Genetics of congenital central hypogonadism

The diagnostic suspicion of congenital central hypogonadism is based on clinical signs. Biochemical confirmation is challenging, especially after the postnatal activation stage of the hypothalamic-pituitary-testicular axis. Sertoli cell markers, like AMH and inhibin B, have become useful tools for the diagnosis of male central hypogonadism during childhood. Different mechanisms can participate in the aetiopathogenesis of central hypogonadism, leading to a deficiency in the production of gonadotrophins. Advances in genetic studies, mainly next generation sequencing techniques, have allowed the discovery of a large number of genes related to central hypogonadism. However, a causal variant is found in approximately half of the patients. Central hypogonadism has been classically described as a pathology with variable expressivity and incomplete penetrance. Currently, these characteristics are known to be partially explained by the presence of oligogenicity, that is the participation of variants in more than one gene in the aetiology of central hypogonadism in the same patient.