Whilst the timing of pubertal onset varies within and between different populations, it is a highly heritable trait. The timing of sexual maturation is highly correlated within families and in twin studies, suggesting strong genetic determinants. However, despite this strong heritability, our knowledge of the genetic control of puberty remains limited. Disturbances of puberty (precocious, delayed or arrested) encompass an important group of pathologies. Firstly, they are common, affecting up to 4% of adolescents. In addition, abnormal timing of pubertal development is associated with adverse health and psychosocial outcomes. This has importance both for the individual, but also has a potential major impact on public health, especially in view of the secular trend towards an earlier age of puberty onset. Self-limited delayed puberty (DP) and familial central precocious puberty (CPP) are common inherited conditions defined by disordered pubertal timing, each with an established genetic basis. Self-limited DP, also known as constitutional delay of growth and puberty, is a highly heritable condition, which segregates in an autosomal dominant pattern (with or without complete penetrance) in the majority of families. Like self-limited DP, CPP often has a strong familial basis. Segregation analysis points to an autosomal dominant inheritance pattern with incomplete sex dependent penetrance. Two key imprinted genes have been identified as causal in pedigrees of CPP: MKRN3, and DLK1. MKRN3 is thought to contribute to the puberty brake restraining the hypothalamic-pituitary-gonadal axis via inhibition of GnRH release. Recent discoveries have begun to address the question of genetic regulation in self-limited DP. Using next generation sequencing (NGS) to explore a large DP patient cohort, mutations in the IGSF10 gene were in 10% of probands. Following this discovery, mutations in several further genes involved in the gonadotropin-regulating hormone (GnRH) pathway have been identified in families with self-limited DP: EAP1, HS6ST1 and LGR4. These results provide a new mechanism for delayed puberty: through defects in genes controlling the development of the GnRH neuroendocrine network. Importantly, for the majority of DP patients these are not defects in those genes that are known to produce complete GnRH deficiency in conditions such as hypogonadotropic hypogonadism. Moreover, genetic overlap has been identified between regulators of the timing of puberty in the general population identified from genome wide association studies, and both self-limited DP and CPP, including genes involved in energy metabolism.
18 - 21 May 2019
European Society of Endocrinology