Precocious puberty syndrome

Precocious puberty

Puberty is a complex biological process involving sexual maturation and accelerated growth. These processes normally initiate when pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus begins. Early activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-dependent precocious puberty (also known as central precocious puberty, CPP; development of secondary characteristics before the age of 8 year in girls and 9 years in boys). With the advent of advanced sequencing methods, exome-sequencing of familial cases of CPP have identified genetic defects in transcripts with no previous link to hypothalamic-pituitary-gonadal regulation. Loss-of-function mutations in the Makorin ring finger 3 (MKRN3) were initially identified in CPP families [1-4]. Consistent with the genes imprinting status the phenotype was only present upon paternal transmission of the mutation. Subsequently, mutations in MKRN3 have been shown to be the most frequent cause of familial CPP and they have also been detected in nearly 4% in a cohort of 215 non-familial idiopathic CCP [5]. The MKRN3 gene (also known as ZNF127) is an intronless transcript located on chromosome 15q11.2 in the PWS critical region, encoding for a protein with C3H zinc-finger and RING zinc-finger motifs. Unlike other imprinting disorders that can result from multiple mechanisms, it is currently unknown if CCP can arise from loss of MKRN3 expression due to deletion, segmental maternal uniparental disomy or an imprinting defect.


[1] Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med 2013, 368:2467-75.

[2] de Vries L, Gat-Yablonski G, Dror N, Singer A, Phillip M. A novel MKRN3 missense mutation causing familial precocious puberty. Hum Reprod 2014, 29:2838-43.

[3] Schreiner F, Gohlke B, Hamm M, Korsch E, Woelfle J. MKRN3 mutations in familial central precocious puberty. Horm Res Paediatr 2014, 82:122-6.

[4] Settas N, Dacou-Voutetakis C, Karantza M, Kanaka-Gantenbein C, Chrousos GP, Voutetakis A. Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene. J Clin Endocrinol Metab 2014, 99:E647-51.

[5] Macedo DB, Abreu AP, Reis AC, Montenegro LR, Dauber A, Beneduzzi D. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab 2014, 99:E1097-103