Clinical meaning
Precocious puberty is defined as the onset of secondary sexual characteristics before age 8 in females or age 9 in males. It is classified as central (GnRH-dependent, gonadotropin-mediated) or peripheral (GnRH-independent, autonomous sex steroid production).
Central precocious puberty (CPP) results from premature activation of the hypothalamic GnRH pulse generator. The most common cause in girls is idiopathic, while in boys CNS pathology is more frequently identified. Hypothalamic hamartomas are the most common identifiable CNS lesion - these ectopic masses contain GnRH-secreting neurons that function autonomously. Other causes include CNS tumors (gliomas, astrocytomas), hydrocephalus, post-CNS infection, and neurofibromatosis type 1. At the molecular level, gain-of-function mutations in KISS1 or KISS1R (GPR54) and loss-of-function mutations in MKRN3 (makorin ring finger protein 3, an inhibitor of GnRH secretion) have been identified in familial CPP.
Peripheral precocious puberty (PPP) involves sex steroid production independent of GnRH and gonadotropins. McCune-Albright syndrome results from postzygotic activating mutations in GNAS1, causing constitutive activation of the Gsα subunit and autonomous cAMP production in affected tissues - leading to autonomous ovarian follicle activation, café-au-lait macules, and polyostotic fibrous dysplasia. Other causes include congenital adrenal hyperplasia (21-hydroxylase deficiency causing excess adrenal androgens), sex-steroid-secreting tumors (granulosa cell, Leydig cell, adrenal), familial male-limited precocious puberty (testotoxicosis from activating LH receptor mutations), and exogenous sex steroid exposure.