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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- Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations (vol 106, pg 1041, 2021)(2021) SERAPHIM, C. E.; CANTON, A. P. M.; MONTENEGRO, L.; PIOVESAN, M. R.; MACEDO, D. B.; CUNHA, M.; GUIMARAES, A.; RAMOS, C. O.; BENEDETTI, A. F. F.; LEAL, De Castro A.; GAGLIARDI, P. C.; ANTONINI, S. R.; GRYNGARTEN, M.; ARCARI, A. J.; ABREU, A. P.; KAISER, U. B.; SORIANO-GUILLEN, L.; ESCRIBANO-MUNOZ, A.; CORRIPIO, R.; I, J. Labarta; TRAVIESO-SUAREZ, L.; V, N. Ortiz-Cabrera; ARGENTE, J.; MENDONCA, B. B.; BRITO, V. N.; LATRONICO, A. C.
- Brain MRI in Girls With Central Precocious Puberty: A Time for New Approaches Comment(2021) CANTON, Ana Pinheiro Machado; LATRONICO, Ana Claudia
- Anthropometric, metabolic, and reproductive outcomes of patients with central precocious puberty treated with leuprorelin acetate 3-month depot (11.25 mg)(2021) RAMOS, Carolina O.; CANTON, Ana P. M.; SERAPHIM, Carlos Eduardo; FARIA, Aline Guimaraes; TINANO, Flavia Rezende; MENDONCA, Berenice B.; LATRONICO, Ana C.; BRITO, Vinicius N.Objectives: Longer-acting gonadotropin-releasing hormone analogs (GnRHa) have been widely used for central precocious puberty (CPP) treatment. However, the followup of patients after this treatment are still scarce. Our aim was to describe anthropometric, metabolic, and reproductive follow-up of CPP patients after treatment with leuprorelin acetate 3-month depot (11.25 mg). Methods: Twenty-two female patients with idiopathic CPP were treated with leuprorelin acetate 3-month depot (11.25 mg). Their medical records were retrospectively evaluated regarding clinical, hormonal, and imaging aspects before, during, and after GnRHa treatment until adult height (AH). Results: At the diagnosis of CPP, the mean chronological age (CA) was 8.2 +/- 1.13 year, and mean bone age (BA) was 10.4 +/- 1.4 year. Mean height SDS at the start and the end of GnRHa treatment was 1.6 +/- 0.8 and 1.3 +/- 0.9, respectively. The mean duration of GnRHa treatment was 2.8 +/- 0.8 year. Mean predicted adult heights (PAH) at the start and the end of GnRH treatment was 153.2 +/- 8.6 and 164.4 +/- 7.3 cm, respectively (p<0.05). The mean AH was 163.2 +/- 6.2 cm (mean SDS: 0.1 +/- 1). All patients were within their target height (TH) range. There was a decrease in the percentage of overweight and obesity from the diagnosis until AH (39-19% p>0.05). At the AH, the insulin resistance and high LDL levels were identified in 3/17 patients (17.6%) and 2/21 patients (9.5%), respectively. The mean CA of menarche was 12.2 +/- 0.5 years. At the AH, PCOS was diagnosed in one patient (4.8%). Conclusions: Long-term anthropometric, metabolic, and reproductive follow-up of patients with CPP treated with longer-acting GnRHa revealed effectivity, safety, and favorable outcomes.
- Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations(2021) 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; LEAL, Andrea de Castro; GAGLIARDI, Priscila C.; ANTONINI, Sonir R.; GRYNGARTEN, Mirta; ARCARI, Andrea J.; ABREU, Ana Paula; KAISER, Ursula B.; SORIANO-GUILLEN, Leandro; ESCRIBANO-MUNOZ, Arancha; CORRIPIO, Raquel; I, Jose Labarta; TRAVIESO-SUAREZ, Lourdes; ORTIZ-CABRERA, Nelmar Valentina; ARGENTE, Jesus; MENDONCA, Berenice B.; BRITO, Vinicius N.; LATRONICO, Ana ClaudiaContext: 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.
