title: High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic.
abstract: OBJECTIVE
  Recently, loss-of-function mutations in the MKRN3 gene have been implicated in the etiology of familial central precocious puberty (CPP) in both sexes. We aimed to analyze the frequency of MKRN3 mutations in boys with CPP and to compare the clinical and hormonal features of boys with and without MKRN3 mutations.
  
  
  METHODS
  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 MKRN3, KISS1 and KISS1R genes were sequenced.
  
  
  RESULTS
  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 distinct 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 MKRN3 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 MKRN3 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).
  
  
  CONCLUSIONS
  We demonstrated a high frequency of MKRN3 mutations in boys with CPP, previously classified as idiopathic, suggesting the importance of genetic analysis in this group. The boys with CPP due to MKRN3 mutations had classical features of CPP, but with puberty initiation at a borderline age.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Bessa
authors.forename: Delanie B
authors.initials: DB
authors.lastname: Macedo
authors.forename: Vinicius N
authors.initials: VN
authors.lastname: Brito
authors.forename: Monica M
authors.initials: MM
authors.lastname: França
authors.forename: Luciana R
authors.initials: LR
authors.lastname: Montenegro
authors.forename: Marina
authors.initials: M
authors.lastname: Cunha-Silva
authors.forename: Leticia G
authors.initials: LG
authors.lastname: Silveira
authors.forename: Tiago
authors.initials: T
authors.lastname: Hummel
authors.forename: Ignacio
authors.initials: I
authors.lastname: Bergadá
authors.forename: Debora
authors.initials: D
authors.lastname: Braslavsky
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Abreu
authors.forename: Andrew
authors.initials: A
authors.lastname: Dauber
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007223:Infant; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009154:Mutation / Q000235:genetics*; D011629:Puberty, Precocious / Q000097:blood / Q000235:genetics*; D012189:Retrospective Studies; D012261:Ribonucleoproteins / Q000235:genetics*; D012727:Sex Characteristics; D018709:Statistics, Nonparametric; D013739:Testosterone / Q000097:blood; D044767:Ubiquitin-Protein Ligases
chemical_list: D012261:Ribonucleoproteins; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C119425:MKRN3 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Genetics; Gonadotropin-releasing hormone; MKRN3 gene; Male precocious puberty