ESPE Abstracts (2022) 95 P1-545

1University of São Paulo, São Paulo, Brazil; 2Queen Mary University of London, London, United Kingdom; 3Oxford Children’s Hospital, Oxford, United Kingdom; 4Children’s State Hospital of Vila Velha, Vila Velha, Brazil; 5Fondation Ophtalmologique Adolphe de Rothschild, Paris, France; 6Universidad de Sevilla, Sevilla, Spain; 7University Hospital Virgen of Arrixaca, Murcia, Spain; 8Imperial College London, London, United Kingdom; 9Universidad Autónoma de Madrid, Madrid, Spain

Background: Genetic causes of central precocious puberty (CPP) has been increasingly recognized, extending our knowledge of the triggering factors of human pubertal timing. Distinct etiologies remain to be elucidated in sporadic and familial cases. Methyl-CpG-binding protein 2 (MECP2) is a chromatin-associated protein that can activate or repress gene transcription, playing a role in neuronal maturation. It is encoded by MECP2 gene located at chromosome Xq28, with high brain expression. Loss-of-function mutations in MECP2 are usually associated with Rett syndrome, a severe neurodevelopment disorder with female predominance characterized by regression of acquired skills, such as communication and hand movements, seizures, and intellectual disability. Early pubertal development (early thelarche, pubarche and, less often, menarche) has been demonstrated in typical Rett syndrome girls.

Objective: We investigated whether MECP2 defects are associated with an idiopathic CPP phenotype with or without mild neurodevelopmental abnormalities.

Methods: A total cohort of 331 multiethnic idiopathic CPP patients (310 girls; 38% familial cases) was investigated for MECP2 allelic variants. 133 CPP patients underwent multigene sequencing studies based on large-scale approaches (whole-exome sequencing n=62; targeted gene sequencing n=71) and a further 198 CPP patients were analyzed through MECP2 Sanger sequencing. Immunohistochemistry and immunofluorescence studies were performed in pubertal female mice to determine Mecp2 expression in hypothalamic nuclei.

Results: Three rare heterozygous exonic variants in MECP2 gene were identified in 5 girls from 4 unrelated families with CPP: a de novo p.Arg97Cys variant in two monozygotic twin sisters with CPP and microcephaly; a de novo p.Ser176Arg variant in one girl with sporadic CPP, obesity and autism; and a p.Ala6_Ala8dup insertion in two unrelated girls with sporadic CPP (one of them with a maternally inherited variant). These three exonic variants were predicted as likely damaging by in silico proteomic tools. Additionally, 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). These CPP girls did not manifest typical Rett syndrome. In female mice, experiments identified abundant staining for Mecp2 in multiple hypothalamic nuclei (arcuate, suprachiasmatic, and paraventricular) and co-localization of Mecp2 and GnRH within GnRH neurons, demonstrating Mecp2 expression in key hypothalamic nuclei responsible for GnRH regulation.

Conclusion: We identified rare dominant MECP2 defects in multiple unrelated idiopathic CPP girls with or without mild neurodevelopmental abnormalities, revealing a new X-linked form of premature reactivation of the hypothalamic-pituitary-gonadal axis.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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