VINICIUS NAHIME DE BRITO
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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- DLK1 Is a Novel Link Between Reproduction and Metabolism(2019) GAMES, Larissa G.; CUNHA-SILVA, Marina; CRESPO, Raiane P.; RAMOS, Carolina O.; MONTENEGRO, Luciana R.; CANTON, Ana; LEES, Melissa; SPOUDEAS, Helen; DAUBER, Andrew; MACEDO, Delanie B.; BESSA, Danielle S.; MACIEL, Gustavo A.; BARACAT, Edmund C.; JORGE, Alexander A. L.; MENDONCA, Berenice B.; BRITO, Vinicius N.; LATRONICO, Ana ClaudiaBackground: Delta-like homolog 1 (DLK1), also called preadipocyte factor 1, prevents adipocyte differentiation and has been considered a molecular gatekeeper of adipogenesis. A DLK1 complex genomic defect was identified in five women from a single family with central precocious puberty (CPP) and increased body fat percentage. Methods: We studied 60 female patients with a diagnosis of CPP or history of precocious menarche. Thirty-one of them reported a family history of precocious puberty. DLK1 DNA sequencing was performed in all patients. Serum DLK1 concentrations were measured using an ELISA assay in selected cases. Metabolic and reproductive profiles of adult women with CPP caused by DLK1 defects were compared with those of 20 women with idiopathic CPP. Results: We identified three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Va1271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1. Serum DLK1 concentrations were undetectable in three affected women. Metabolic abnormalities, such as overweight/obesity, early-onset glucose intolerance/type 2 diabetes mellitus, and hyperlipidemia, were more prevalent in women with the DLK1 mutation than in the idiopathic CPP group. Notably, the human metabolic alterations were similar to the previously described dlk1-null mice phenotype. Two sisters who carried the p.Gly199Alafs*11 mutation also exhibited polycystic ovary syndrome and infertility. Conclusions: Loss-of-function mutations of DLK1 are a definitive cause of familial CPP. The high prevalence of metabolic alterations in adult women who experienced CPP due to DLK1 defects suggests that this antiadipogenic factor represents a link between reproduction and metabolism.
- Pioneering studies on monogenic central precocious puberty(2019) CANTON, Ana Pinheiro Machado; SERAPHIM, Carlos Eduardo; BRITO, Vinicius Nahime; LATRONICO, Ana ClaudiaPubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism.
- Premature Pubarche due to Exogenous Testosterone Gel or Intense Diaper Rash Prevention Cream Use: A Case Series(2019) RAMOS, Carolina de Oliveira; MACEDO, Delanie Bulcao; BACHEGA, Tania Aparecida Sartori Sanchez; NASCIMENTO, Marilza Leal; MADUREIRA, Guiomar; LATRONICO, Ana Claudia; BRITO, Vinicius Nahime; MENDONCA, Berenice Bilharinho deBackground/Aims: Premature pubarche is associated with conditions such as virilizing congenital adrenal hyperplasia, androgen-secreting tumors, and exogenous exposure to androgen products. We describe the clinical and hormonal features of a series of children who were referred to endocrine evaluation due to premature pubarche. Methods: This is a retrospective case series study of 14 children with premature pubarche and/or virilization. Five were unintentionally exposed to testosterone gel (parental use). Nine patients were intensely exposed to diaper rash prevention creams. Clinical and laboratory data were revised. Results: Moderate to severe virilization was detected in the 5 patients (2 boys and 3 girls) who were exposed to testosterone gel. These patients had pubic hair development associated with clitoromegaly (3/3), penile enlargement (2/2), and accelerated growth (5/5). Testosterone levels were elevated in 4/5 patients associated with normal prepubertal gonadotropin levels and adrenal androgen precursors. The 9 children who were intensely exposed to diaper rash prevention creams had mild pubarche (intermediate hair) without any other clinical manifestation of pubertal development. Three of them exhibited pubic hair thinning after cream withdrawal. Conclusion: Unintentional topical androgen exposure or the intense use of diaper rash prevention cream should be ruled out in children with precocious pubarche and/or virilization signs to avoid misdiagnosis and expendable investigation.
conferenceObject Investigation of imprinting alterations in MKRN3 and DLK1 in a cohort of girls with central precocious puberty through specific DNA methylation analysis(2019) CANTON, Ana; STEUNOU, Virginie; BRITO, Vinicius; SOBRIER, Marie Laure; MONTENEGRO, Luciana; BESSA, Danielle; MENDONCA, Berenice B.; NETCHINE, Irene; LATRONICO, Ana Claudia