ESPE Abstracts

Introduction: Delayed puberty (DP), affecting over 2% of adolescents, is defined as pubertal onset 2-2.5 SDs later than the general population. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic and genotypic discrepancies between the two diagnoses to improve diagnostic accuracy and patient treatment.

Methods: This was a retrospective study of a UK DP cohort managed from 2015-2023 identified through the NIHR clinical research network. Patients were diagnosed with SLDP if they had attained Tanner stage G4/B4 by age 18yrs. Otherwise, they were diagnosed with HH if they had not commenced (complete, cHH) or had arrested puberty (partial, pHH) before age 18yrs. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment were analysed. Genetic scores, ranging from 1-5, were assigned after whole-exome sequencing and identification of predicted pathogenic variants in genes associated with either SLDP or HH (1=known SLDP variant, 2=likely SLDP variant, 3=no or overlap variant, 4=likely HH variant, 5=known HH variant). Statistical analysis was completed using IBM SPSS and R.

Results: 78 patients were included in this study. 52 (66.7%) patients had SLDP and 26 (33.3%) had HH, of whom 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight SD than HH patients (P=0.004, P=0.021). HH patients had lower testicular volumes, particularly cHH patients (P=0.019). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (P=0.007). 15.4% of SLDP, compared to 38.5% of HH patients, had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. P=0.023). Mean first recorded LH and inhibin B were lower in males with HH, particularly in cHH patients (P=0.01, P=0.001), but were not discriminatory due to overlapping ranges. Genetic score of SLDP patients was lower than HH patients (3.00±0.55 as compared to 3.47±0.70; P=0.008). No significant differences were identified in FSH, testosterone, AMH or bone age delay.

Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH. These could be incorporated into an integrated framework or scoring system to aid clinician decision-making and management optimisation. However, the distinction between partial HH and SLDP remains problematic.