Human puberty is triggered by the reemergence of GnRH pulsatile secretion, with progressive activation of gonadal function. Several mutations have been identified in an increasing number of genes that influence the onset of puberty. Mutations in GNRH1, KISS1R and GNRHR genes cause normosmic IHH, interfering with the normal synthesis, secretion or action of GnRH. More recently, mutations in TAC3 and TACR3 genes, which encode neurokinin B and its receptor, have been implicated in normosmic IHH, although their precise functions in reproduction remain unclear. Mutations in KAL1, FGFR1, FGF8, PROK2 and PROKR2 are related to disruption of the development and migration of GnRH neurons, thereby resulting in Kallmann syndrome, a complex genetic condition characterized by isolated hypogonadotropic hypogonadism (IHH) and olfactory abnormalities. Furthermore, mutations in CHD7 gene, a major gene involved in the etiology of CHARGE syndrome, were also described in some patients with Kallmann syndrome and normosmic IHH. Notably, the evidence of association of some of the genes implicated with GnRH neurons development and migration with both Kallmann syndrome and normosmic IHH, blurring the simplest clinical distinction between ontogenic and purely functional defects in the axis. Digenic or oligogenic inheritance of IHH has also been described, illustrating the extraordinary genetic heterogeneity of IHH. Interestingly, rare gain-of-function mutations of the genes encoding the kisspeptin and its receptor were recently associated with central precocious puberty phenotype, indicating that the premature activation of the reproductive axis may be also caused by genetic mutations. These discoveries have yielded significant insights into the current knowledge of this important life transition.
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