Endocrine Abstracts

Introduction: Hypogonadotropic hypogonadism (HH) is a rare condition with a variable presentation where molecular diagnosis is often not reached.

Objectives: To assess the clinical/biochemical profile in patients with HH, the diagnostic yield of genetic panels and correlations between phenotype and genetic result.

Methods: Retrospective clinical data was collected for patients with suspected HH form West of Scotland who underwent NGS analysis of 21 HH or 56 DSD-associated genes between 2018-2025. Phenotype was analysed separately for children (<18 y) and adults. Male patients were grouped according to external masculinisation score (EMS) into severely (4-7), moderately (7.5-10) and mildly/not undervirilised (10.5-12). Genetic variants were classified according to ACMG guidelines. Chi-square test was performed for correlation analysis.

Results: Of the 78 patients who underwent genetic testing, 9 did not fit the inclusion criteria leaving 69 (46XY – 57, 46XX – 12) eligible for analysis. Median age at first clinical assessment, genetic request and genetic report was 17.1, 18.4, and 18.6 years, respectively. Six (8.8%) patients had other pituitary hormone deficiencies. The most common presentation in children (35 patients) was delayed puberty (41.2%) and in adults - symptoms of low testosterone (29.4%). EMS was available for 50 patients with severe, moderate, and mild/no undervirilization in 2, 23 and 25, respectively. All patients had baseline gonadotrophins and 34.8% had a LHRH-stimulation test. Pituitary MRI was performed in 52 patients, of whom 5 had absent/hypoplastic olfactory bulbs and 8 had other abnormalities. 10 pathogenic/likely pathogenic (P/LP) variants were found in 9 (13%) patients, 12 variants of unknown significance (VUS) in 9 (13%), and no variants found in 51 patients. The presence of a P/LP variant correlated with lower EMS (P =0.008) but not with anosmia (P =0.27) or olfactory bulb abnormalities on MRI (P =0.14). Of the 17 patients who reported anosmia, 5 had olfactory bulb abnormalities, none with an identified genetic cause.

Conclusions: When used as part of routine clinical practice, a targeted gene panel leads to a molecular diagnosis in approximately 13% of the patients. The likelihood of a pathological variant was correlated with the genital phenotype but not with anosmia or olfactory bulb abnormalities on MRI.