Pubertal onset results from reactivation of the gonadotropic axis by neuroendocrine mechanisms which remain to be defined. Human genetics is one of the approaches to characterize disease mechanisms and therefore novel physiological system. Two different type of phenotype due to abnormal timing of the pubertal onset are described: advance of the pubertal onset also call central precocious puberty and delayed or absence of puberty. The latter is due to gonadotropic deficiency reflecting hypothalamic or pituitary defects. Genetics of both conditions are clearly different. Multifunctional and polygenic models of transmission have been described in central precocious puberty whereas autosomal or X-linked dominant and recessive transmissions have been reported in gonadotropic deficiency. Several genes defects have now been described as a cause of gonadotropic deficiency. These genes were studied as they were natural candidate genes, they were revealed by genome mapping in informative families or by chromosomal analysis of patients with contiguous gene syndrome but also by analogy with the phenotype observed after their invalidation in mice. These genes encode for proteins involved in the normal migration of GnRH neurones from the olfactory placode toward the hypothalamus, for transcription factors involved in the normal pituitary development or for proteins playing a major role in the neuroendocrine regulation of the gonadotropic axis. Mutations in two or more genes may explain the high phenotype expressivity observed in familial cases with gonadotropic deficiency and reveal oligogenic model of transmission. Some of these genes described in gonadotropic deficiency are now interesting candidate genes for the genetic determinism of central precocious puberty.
03 - 07 May 2008
European Society of Endocrinology