ESPE Abstracts

Background: In 2013, Abreu et al identified loss-of function mutation in the MKRN3 gene of fifteen patients from five families with idiopathic central precocious puberty (iCPP), highlighting the implication of this maternally imprinted gene in this still poorly understood condition. Since this study, other mutations have been described and now represent the most common genetic cause of iCPP.

Objective: The objective of the study was to document the clinical course of puberty in nine girls and one boy harbouring pathogenic MKRN3 variants.

Design and participants: This is an observational case series study of patients with iCPP followed in our center.

Results: We identified eight different variants predicted to be deleterious by in silico analysis in the MKRN3 gene of ten patients with iCPP from eight unrelated families. Six of the eight pathogenic variants were undescribed as far as we know: two of them were missense mutations, three were nonsense mutations and one was a frameshift mutation. In all cases for which we had datas, the mutation was inherited from the father. The 4 years-old twin brothers of one patient were also carriers but still prepubescent. Index cases had a very rapid pubertal development and frank peak LH response to the GnRH test. Final height of affected adult relatives were in the target for males but below target height in females.

Conclusion: We identified six novel MKRN3 mutations in children with CPP. One of them had no known family history at the time of the analysis but a very early and rapid pubertal onset. An MKRN3 defect should be considered in all patient with CPP at a very young age or with a history of CPP in the paternal family. Family study of a patient also allowed us to detect a MKRN3 mutation in her two still prepubescent brothers, highlighting the value of regular clinical follow-up of early diagnosed patients without the necessity of a cerebral MRI. iCPP seems to impact adult height in females’ adult relatives carrying MKRN3 mutations unlike males, but this remains to be confirmed because only a few adults could be studied.