HH is a rare, congenital mass or lesion comprising mature neurons and glial cells but with an abnormal distribution[5]. However, the cytologically normal small neurons of HH are readily identified as opposed to the large pyramidal neurons of the normal hypothalamus or pyramidal-type neurons seen in ganglioglioma[6]. Moreover, the glial components of HH are normal and can be readily distinguished from other tumors. The pathogenesis of HH resulting in CPP remains to be verified because conflicting results have been reported in the literature [7].
An interesting finding of the present study is that KMT2C gene mutation was detected in the tissue samples of all three patients. Here, we attempted to elucidate its underlying relationship with PP. Although the location of HH lesion causing CPP has been well reported, the molecular mechanism in the early onset of puberty has not been defined. In the presence of GnRH, the pulsating secretion of pituitary gonadotropic hormone is a necessary condition for the onset of puberty. GnRH secretion in the human hypothalamus is regulated by kisspeptin, neurokinin B, dynorphin, and their corresponding receptors [8]. Estrogen is also involved in the release of GnRH, leading to the development of PP. In a comparative study that enrolled 73 patients with CPP and 101 normal adolescent girls, Rea gene (estrogen receptor) polymorphisms were found to be associated with early menarche [9]. Another study has identified eight polymorphisms in the ER alpha gene, which is a ligand-activated nuclear receptor that directs proliferation and differentiation in cancer cells including mammary cancer cells [10]. These findings suggest that increased estrogen receptor sensitivity may be caused by mutation or polymorphism of the ER alpha gene, which is related to the etiology of PP. Regulatory functions of ER alpha require a stable genomic environment [11]. KMT2C is required for ER alpha activity and breast cancer proliferation [11]. KMT2C gene mutation negatively regulates the expression of estrogen-dependent genes, and its deficiency can impair estrogen-driven breast cancer proliferation and promote tumor growth. Thus, KMT2C is one of the most commonly mutated genes in ER-positive breast cancer [12]. As discussed, we found KMT2Cmutations in all three patients and the upregulation of estrogen in one of the patients post-surgery (could not be determined in the other two patients). Based on the knowledge that theKMT2C gene is closely related to estrogen and its corresponding GnRH release; we speculated that KMT2C is implicated in the occurrence of CPP through altering the levels of estrogen.
Compared with the GLI3 gene reported involved in Pallister-Hall syndrome, which is occasionally associated with HH, the KMT2C gene is close to it spatially. The KMT2C gene is on the chromosomesame as GLI3 gene. However, no GLI3 mutation was identified in any of the patients in our study, indicating the likely involvement of other pathways. Further studies including the enrollment of more cases, experimental tests, and the use of animal models are necessary to elucidate the mechanism and to verify our hypothesis.