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

Central precocious puberty (CPP) occurs when the hypothalamus prematurely releases gonadotropin-releasing hormone (GnRH), triggering early sexual maturation and the onset of puberty. Mutations in five genes, including KISS1 , KISS1R , DLK1 , MKRN3 , and PROKR2 , have been reported in both sporadic and familial CPP cases. Routine screening of these genes is essential for distinguishing between CPP and early physiological puberty. This study aims to evaluate the role of genetic diagnosis in offering personalized management for familial cases of CPP. Clinical, biochemical, and imaging assessments were conducted on two related girls. The coding regions and flanking intronic sequences of the five genes were sequenced using Sanger sequencing and screened for potential mutations. We identified a heterozygous MKRN3 c.482insC (rs763195944) loss-of-function mutation in a girl diagnosed with CPP at 6.1 years (Tanner stage: P2A2B3). She was treated with a GnRH analogue for five years, and her pubertal development has been well managed (Tanner stage: P3A3B3, at 11 years). No pathogenic variants were found in the KISS1 , KISS1R , DLK1 , or PROKR2 genes. Consequently, we recommended clinical follow-up only for her unmutated maternal cousin, who was diagnosed with premature thelarche (Tanner stage: P3A3B3, at 8.8 years). Routine genetic screening of CPP-related genes can assist clinicians in making accurate treatment decisions for patients exhibiting a growth spurt, rapid onset of puberty, and a family history of CPP. This approach enables more targeted and personalized management of the condition. • MKRN3 mutations are the main genetic cause linked to central precocious puberty (CPP). • Routine MKRN3 mutation screening is recommended to improve CPP management. • Detecting MKRN3 mutations aids early diagnosis, timely treatment, and supports genetic counseling in familial CPP cases.