Clinical and Genetic Characterization of Familial Central Precocious Puberty

Abstract Context Central precocious puberty (CPP) can have a familial form in approximately one-quarter of the children. The recognition of this inherited condition increased after the identification of autosomal dominant CPP with paternal transmission caused by mutations in the MKRN3 and DLK1 genes. Objective We aimed to characterize the inheritance and estimate the prevalence of familial CPP in a large multiethnic cohort; to compare clinical and hormonal features, as well as treatment response to GnRH analogs (GnRHa), in children with distinct modes of transmission; and to investigate the genetic basis of familial CPP. Methods We retrospectively studied 586 children with a diagnosis of CPP. Patients with familial CPP (n = 276) were selected for clinical and genetic analysis. Data from previous studies were grouped, encompassing sequencing of MKRN3 and DLK1 genes in 204 patients. Large-scale parallel sequencing was performed in 48 individuals from 34 families. Results The prevalence of familial CPP was estimated at 22%, with a similar frequency of maternal and paternal transmission. Pedigree analyses of families with maternal transmission suggested an autosomal dominant inheritance. Clinical and hormonal features, as well as treatment response to GnRHa, were similar among patients with different forms of transmission of familial CPP. MKRN3 loss-of-function mutations were the most prevalent cause of familial CPP, followed by DLK1 loss-of-function mutations, affecting, respectively, 22% and 4% of the studied families; both affected exclusively families with paternal transmission. Rare variants of uncertain significance were identified in CPP families with maternal transmission. Conclusion We demonstrated a similar prevalence of familial CPP with maternal and paternal transmission. MKRN3 and DLK1 loss-of-function mutations were the major causes of familial CPP with paternal transmission.