OR06-5 Genetic Origin Of Classic And Milder Adult-onset Forms Of Isolated Hypogonadotropic Hypogonadism

Multiple metabolic and inflammatory mechanisms are considered the determinants of acquired functional isolated hypogonadotropic hypogonadism in males, whereas classic IHH is a rare congenital condition with a strong genetic background.Since we recently uncovered a frequent familiarity for classic IHH among patients with mild adult-onset hypogonadism (AO-IHH), here we performed agenetic characterization by next generation sequencing of 160 males with classic or “functional” forms. The prevalence of rare variants in 28 candidate genes showed to be significantly higher than in controls in all IHH patients, independently of the age of IHH onset, degree of hypogonadism or presence of obesity. Interestingly, it did not differ among patients with classic or milder forms of IHH, however particular genes appear to be more specifically associated with one or the other category of IHH. ROC curves showed that Total Testostrone <6.05 nmol/L and an age of onset <41 years are the most specific highly sensitive cutoffs to identify patients with significantly higher chances of harboring rare IHH gene variants. In conclusion, since classic and milder phenotypes of IHH have a largely overlapping genetic origin we conclude that rare variants in IHH genes predispose also to adult-onset and/or milder hormonal deficiencies. The identification of a genetic predisposition can improve the familial and individual management of AO-IHH and explain the heritability of congenital IHH.