Endocrine Abstracts

Congenital hypogonadotropic hypogonadism (CHH) is a pathological condition characterised by lack of pubertal onset and must be differentiated from self-limited delayed puberty (SLDP). There is a significant overlap between these two conditions both in clinical and biochemical features, with current diagnostic approaches lacking sensitivity. Thus, paediatric endocrine clinicians are faced with difficulty in ascertaining the correct diagnosis in adolescence. The presence of certain red flags - cryptorchidism and micropenis in males, anosmia or midline defects may indicate gonadotrophin deficiency, but these signs are frequently absent, particularly in patients with partial CHH phenotypes. Published data from our group demonstrated the utility of whole exome sequencing in differentiating CHH from SLDP in our UK cohort. In this project, we analysed the phenotypic and genomic data of patients presenting in adolescence with central delayed puberty who had reached 18 years, with a final diagnosis of CHH or SLDP. We aimed to define a pragmatic scoring system based on clinical, biochemical and genotypic data to enable accurate diagnosis between these two conditions. Eighty patients with pubertal delay, from two separate datasets, were included in this study. A scoring system was developed from 46 patients (13 CHH, 33 SLDP) in Dataset 1 (2015-2020). Five key clinical parameters (testicular volume <3mls, cleft lip or palate, anosmia, micropenis or cryptorchidism, family history of SLDP or CHH), alongside biochemical markers (Inhibin-B and AMH) together with genotypic score (1-5 based on variants of interest in known SLDP or CHH genes) were included in a predictive score (maximum points 13 in males, 11 in females) to estimate the likelihood of CHH. This scoring system was fine-tuned and validated in a second group of 34 patients (19 CHH, 15 SLDP) (Dataset 2, 2020-22). Final diagnosis of CHH or SLDP correlated with score in 88% (30/34) of patients in Dataset 2. By utilising a diagnostic score, we were able to accurately differentiate patients with CHH from SLDP at presentation in the large majority of this study. A combined clinical, biochemical and genetic scoring system may thus provide a useful approach to improve diagnostic accuracy and management for patients with central pubertal delay.