EP1191 - ECE_1348 - Clinical relevance of genetic diagnosis in congenital hypogonadotropic hypogonadism

Abstract

Congenital isolated hypogonadotropic hypogonadism (CHH) is a rare genetic disorder that is associated with deficient secretion and/or action of the Gonadotropin-releasing hormone (GnRH). The incidence is estimated to be 1:15.000-50.000 with a male-to-female ratio of 5:1. CHH spectrum of clinical expression ranges from complete absence of sexual development to partial completion of puberty. It can be associated with multisystem anomalies such as anosmia (known as Kallman syndrome). Timely diagnosis and treatment are crucial for fertility preservation. Pathogenic variants in more than 60 genes have been identified as the cause of CHH. Genetic testing can help lead to an early diagnosis, providing prognostic information and allowing genetic counseling to be adapted. Our objective was to reassess patients with diagnosis of CHH without initial genetic testing or with negative results from previous genetic testing panels. A descriptive retrospective observational study was conducted in a series of eight patients with CHH. Genetic re-evaluation was performed using a next-generation gene panel associated with CHH. Clinical variables, magnetic resonance imaging (MRI) findings, presence of offspring, and genetic results were collected for statistical analysis. All 8 patients were men, (current mean age 51.9 ± 13.3 years). The mean age at diagnosis of CHH was 24.3 ± 13.3 years. Genetic reassessment was performed after an average of 24.4 years from initial diagnosis (range 14-34 years). The genetic study identified pathogenic variants in four patients (50%). Among the two patients (25%) who had undergone previous genetic testing with negative results, the updated genetic panel identified a pathogenic variant in one case, whereas the other remained negative. GNRHR, ANOS1, SOX10, PROK2, were the genes identified. Regarding the phenotype, two patients (25%) presented anosmia and one hyposmia (12.5%). Anomalies in MRI were observed in three patients (37.5%). Gonadotropin therapy was administered to six of the eight patients (75%), with the aim of pubertal induction in two cases and fertility induction in four cases. Three of eight (37.5%) patients had offspring. Genetic testing in CHH is challenging; however, it allows an earlier and more precise diagnosis. This enables timely initiation of hormonal therapy, optimizing pubertal development and reproductive function. In addition, genetic testing provides prognostic information that supports tailored genetic counselling. Therefore, the implementation of new genetic panels supports personalized medicine and enhances patients’ quality of life.