was notable for a brother with infertility, who was also found to carry the same homozygous GNRHR variant. While mutations in GNRHR are well-established causes of CHH, this particular variant is currently classified as a variant of uncertain significance (VUS). Notably, it has also been reported in a male Korean patient with CHH, suggesting potential pathogenic relevance.

Management:
The patient received counseling about her diagnosis. A plan was established to initiate hormonal replacement therapy, with multidisciplinary follow-up including endocrinology, genetics, and gynecology.

Conclusion:
This case highlights a rare homozygous GNRHR c.113G>A (p.Arg38Gln) variant associated with CHH in a phenotypic female with a 46,XX karyotype, as well as in her affected brother. It underscores the importance of genetic evaluation in adolescents presenting with primary amenorrhea, delayed puberty, or infertility. By reporting these siblings, we contribute to the limited evidence on this variant, potentially supporting its future reclassification from VUS to likely pathogenic.

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