Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.
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Seraphim Carlos Eduardo, Canton Ana Pinheiro Machado, Montenegro Luciana, Piovesan Maiara Ribeiro, Macedo Delanie B, Cunha Marina, Guimaraes Aline, Ramos Carolina Oliveira, Benedetti Anna Flavia Figueiredo, de Castro Leal Andrea, Gagliardi Priscila C, Antonini Sonir R, Gryngarten Mirta, Arcari Andrea J, Abreu Ana Paula, Kaiser Ursula B, Soriano-Guillén Leandro, Escribano-Muñoz Arancha, Corripio Raquel, Labarta José I, Travieso-Suárez Lourdes, Ortiz-Cabrera Nelmar Valentina, Argente Jesús, Mendonca Berenice B, Brito Vinicius N, Latronico Ana Claudia
Аннотация
OBJECTIVE: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects.
METHODS: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group.
RESULTS: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization.
CONCLUSION: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.