ESPE Abstracts

Central precocious puberty (CPP) is defined by the premature development of secondary sexual characteristics due to the early reactivation of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Characteristically, the overall frequency of CPP is much higher in girls than in boys. Loss-of-function mutations in two maternal imprinted genes (MKRN3 and DLK1) have been identified as the most frequent etiologies of familial CPP, indicating an essential role for DNA methylation among the mechanisms underlying pubertal timing. Both genes are located at critical regions of neurodevelopment syndromes that may be associated with CPP (MKRN3 at chromosome 15q11-q13 of Prader-Willi syndrome and DLK1 at chromosome 14q32.2 of Temple syndrome). Recently, we have demonstrated a X-linked form of CPP associated with rare variants in MECP2, a key component of the human DNA methylation machinery, whose inactivation has previously been associated with Rett syndrome. We identified seven girls (from six unrelated families) with CPP carrying four rare heterozygous MECP2 variants (p.Arg97Cys, p. Ser176Arg, p.Ala6_Ala8dup, and c.*36_*37insT). None of these girls with CPP and MECP2 variants manifested classical Rett syndrome. The MECP2 protein belongs to the methyl-binding domain family, that in mammals are mediators of DNA methylation, a major epigenetic mechanism that occurs predominantly in the context of CpG dinucleotides. The known functions of MECP2 involve repression or activation of gene transcription and regulation of chromatin structure, playing a role in the epigenetic regulation of target gene expression. The girls identified with rare heterozygous MECP2 variants had a sporadic form of CPP. This clinical form is in line with the identification of de novo variants, a pattern considered as strong evidence for pathogenicity. Such cases might be considered syndromic forms of CPP and therefore represent part of the spectrum of neurodevelopmental disorders related to MECP2. We demonstrated that Mecp2 is highly expressed in key areas of the hypothalamus responsible for GnRH function in female mice and co-localized with GnRH in most GnRH neurons in these regions. Investigation of genetic causes has revealed children with CPP presenting with the familial form or in association with multiple phenotypes (syndromic form), especially neurodevelopmental abnormalities.