ESPE Abstracts

Introduction: Central precocious puberty (CPP) is a condition characterized by early signs of sexual development. Mutations in the MKRN3 gene located on chromosome 15q11.2 are rare but are among the most common causes of familial precocious puberty. Early signs of puberty may occur due to the inability to produce this inhibitory protein normally or due to its malfunction resulting from mutations in the MKRN3 gene. Mutations in the MKRN3 gene follow autosomal dominant inheritance. Here, we present three sisters with CPP associated with a pathogenic variant in the MKRN3 gene.

Cases: A seven-year-old girl presented with complaints of genital hair growth, oily hair, acne, and irritability. LH and estradiol levels were consistent with puberty. Uterine size was increased. Pituitary MRI was normal. GnRH analog therapy was initiated for CPP. Three months later, breast development was noted in her twin sister. Investigations in this case were consistent with CPP, and treatment was initiated accordingly. Three years later, early breast development was also observed in the seven-year-old sister, who was diagnosed with CPP. It was learned that there was a history of precocious puberty in the grandmother and paternal aunt during this period. MKRN3 gene sequence analysis was performed for the three sisters and their parents. Heterozygous pathogenic mutation p.Ala162Glyfs*15 (c.482dup) was detected in the three sisters and their father. The ages at diagnosis of the patients were 7 years, 7 years 3 months, and 7 years, respectively. GnRH analog therapy was continued until the age of 11. There was no progression in their puberty and bone ages during the treatment period.

Conclusion: The MKRN3 gene plays a critical role in regulating the hypothalamic-pituitary-gonadal (HPG) axis. MKRN3 encodes makorin Ring-Finger protein 3, which inhibits the puberty process. In cases where CPP is detected in multiple generations or multiple siblings within the same family, mutations in the MKRN3 gene should be considered. Diagnosis of index cases will be beneficial for close monitoring of other family members and early diagnosis and treatment if necessary.

Keywords: Central precocious puberty, MKRN3 gene mutation, familial precocious puberty