VINICIUS NAHIME DE BRITO
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
7 resultados
Resultados de Busca
Agora exibindo 1 - 7 de 7
- 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.
- The Congenital and Acquired Mechanisms Implicated in the Etiology of Central Precocious Puberty(2023) BRITO, Vinicius N.; CANTON, Ana P. M.; SERAPHIM, Carlos Eduardo; ABREU, Ana Paula; MACEDO, Delanie B.; MENDONCA, Berenice B.; KAISER, Ursula B.; ARGENTE, Jesus; LATRONICO, Ana ClaudiaThe etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.
- Clinical and Genetic Characterization of Familial Central Precocious Puberty(2023) TINANO, Flavia Rezende; CANTON, Ana Pinheiro Machado; MONTENEGRO, Luciana R.; LEAL, Andrea de Castro; FARIA, Aline G.; SERAPHIM, Carlos E.; BRAUNER, Raja; JORGE, Alexander A.; MENDONCA, Berenice B.; ARGENTE, Jesus; BRITO, Vinicius N.; LATRONICO, Ana ClaudiaContext Central precocious puberty (CPP) can have a familial form in approximately one-quarter of the children. The recognition of this inherited condition increased after the identification of autosomal dominant CPP with paternal transmission caused by mutations in the MKRN3 and DLK1 genes. Objective We aimed to characterize the inheritance and estimate the prevalence of familial CPP in a large multiethnic cohort; to compare clinical and hormonal features, as well as treatment response to GnRH analogs (GnRHa), in children with distinct modes of transmission; and to investigate the genetic basis of familial CPP. Methods We retrospectively studied 586 children with a diagnosis of CPP. Patients with familial CPP (n = 276) were selected for clinical and genetic analysis. Data from previous studies were grouped, encompassing sequencing of MKRN3 and DLK1 genes in 204 patients. Large-scale parallel sequencing was performed in 48 individuals from 34 families. Results The prevalence of familial CPP was estimated at 22%, with a similar frequency of maternal and paternal transmission. Pedigree analyses of families with maternal transmission suggested an autosomal dominant inheritance. Clinical and hormonal features, as well as treatment response to GnRHa, were similar among patients with different forms of transmission of familial CPP. MKRN3 loss-of-function mutations were the most prevalent cause of familial CPP, followed by DLK1 loss-of-function mutations, affecting, respectively, 22% and 4% of the studied families; both affected exclusively families with paternal transmission. Rare variants of uncertain significance were identified in CPP families with maternal transmission. Conclusion We demonstrated a similar prevalence of familial CPP with maternal and paternal transmission. MKRN3 and DLK1 loss-of-function mutations were the major causes of familial CPP with paternal transmission.
- Sexuality and fertility desire in a large cohort of individuals with 46, XY differences in sex development(2023) BATISTA, Rafael Loch; INACIO, Marlene; BRITO, Vinicius Nahime; SIRCILI, Maria Helena Palma; BAG, Min Jeong; GOMES, Nathalia Lisboa; COSTA, Elaine Maria Frade; DOMENICE, Sorahia; MENDONCA, Berenice BilharinhoObjective: To analyze aspects of sexual life and fertility desire among 46, XY DSD people, including those who changed their gender. Methods: It is a cross-sectional study including 127 adults (> 16 years of age) with 46, XY DSD (83 females; 44 males) from a Single Brazilian Tertiary-Care Medical Center. Results: Sexual fantasies and masturbation were more frequent in 46, XY DSD males, whereas orgasm and sexual life satisfaction were similar in both genders. More 46, XY DSD men than women had a long-term romantic relationship. 46, XY DSD women with prenatal androgen exposure reported more fear of being romantically rejected. External genitalia appearance at birth did not impact the sexuality of 46, XY DSD women after surgical genital treatment had been completed. Overall, the sexual life was similar between 46, XY men assigned as males and those who changed to the male gender. Regarding sexual orientation, most self-reported as heterosexual (91% and 92% of women and men, respectively). The desire for fertility had a similar prevalence in both genders, but more women than men considered infertility a barrier to a long-term romantic relationship. Twelve individuals (7 males) had children; 10 out of 12 have adopted children. Conclusion: Fertility desire was shared among 46, XY DSD people, regardless of gender. Prenatal androgen exposure reduced the desire for motherhood in 46, XY women. 46, XY DSD people who changed from female to male gender presented similar sexual parameters as those assigned as males. Among females, virilized genitalia at birth did not affect sexuality once the surgical treatment is completed.
- Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels(2023) MONTENEGRO, Luciana; SERAPHIM, Carlos; TINANO, Flavia; PIOVESAN, Maiara; CANTON, Ana P. M.; MCELREAVEY, Ken; BRABANT, Severine; BORIS, Natalia P.; MAGNUSON, Melissa; CARROLL, Rona S.; KAISER, Ursula B.; ARGENTE, Jesus; BARRIOS, Vicente; BRITO, Vinicius N.; BRAUNER, Raja; LATRONICO, Ana ClaudiaBackground: Several rare loss-of-function mutations of delta-like noncanonical notch ligand 1 (DLK1) have been described in non-syndromic children with familial central precocious puberty (CPP). Objective: We investigated genetic abnormalities of DLK1 gene in a French cohort of children with idiopathic CPP. Additionally, we explored the pattern of DLK1 serum levels in patients with CPP and in healthy children at puberty, as well as in wild-type female mice. Patients and Methods: Genomic DNA was obtained from 121 French index cases with CPP. Automated sequencing of the coding region of the DLK1 gene was performed in all cases. Serum DLK1 levels were measured by enzyme linked immunosorbent assay (ELISA) in 209 individuals, including 191 with normal pubertal development and in female mice during postnatal pubertal maturation. Results: We identified 2 rare pathogenic DLK1 allelic variants: A stop gain variant (c.372C>A; p.Cys124X) and a start loss variant (c.2T>G; p.Met1?, or p.0) in 2 French girls with CPP. Mean serum DLK1 levels were similar between healthy children and idiopathic CPP children. In healthy individuals, DLK1 levels correlated with pubertal stage: In girls, DLK1 decreased between Tanner stages III and V, whereas in boys, DLK1 decreased between Tanner stages II and V (P =.008 and.016, respectively). Serum levels of Dlk1 also decreased in wild-type female mice. Conclusions: Novel loss-of-function mutations in DLK1 gene were identified in 2 French girls with CPP. Additionally, we demonstrated a pattern of dynamic changes in circulating DLK1 serum levels in humans and mice during pubertal stages, reinforcing the role of this factor in pubertal timing.
- Arterial Stiffness in Transgender Men Receiving Long-term Testosterone Therapy(2023) CUNHA, Flavia Siqueira; BACHEGA, Tania Aparecida Sanchez; COSTA, Elaine Maria Frade; BRITO, Vinicius Nahime; ALVARES, Leonardo Azevedo; COSTA-HONG, Valeria Aparecida; VERARDINO, Renata Gomes Sanches; SIRCILI, Maria Helena Palma; MENDONCA, Berenice Bilharinho de; BORTOLOTTO, Luiz Aparecido; DOMENICE, SorahiaContext: The effects of androgen therapy on arterial function in transgender men (TM) are not fully understood, particularly concerning long-term androgen treatment. Objective: To evaluate arterial stiffness in TM receiving long-term gender-affirming hormone therapy by carotid-femoral pulse wave velocity (cf-PWV). Methods: A cross-sectional case-control study at the Gender Dysphoria Unit of the Division of Endocrinology, HC-FMUSP, Sao Paulo, Brazil. Thirty-three TM receiving intramuscular testosterone esters as regular treatment for an average time of 14 +/- 8 years were compared with 111 healthy cisgender men and women controls matched for age and body mass index. Aortic stiffness was evaluated by cf-PWV measurements using Complior device post-testosterone therapy. The main outcome measure was aortic stiffness by cf-PWV as a cardiovascular risk marker in TM and control group. Results: The cf-PWV after long-term testosterone therapy was significantly higher in TM (7.4 +/- 0.9 m/s; range 5.8-8.9 m/s) than in cisgender men (6.6 +/- 1.0 m/s; range 3.8-9.0 m/s, P <.01) and cisgender women controls (6.9 +/-.9 m/s; range 4.8-9.1 m/s, P =.02). The cf-PWV was significantly and positively correlated with age. Analysis using blood pressure as a covariate showed a significant relationship between TM systolic blood pressure (SBP) and cf-PWV in relation to cisgender women but not to cisgender men. Age, SBP, and diagnosis of hypertension were independently associated with cf-PWV in the TM group. Conclusion: The TM group on long-term treatment with testosterone had higher aging-related aortic stiffening than the control groups. These findings indicate that aortic stiffness might be accelerated in the TM group receiving gender-affirming hormone treatment, and suggest a potential deleterious effect of testosterone on arterial function. Preventive measures in TM individuals receiving testosterone treatment, who are at higher risk for cardiovascular events, are highly recommended.
- Rare variants in the MECP2 gene in girls with central precocious puberty: a translational cohort study(2023) CANTON, Ana P. M.; TINANO, Flavia R.; GUASTI, Leonardo; MONTENEGRO, Luciana R.; RYAN, Fiona; SHEARS, Deborah; MELO, Maria Edna de; GOMES, Larissa G.; PIANA, Mariana P.; BRAUNER, Raja; ESPINO-AGUILAR, Rafael; ESCRIBANO-MUNOZ, Arancha; PAGANONI, Alyssa; READ, Jordan E.; KORBONITS, Marta; SERAPHIM, Carlos E.; COSTA, Silvia S.; KREPISCHI, Ana Cristina; JORGE, Alexander A. L.; DAVID, Alessia; KAISINGER, Lena R.; ONG, Ken K.; PERRY, John R. B.; ABREU, Ana Paula; KAISER, Ursula B.; ARGENTE, Jesus; MENDONCA, Berenice B.; BRITO, Vinicius N.; HOWARD, Sasha R.; LATRONICO, Ana ClaudiaBackground Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype. Methods In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation. Findings Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3 & PRIME;UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice. Interpretation We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process.