- Insights from the genetic characterization of central precocious puberty associated with multiple anomalies(2021) CANTON, Ana Pinheiro Machado; KREPISCHI, Ana Cristina Victorino; MONTENEGRO, Luciana Ribeiro; COSTA, Silvia; ROSENBERG, Carla; STEUNOU, Virginie; SOBRIER, Marie-Laure; SANTANA, Lucas; HONJO, Rachel Sayuri; KIM, Chong Ae; ZEGHER, Francis de; IDKOWIAK, Jan; GILLIGAN, Lorna C.; ARLT, Wiebke; FUNARI, Mariana Ferreira de Assis; JORGE, Alexander Augusto de Lima; MENDONCA, Berenice Bilharinho; NETCHINE, Irene; BRITO, Vinicius Nahime; LATRONICO, Ana ClaudiaSTUDY QUESTION: Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control? SUMMARY ANSWER: In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely pathogenic (epi)genetic defects were identified in 12 (33%) patients, providing insights into the genetics of human pubertal control. WHAT IS KNOWN ALREADY: A few studies have described patients with CPP associated with multiple anomalies, but without making inferences on causalities of CPP. Genetic-molecular studies of syndromic cases may reveal disease genes or mechanisms, as the presentation of such patients likely indicates a genetic disorder. STUDY DESIGN, SIZE, DURATION: This translational study was based on a genetic-molecular analysis, including genome-wide high throughput methodologies, for searching structural or sequence variants implicated in CPP and DNA methylation analysis of candidate regions. PARTICIPANTS/MATERIALS, SETTING, METHODS: A cohort of 197 patients (188 girls) with CPP without structural brain lesions was submitted to a detailed clinical evaluation, allowing the selection of 36 unrelated patients (32 girls) with CPP associated with multiple anomalies. Pathogenic allelic variants of genes known to cause monogenic CPP (KISS1R, KISS1, MKRN3 and DLK1) had been excluded in the entire cohort (197 patients). All selected patients with CPP associated with multiple anomalies (n = 36) underwent methylation analysis of candidate regions and chromosomal microarray analysis. A subset (n = 9) underwent whole-exome sequencing, due to presenting familial CPP and/or severe congenital malformations and neurocognitive abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 36 selected patients with CPP, the more prevalent associated anomalies were metabolic, growth and neurocognitive conditions. In 12 (33%) of them, rare genetic abnormalities were identified: six patients presented genetic defects in loci known to be involved with CPP (14q32.2 and 7q11.23), whereas the other six presented defects in candidate genes or regions. In detail, three patients presented hypomethylation of DLK1/MEG3:IG-DMR (14q32.2 disruption or Temple syndrome), resulting from epimutation (n = 1) or maternal uniparental disomy of chromosome 14 (n = 2). Seven patients presented pathogenic copy number variants: three with de novo 7q11.23 deletions (Williams-Beuren syndrome), three with inherited Xp22.33 deletions, and one with de novo 1p31.3 duplication. Exome sequencing revealed potential pathogenic variants in two patients: a sporadic female case with frameshift variants in TNRC6B and AREL1 and a familial male case with a missense substitution in UGT2B4 and a frameshift deletion in MKKS. LIMITATIONS, REASONS FOR CAUTION: The selection of patients was based on a retrospective clinical characterization, lacking a longitudinal inclusion of consecutive patients. In addition, future studies are needed, showing the long-term (mainly reproductive) outcomes in the included patients, as most of them are not in adult life yet. WIDER IMPLICATIONS OF THE FINDINGS: The results highlighted the relevance of an integrative clinical-genetic approach in the elucidation of mechanisms and factors involved in pubertal control. Chromosome 14q32.2 disruption indicated the loss of imprinting of DLK1 as a probable mechanism of CPP. Two other chromosomal regions (7q11.23 and Xp22.33) represented new candidate loci potentially involved in this disorder of pubertal timing.