ANA PINHEIRO MACHADO CANTON
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Outcomes of Patients with Central Precocious Puberty Due to Loss-of-Function Mutations in theMKRN3Gene after Treatment with Gonadotropin-Releasing Hormone Analog(2020) RAMOS, Carolina de Oliveira; MACEDO, Delanie B.; CANTON, Ana Pinheiro M.; CUNHA-SILVA, Marina; ANTONINI, Sonir R. R.; STECCHINI, Monica Freire; SERAPHIM, Carlos Eduardo; RODRIGUES, Tania; MENDONCA, Berenice Bilharinho; LATRONICO, Ana Claudia; BRITO, Vinicius NahimeIntroduction:Loss-of-function mutation ofMKRN3represents the most frequent genetic cause of familial central precocious puberty (CPP). The outcomes of gonadotropin-releasing hormone analog (GnRHa) treatment in CPP patients withMKRN3defects are unknown.Objective:To describe the clinical and hormonal features of patients with CPP with or withoutMKRN3mutations after GnRHa treatment. Anthropometric, metabolic and reproductive parameters were evaluated.Patients and Methods:Twenty-nine female patients with CPP due to loss-of-function mutations in theMKRN3and 43 female patients with idiopathic CPP were included. Their medical records were retrospectively evaluated for clinical, laboratory, and imaging study, before, during, and after GnRHa treatment. All patients with idiopathic CPP and 11 patients with CPP due toMKRN3defects reached final height (FH).Results:At the diagnosis, there were no significant differences between clinical and laboratory features of patients with CPP with or withoutMKRN3mutations. A high prevalence of overweight and obesity was observed in patients with CPP with or withoutMKRN3mutations (47.3 and 50%, respectively), followed by a significant reduction after GnRHa treatment. No significant differences in the values of mean FH and target height were found between the 2 CPP groups after GnRHa treatment. Menarche occurred at the expected age in patients with or without CPP due toMKRN3mutations (11.5 +/- 1.3 and 12 +/- 0.6 years, respectively). The prevalence of polycystic ovarian syndrome was 9.1% in patients with CPP due toMKRN3mutations and 5.9% in those with idiopathic CPP.Conclusion:Anthropometric, metabolic, and reproductive outcomes after GnRHa treatment were comparable in CPP patients, with or withoutMKRN3mutations, suggesting the absence of deleterious effects ofMKRN3defects in young female adults' life.
- Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study(2020) MONTENEGRO, Luciana; I, Jose Labarta; PIOVESAN, Maira; CANTON, Ana P. M.; CORRIPIO, Raquel; SORIANO-GUILLEN, Leandro; TRAVIESO-SUAREZ, Lourdes; MARTIN-RIVADA, Alvaro; BARRIOS, Vicente; SERAPHIM, Carlos E.; BRITO, Vinicius N.; LATRONICO, Ana Claudia; ARGENTE, JesusBackground: Central precocious puberty (CPP) has been associated with loss-of-function mutations in 2 paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood. Objective: Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations. Patients: A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic deoxyribonucleic acid was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed. Results: Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401_404 + 8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (<0.4 ng/mL), indicating that the deletion led to complete lack of DLK1 production. Three others rare allelic variants of DLK1 were also identified (p.Asn134=; g.-222 C>A and g.-223 G>A) in 2 girls with CPP. However, both had normal DLK1 serum levels. Conclusion: Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing.