ESPE Abstracts

Background: Precocious puberty is defined as breast development before 8 years in girls and gonad development before 9 years in boys. Central precocious puberty (CPP) results from early activation of the hypothalamic-gonadal axis. One third of idiopathic CPP is reported to be familial. Genetic mutations were initially described in kiss-peptin-1 (KISS1) and its receptor (KISS1R). More recently, Abreu et al identified heterogeneous mutations in the makorin RING finger 3 (MKRN3) gene. We report a sibling pair presenting with signs of precocious puberty within a few months of each other. Next-generation exome sequencing identified a paternally inherited heterozygous MKRN3 mutation in both siblings.

Case: A 5 year old girl presented with breast bud development aged 5.8 years. Peak LH and FSH were 28.3 IU/L and 12.6 IU/L respectively, confirming CPP. No pituitary lesion was seen on MRI; bone age was advanced by 3 years. Treatment with a long acting LHRH analogue was commenced. Her brother was assessed at 8.3 years with signs of precocious puberty including 8 ml testicular volumes, pubic hair, muscular appearance and body odour. Peak LH and FSH were 24.0 IU/L and 6.3 IU/L respectively; subsequent MRI head scan was normal. He also commenced treatment with a LHRH analogue. Exploration of family history suggested a paternal ‘parent of origin’ effect. Their father did not enter puberty early however the paternal grandmother and paternal great-aunt had menarche at 8 years. KISS1R analysis did not identify a mutation in either child. MKRN3 analysis using exome sequencing identified a heterozygous frameshift variant p.(Met297fs) (c. 890_893del) in exon 1 in both children.

Discussion: The mechanism that reactivates pulsatile GnRH secretion to initiate puberty is poorly understood. MKRN3 defects in sporadic CPP have been identified supporting a fundamental role for this peptide in the initiation of puberty. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi critical region (chromosome 15q11-q13) and mutations represent an uncommon mode of transmission in CPP; exclusively paternal transmission is reported in only 1% of familial precocious puberty. Multiple loss of function mutations have been described in patients with CPP suggesting an important inhibitory effect of MKRN3 peptide on GnRH secretion. To our knowledge, the frameshift variant identified in the MKRN3 gene in our cases has not previously been described. Identification of further mutations in MKRN3 causing CPP may help to elucidate the mechanism of action of this important regulator in pubertal initiation.