High Frequency of <b><i>MKRN3</i></b> Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic

Abstract

<b><i>Background/Aims:</i></b> Recently, loss-of-function mutations in the <i>MKRN3</i> gene have been implicated in the etiology of familial central precocious puberty (CPP) in both sexes. We aimed to analyze the frequency of <i>MKRN3</i> mutations in boys with CPP and to compare the clinical and hormonal features of boys with and without <i>MKRN3</i> mutations. <b><i>Methods:</i></b> This was a retrospective review of clinical, hormonal and genetic features of 20 male patients with idiopathic CPP evaluated at an academic medical center. The entire coding regions of <i>MKRN3</i>, <i>KISS1 </i>and<i> KISS1R</i> genes were sequenced. <b><i>Results:</i></b> We studied 20 boys from 17 families with CPP. All of them had normal brain magnetic resonance imaging. Eight boys from 5 families harbored four<b> </b>distinct<b> </b>heterozygous MKRN3 mutations predicted to be deleterious for protein function, p.Ala162Glyfs*14, p.Arg213Glyfs*73, p.Arg328Cys and p.Arg365Ser. One boy carried a previously described KISS1-activating mutation (p.Pro74Ser). The frequency of <i>MKRN3</i> mutations among these boys with idiopathic CPP was significantly higher than previously reported female data (40 vs. 6.4%, respectively, p < 0.001). Boys with <i>MKRN3</i> mutations had typical clinical and hormonal features of CPP. Notably, they had later pubertal onset than boys without MKRN3 abnormalities (median age 8.2 vs. 7.0 years, respectively, p = 0.033). <b><i>Conclusion:</i></b> We demonstrated a high frequency of <i>MKRN3</i> mutations in boys with CPP, previously classified as idiopathic, suggesting the importance of genetic analysis in this group. The boys with CPP due to <i>MKRN3</i> mutations had classical features of CPP, but with puberty initiation at a borderline age.