Screening of MKRN3, DLK1, KISS1, KISS1R, and PROKR2 genes sequences in related girls with precocious puberty for a personalized management

Central precocious puberty (CPP) occurs when the hypothalamus releases gonadotropin-releasing hormone (GnRH) at an early age, leading to sexual maturation and the onset of puberty. Mutations in the KISS1 , KISS1R , DLK1 , MKRN3 , and PROKR2 genes have been reported in sporadic and familial cases. Routine screening of these genes is crucial to differentiate between CPP and early physiological forms. This study aims to assess the utility of genetic diagnosis in providing personalized management of familial CPP. Clinical, biochemical, and imaging assessments were performed on two related girls. The five genes’ coding and flanking intronic sequences were Sanger sequenced and screened for mutations. We identified a heterozygous MKRN3 c.482insC (rs763195944) loss-of-function mutation in one girl diagnosed with CPP at 6.1 years (Tanner: P2A2B3). The girl was treated with a GnRH analog for five years, and her pubertal development has been well controlled (P3A3B3 at 11 years). No pathogenic variants in the KISS1 , KISS1R , DLK1 , and PROKR2 genes were found. Therefore, we recommended only clinical follow-up for her unmutated maternal cousin, diagnosed with premature thelarche (P3A3B3 at 8.8 years). Routine genetic screening of CPP genes would help clinicians make precise decisions regarding treating patients with a growth spurt, rapid puberty onset, and a family history of CPP.