Introduction: Gain-of-function mutations in KISS1 and KISS1R genes and loss-of-function mutations in the gene encoding the makorin RING-finger protein 3 (MKRN3) expressed only in the paternal allele are the most common genetic reasons of familial central precocious puberty (CPP).
Aim: We report a case of familial CPP and a pathogen variant in the MKRN3 gene.
Case: The girl who was 7 years and 4 months old with breast and pubic hair development of three months duration referred to pediatric endocrinology clinic. Medical history was usual and her parents were unrelated. Her father, paternal uncle and cousins had a history of CPP although without documentation. At the time of first visit; weight was 34 kg (2.06 SD), height 127 cm (0.78 SD), BMI at 97 centiles, with a target height of 148.1 cm (-2.01 SD, mother height -1.52 SD, father height -3.44 SD), breast Tanner stage II, pubic hair Tanner stage II. On physical examination, no other abnormalities were observed. Laboratory findings; FSH: 4.1 IU/L (N: 0.1-4.3), LH: 0.8 mIU/mL (N: <0.1), E2:17 pg/mL (N: <12), and thyroid function tests and routine blood studies were normal. Bone age according to Greulich-Pyle was 10.5 years. On pelvic ultrasound, uterine length was determined 50 mm, left ovary 3.3 ml and right ovary 3.3 ml. GnRH stimulation test was performed and it was indicative of CPP. Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region revealed normal findings. Considering the family medical history of father side, we suspected a genetic cause for the CPP, and therefore, we focused on MKRN3. MKRN3 gene analysis showed a previously identified c.482dupC heterozygous variant in the patient and her father. The variant caused premature stop codon as a result of frameshift and therefore was thought to be pathogenic. Treatment with Gonadotropin-releasing hormone analog was started (3.75 mg of depot leuprolide acetate, every 4 weeks). She is 9 years and 3 months old now, and weight 47 kg (2.25 SD), height 139.5 cm (0.55 SD). Bone age is 12 years and breast and pubic hair are Tanner stage III. Clinical follow-up is continued with GnRH analog treatment.
Conclusion: In the evaluation of CPP cases, family history and genetic analysis are important in terms of early diagnosis and treatment with genetic counseling of the next generations.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology