OR41-4 Idiopathic Central Precocious Puberty in Boys: Clinical, Hormonal and Genetic Findings

Program: Abstracts - Orals, Poster Previews, and Posters
Session: OR41-Pediatric Endocrinology
Sunday, March 8, 2015: 9:30 AM-11:00 AM
Presentation Start Time: 10:15 AM
Room 33 (San Diego Convention Center)
Danielle de Souza Bessa1, Delanie B. Macedo1, Ana Paula Abreu2, Andrew Dauber, MD3, Leticia Gontijo Silveira1, Francis de Zegher4, Priscila C. Gagliardi5, Korcan Demir6, Carlos Alberto Longhi7, Carla Rosenberg8, Ana Cristina Victorino Krepischi8, Berenice B Mendonca9, Vinicius N. Brito1, Sonir Roberto Antonini10, Ursula B Kaiser, MD, PHD2 and Ana Claudia Latronico, MD, PhD1
1Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 2Brigham and Women's Hospital/Harvard Med School, Boston, MA, 3Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 4University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium, 5Nemours Children's Clinic, Jacksonville, FL, 6Children's Hospital, Gaziantep, Turkey, 7Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, Brazil, 8Instituto de Biociências da Universidade de São Paulo, São Paulo, Brazil, 9Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, LIM 42, Hospital das Clínicas, Faculdade de Medicina, São Paulo University, São Paulo, Brazil, São Paulo, Brazil, 10Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
Background: Central precocious puberty (CPP) in boys is defined by the development of secondary sexual characteristics before the age of 9 years due to early activation of the hypothalamic–pituitary–gonadal axis. Notably, the idiopathic form of CPP is a rare condition in boys. Recently, the importance of genetic factors was demonstrated in the etiology of CPP in both sexes. Objective: To review the clinical, hormonal and genetic findings in boys with idiopathic CPP. Patients and methods: We studied 14 boys with idiopathic CPP from different origins (Brazil, Turkey, USA and Belgium). Clinical and hormonal data were obtained from all patients. Central nervous system magnetic resonance imaging was normal in all of them. All cases were previously screened for MKRN3 and KISS1 mutations. Whole exome sequencing was performed in 8 patients, including 2 brothers. In addition, comparative genomic hybridization array (CGH array) was performed in 3 boys with CPP. Results: The median age of pubertal onset was 6.5 years (range 0.9 - 9.0 years), but the first signs of puberty are notably more difficult to determine in boys than in girls. Five patients had family history of premature sexual development. At the first evaluation (median 8.7 years), the patients had genital Tanner stage 2-4 at physical examination and median bone age advancement of 1.9 years. All 14 boys had pubertal levels of basal LH (median 1.6 IU/L, range 0.7 - 6.7 IU/L) and testosterone (median 92 ng/dL, range 19 - 548 ng/dL). Loss-of-function MKRN3 mutations were identified in all 5 familial cases, including 2 frameshift mutations (p.Arg213Glyfs*73, p.Ala162Glyfs*14) and 1 missense mutation (p.Arg365Ser). The boys with MKRN3 defects presented with signs of puberty from 5.9 to 8.5 years. One sporadic case, with very early pubertal onset (1.0 year), had a KISS1 missense mutation (p.Pro74Ser). The CGH-array performed in 3 Turkish boys with sexual development before 5 years showed no abnormalities. Conclusion: Loss-of-function mutations in MKRN3 gene represent a prevalent cause of CPP in boys without hypothalamic lesions, particularly in familial cases. A detailed family history is critical for the diagnosis in boys with apparently idiopathic CPP.

Nothing to Disclose: DDSB, DBM, APA, AD, LGS, FD, PCG, KD, CAL, CR, ACVK, BBM, VNB, SRA, UBK, ACL

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