ESPEYB18 7. Puberty Clinical Guidance (7 abstracts)
7.2. Genotype-phenotype correlations in central precocious puberty caused by MKRN3 mutations
Seraphim CE , Canton APM , Montenegro L , Piovesan MR , Macedo DB , Cunha M , Guimaraes A , Ramos CO , Benedetti AFF , de Castro Leal A , Gagliardi PC , Antonini SR , Gryngarten M , Arcari AJ , Abreu AP , Kaiser UB , Soriano-Guillén L , Escribano- Muñoz A , Corripio R , Labarta JI , Travieso-Suárez L , Ortiz-Cabrera NV , Argente J , Mendonca BB , Brito VN & Latronico AC
J Clin Endocrinol Metab. 2021 Mar 25;106(4):1041–1050. 10.1210/clinem/dgaa955. PMID: 33383582. https://academic.oup.com/jcem/article-abstract/106/4/1041/6056669?redirectedFrom=fulltext
In brief: This paper describes the clinical and hormonal features of a large cohort of patients with central precocious puberty (CPP) caused by mutations in MKRN3. The authors found that phenotypic features of patients with MKRN3 mutations is similar to those with idiopathic CPP.
Comment: Inactivating mutations in MKRN3 were first identified in 2013 in families presenting with CPP (1). Later studies identified MKRN3, a maternally imprinted gene encoding the makorin RING-finger protein-3, as an essential inhibitory component of the gene network governing puberty (2-4). MKRN3 mutations that cause CPP include frameshift, stop gain and missense mutations affecting the coding or gene promoter region (5). MKRN3 mutation is currently the most common monogenic cause of familial CPP (5).
In this study, a multi-ethnic cohort of 716 patients with familial or idiopathic CPP was screened for MKRN3 mutations using Sanger sequencing and compared to 156 Brazilian girls with idiopathic CPP. Forty-five girls and 26 boys from 36 unrelated families presented loss-of-function mutations. Among the patients with MKRN3 mutations, first pubertal signs occurred at 6.2±1.2 years in girls and 7.1±1.5 years in boys, and bone age advancement was 2.0±1.6 and 1.8±1.3 years, respectively. Basal LH levels were 1.9±1.8 IU/l in girls and 1.6±1.2 IU/l in boys. The patients with severe mutations (frameshift mutations, stop gain variants or promoter region deletions) had greater bone age advancement and higher basal LH levels than patients with missense mutations. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation than girls with idiopathic CPP, independently of family history.
Overall, this study suggests that the phenotypic presentation of patients with MKRN3 mutations is similar to those with idiopathic CPP. They present a shorter time between pubertal onset and first evaluation, as well as higher FSH levels. Severe mutations (as predicted by in silico analysis) lead to greater bone age advancement and higher basal LH levels.
Reference: 1. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T, Kochi C, Longui CA, Beckers D, de Zegher F, Montenegro LR, Mendonca BB, Carroll RS, Hirschhorn JN, Latronico AC, Kaiser UB. (2013) Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med 368:2467–2475.2. Liu H, Kong X, Chen F. (2017) Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation. Oncotarget 8:85102–851093. Maione L, Naulé L, Kaiser UB. (2020) Makorin RING finger protein 3 and central precocious puberty. Curr Opin Endocr Metab Res. 14:152–159.4. Abreu AP, Toro CA, Song YB, Navarro VM, Bosch MA, Eren A, Liang JN, Carroll RS, Latronico AC, Rønnekleiv OK, Aylwin CF, Lomniczi A, Ojeda S, Kaiser UB. (2020) MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons. J Clin Invest. 3;130(8):4486–45005. Valadares LP, Meireles CG, De Toledo IP, Santarem de Oliveira R, Gonçalves de Castro LC, Abreu AP, Carroll RS, Latronico AC, Kaiser UB, Guerra ENS, Lofrano- Porto A. (2019) MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis. J Endocr Soc. 25;3(5):979–995
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ESPE Yearbook of Paediatric Endocrinology
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