ESPE Abstracts

Background: Genetic factors play an important key role in regulating the timing of puberty. The premature activation of pulsatile release of gonadotropin-releasing hormone(GnRH) before 8 and 9 years of age in girls and boys causes central precocious puberty(CPP). Pathogenic variants in DLK1 are associated with isolated familial CPP. Here, we report three siblings with a diagnosis of CPP with novel variant in DLK1.

Case Report: Patient 1(P1) is the first-born child of nonconsanguineous parents. Birth weight (BW) was appropriate for gestational age(AGA) with -1.3SDS. She was referred to the pediatric endocrinology outpatient-clinics for breast development at the age of 7-years. At presentation, height and body mass index(BMI)-SDS were +1.82 and +0.2 respectively. Pubertal stage was Tanner 4. Bone age(BA) was 10.5 years, predicted adult height(PAH) (-1.3SDS) was below the target height (+0.1SDS). She received GnRH analog(a) between the age of 8.7 and 10.8-years. Menarche occurred at 11.3-years of age. Patient 2(P2) was younger sibling of P1. BW was -1.2SDS. She presented due to early menarche at the age of 9-years. At presentation, height and BMI-SDS were +2.2 and -0.7 respectively. Pubertal stage was Tanner-3. BA was 12-years, PAH was calculated as -0.94SDS. GnRHa treatment has been planned, however the family was lost to follow-up. After 7-years, we recontacted the family and patients were summoned. AH-SDS of P1 and P2 was -1.2 and -1.4, respectively. Molecular analysis revealed a novel heterozygous c.357C>G (P.Tyr119Ter) variant in DLK1. The segregation analysis showed paternal origin of this variant. Same variant was also in the 6-year-old sister(P3). At follow-up of P3, breast development started at the age of 7.5-years. At this time, height and BMI-SDS were -1.2 and -0.7 respectively. Pubertal stage was Tanner-2. BA was 9.5-years and PAH-SDS was calculated as -2.2. Hormonal profile was as follows LH 2.3 mIU/ml, FSH 3.3 mIU/ml ve E2 37.6 pmol/L. Thus, GnRHa treatment was started. Recently, serum DLK1 levels were measured in 3 siblings and parents by ELISA assay, which were low in 3 siblings. These results supported the loss-of-function in DLK1.

Conclusion: The study has shown that the paternally inherited variant in DLK1 lead to protein truncation with early "stop" codon formation, which is associated with familial CPP. By molecular analysis, opportunity to make predictions, provide early diagnosis, and follow-up/treatment opportunities for CPP were provided for family members.