MON-145 - Genetic and Clinical Landscape of CHH: A Scoping Review and Irishcohort Study

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder of the hypothalamic–pituitary–gonadal (HPG) axis, characterised by delayed or absent puberty, infertility, and variable syndromic features. This study aimed to characterise the genetic and clinical landscape of CHH in Ireland and contextualise these findings within the international evidence base. A dual-method design was employed, combining (1) a scoping review and (2) a retrospective cohort analysis. The scoping review, conducted according to Joanna Briggs Institute (JBI) methodology and reported using PRISMA-ScR guidelines, systematically mapped studies published between 2015 and 2025. Seventy-three studies were included, highlighting substantial genetic heterogeneity, with frequent variants in FGFR1, ANOS1, CHD7, GNRHR, KISS1/KISS1R, and PROKR2.

The retrospective cohort encompassed all CHH patients attending the Reproductive Endocrine Clinic at Tallaght University Hospital (TUH) up to June 2025. Thirty patients were identified (66.7% female; mean age 30.8 years), of whom 23 (76.7%) underwent genetic testing. Pathogenic or likely pathogenic variants were identified in seven patients (30.4% of those tested; 23.3% overall), primarily in FGFR1, with additional variants in KISS1, PROKR2, and GNRHR. Phenotype–genotype correlations mirrored international trends, with anosmia linked to PROKR2, while normosmic CHH was associated with KISS1, FGFR1 and GNRHR. Nearly half of the genetically tested cohort had negative results, reflecting the limitations of exome-based testing and the likely contribution of noncoding or structural variants.

This integrated analysis demonstrates broad concordance between Irish and global CHH patterns. The findings support standardised molecular evaluation, multidisciplinary care, and prospective registries to optimise personalised management and reproductive planning, while facilitating
future gene discovery.

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