How puberty is initiated is an enigma that still captivates scientists. Many of the recent advances in our understanding of the mechanisms involved in reactivation of the hypothalamic–pituitary–gonadal, or reproductive, axis at puberty have been based on the characterization of genetic mutations associated with reproductive disorders in humans. The majority of the mutations to date were identified in patients with isolated hypogonadotropic hypogonadism, a disorder that is much less common than central precocious puberty.32,33 Genomewide association studies have identified multiple loci associated with pubertal timing,4 but aside from LIN28B (a hetero-chronic regulator of developmental timing),34 it has been difficult to implicate specific novel genes within these associated loci. Despite numerous efforts to identify genes associated with the premature activation of puberty, only two rare mutations in candidate genes have been identified in patients with central precocious puberty.19,20 To our knowledge, no strong evidence for additional causal mutations has been presented.
