RF14 | PSAT120 X-Linked Central Precocious Puberty Associated with MECP2 Defects

Methyl-CpG-binding protein 2 (MECP2) is a chromatin-associated protein that can both activate and repress transcription, playing an essential role in neuronal maturation. MECP2 is encoded by an X-linked gene (chromosome Xq28) with high expression in the brain, including the hypothalamic region. Loss-of-function mutations in MECP2 are usually associated with Rett syndrome, a rare genetic disorder characterized by normal early development followed by regression of acquired skills, such as purposeful hand movements and the ability to communicate, repetitive hand stereotypies, slowed brain growth, seizures, and intellectual disability with female predominance. Notably, early pubertal development (early thelarche, pubarche and, less often, menarche) has been demonstrated in girls with Rett syndrome. In this original study, a total of 329 CPP patients (308 girls and 21 boys) were investigated for MECP2 defects. Familial cases were identified in 38% of this CPP cohort. First, 129 CPP patients were enrolled for multigene sequencing studies (whole-exome sequencing n=58; targeted gene sequencing n=71) as part of genetic investigations based on large-scale approaches. Three rare heterozygous sequence variants predicted to be deleterious in MECP2 gene were identified in 5 girls from 4 unrelated families with CPP: the p.Arg97Cys de novo missense variant in two monozygotic twin sisters with CPP and microcephaly; the p.Ser176Arg de novo missense variant in one girl with sporadic CPP, obesity and autism; and the p.Ala6_Ala8dup insertion in two unrelated girls with sporadic CPP (one with a maternally inherited variant). To expand the investigation for potentially damaging sequence variants of MECP2, a larger multiethnic cohort of 200 CPP patients was further analyzed through Sanger sequencing. One rare heterozygous 3'UTR insertion in MECP2 (c.*36_*37insT) was identified in two unrelated girls with sporadic CPP (one with a maternally inherited variant and other with a de novo variant). None of these MECP2 variants have been previously reported in Rett syndrome cases. The girls with CPP associated with MECP2 defects did not manifest typical Rett syndrome. The three patients with more deleterious MECP2 variants, according to in silico prediction tools, had neurobehavioral phenotypes, likely corresponding to a genotype-phenotype correlation. Immunohistochemistry and immunofluorescence studies were performed in pubertal female mice. Abundant staining for Mecp2 was demonstrated in multiple hypothalamic nuclei (arcuate, suprachiasmatic, and paraventricular) and in the median eminence. Co-localization of Mecp2 and GnRH within GnRH neurons was suggested in double labelling experiments. Hence, Mecp2 expression was demonstrated in key hypothalamic nuclei responsible for GnRH regulation in female mice. In conclusion, we have identified rare dominant MECP2 defects in multiple unrelated girls with CPP with or without mild neurodevelopmental abnormalities, revealing a new X-linked form of premature reactivation of the hypothalamic-pituitary-gonadal axis. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:30 p.m. - 12:35 p.m.