Carlos Eduardo Seraphim1, Ana Pinheiro Machado Canton1, Luciana Montenegro1, Maiara Ribeiro Piovesan1, Delanie B Macedo2, Marina Cunha1, Aline Guimaraes1, Carolina Oliveira Ramos1, Anna Flavia Figueiredo Benedetti1, Andrea de Castro Leal3, Priscila C Gagliardi4, Sonir R Antonini5, Mirta Gryngarten6, Andrea J Arcari6, Ana Paula Abreu2, Ursula B Kaiser2, Leandro Soriano-Guillén7, Arancha Escribano-Muñoz8, Raquel Corripio9, José I Labarta10, Lourdes Travieso-Suárez11, Nelmar Valentina Ortiz-Cabrera11, Jesús Argente11, Berenice B Mendonca1, Vinicius N Brito1, Ana Claudia Latronico1. 1. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. 2. Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 3. Departamento de Saúde Integrada da Universidade do Estado do Pará (UEPA), Santarém, Pará, Brazil. 4. Division of Endocrinology, Diabetes, and Metabolism, Nemours Children's Clinic, Jacksonville, FL, USA. 5. Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Brazil. 6. Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (Consejo Nacional de Investigaciones Científicas y Técnicas - FEI - División de Endocrinología, Hospital de Niños Ricardo Gutiérrez), Buenos Aires, Argentina. 7. Department of Pediatrics, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish PUBERE Registry, Madrid, Spain. 8. Endocrinology Unit, Department of Pediatrics, University Hospital Virgen of Arrixaca, Spanish PUBERE Registry, Murcia, Spain. 9. Pediatric Endocrinology Department, Corporació Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí I3PT. Universitat Autònoma de Barcelona. Spanish PUBERE Registry, Sabadell, Spain. 10. Pediatric Endocrinology Unit, Department of Pediatrics, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria de Aragón, Spanish PUBERE Registry, Zaragoza, Spain. 11. Hospital Infantil Universitario Niño Jesús, Department of Endocrinology and Department of Pediatrics, Universidad Autónoma de Madrid, Spanish PUBERE Registry, CIBER of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III, IMDEA Institute, Madrid, Spain.
Abstract
CONTEXT: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). 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.
CONTEXT: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). 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.
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