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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- The benign spectrum of hypothalamic hamartomas: Infrequent epilepsy and normal cognition in patients presenting with central precocious puberty(2013) CUKIER, Priscilla; CASTRO, Luiz Henrique Martins; BANASKIWITZ, Natalie; TELES, Leandro Roberto; FERREIRA, Luiz Roberto Kobuti; ADDA, Carla Cristina; LEITE, Claudia da Costa; ARNHOLD, Ivo J. P.; MENDONCA, Berenice Bilharinho; LATRONICO, Ana Claudia; BRITO, Vinicius NahimePurpose: Hypothalamic hamartoma (HH) is the main structural cause of central precocious puberty (CPP). HH is frequently associated with cognitive impairment and epileptic encephalopathies. Disease severity in case series from neurology services may be biased towards more neurologically impaired patients. Aim: To perform a prospective cognitive evaluation in patients with HH presenting with CPP in an endocrinology outpatient clinic setting. Methods: We evaluated fifteen consecutive patients with CPP due to HH presenting to an endocrinology outpatient clinic. CPP was diagnosed at a median age of 0.7 yr (0.4-7 yr). Mean age at neurologic evaluation was 13.9 yrs. Eight patients (53.3%) were male. Epileptic seizures occurred in 5/15 (33%) patients. Two patients presented a single unprovoked seizure (SUS). Three patients were diagnosed with epilepsy. Cognitive evaluation, using age-appropriate Wechsler Intelligence Scale, was performed in 11 patients. Results: All patients without epilepsy, including two patients with a history of a SUS, had normal neurologic and cognitive evaluation. Epilepsy and SUS were only seen in patients with sessile HH. Three patients with epilepsy presented cognitive or behavioral findings. Reduced intelligence quotients (IQ), in the borderline range, were noted in both patients with epilepsy who underwent full cognitive evaluation. We found no significant correlation between HH diameter or shape and mean full-scale IQ. Conclusions: Patients who presented with isolated CPP without epilepsy displayed normal cognition when evaluated after a mean period of 13 years. Occurrence of epilepsy, seen in a minority of patients, but not of a single seizure, was associated with mild cognitive deficit and behavioral disturbances in this case series.
- Molecular and Gene Network Analysis of Thyroid Transcription Factor 1 (TTF1) and Enhanced at Puberty (EAP1) Genes in Patients with GnRH-Dependent Pubertal Disorders(2013) CUKIER, Priscilla; WRIGHT, Hollis; RULFS, Tomke; SILVEIRA, Leticia Ferreira Gontijo; TELES, Milena Gurgel; MENDONCA, Berenice Bilharinho; ARNHOLD, Ivo J. P.; HEGER, Sabine; LATRONICO, Ana Claudia; OJEDA, Sergio R.; BRITO, Vinicius NahimeBackground/Aim: TTF1 and EAP1 are transcription factors that modulate gonadotropin-releasing hormone expression. We investigated the contribution of TTF1 and EAP1 genes to central pubertal disorders. Patients and Methods: 133 patients with central pubertal disorders were studied: 86 with central precocious puberty and 47 with normosmic isolated hypogonadotropic hypogonadism. The coding region of TTF1 and EAP1 were sequenced. Variations of polyglutamine and polyalanine repeats in EAP1 were analyzed by GeneScan software. Association of TTF1 and EAP1 to genes implicated in timing of puberty was investigated by meta-network framework GeneMANIA and Cytoscape software. Results: Direct sequencing of the TTF1 did not reveal any mutation or polymorphisms. Four EAP1 synonymous variants were identified with similar frequencies among groups. The most common EAP1 5'-distal polyalanine genotype was the homozygous 12/12, but the genotype 12/9 was identified in 2 central precocious puberty sisters without functional alteration in EAP1 transcriptional activity. TTF1 and EAP1 were connected, via genetic networks, to genes implicated in the control of menarche. Conclusion: No TTF1 or EAP1 germline mutations were associated with central pubertal disorders. TTF1 and EAP1 may affect puberty by changing expression in response to other members of puberty-associated gene networks, or by differentially affecting the expression of gene components of these networks. (C) 2013 S. Karger AG, Basel
- Long-Term Outcomes of Patients with Central Precocious Puberty due to Hypothalamic Hamartoma after GnRHa Treatment: Anthropometric, Metabolic, and Reproductive Aspects(2018) RAMOS, Carolina O.; LATRONICO, Ana C.; CUKIER, Priscilla; MACEDO, Delanie B.; BESSA, Danielle S.; CUNHA-SILVA, Marina; ARNHOLD, Ivo J.; MENDONCA, Berenice B.; BRITO, Vinicius N.Background: Hypothalamic hamartoma (HH) represents the commonest cause of organic central precocious puberty (CPP). Follow-up of these patients in adulthood is scarce. Objective: To describe the anthropometric, metabolic, and reproductive parameters of patients with CPP due to HH before and after treatment with gonadotropin-releasing hormone analog (GnRHa). Methods: We performed a retrospective and cross-sectional study in a single tertiary center including 14 patients (7 females) with CPP due to HH. Results: The mean duration of GnRHa treatment was 7.7 +/- 2.4 years in boys and 7.9 +/- 2.1 years in girls. GnRHa treatment was interrupted at the mean chronological age (CA) of 12.1 +/- 1.1 years in boys and 10.7 +/- 0.5 years in girls. At the last visit, the mean CA of the male and female patients was 21.5 +/- 3.2 and 24 +/- 3.9 years, respectively. Eleven of the 14 patients reached normal final height (FH) (standard deviation score -0.6 +/- 0.9 for males and -0.6 +/- 0.5 for females), all of them within the target height (TH) range. The remaining 3 patients had predicted height within the TH range. The mean body mass index and the percentage of body fat mass was significantly higher in females, with a higher prevalence of metabolic disorders. All patients presented normal gonadal function in adulthood, and 3 males fathered a child. Conclusion: All patients with CPP due to HH reached normal FH or near-FH. A higher prevalence of overweight/obesity and hypercholes-terolemia was observed in the female patients. Finally, no reproductive disorder was identified in both sexes, indicating that HH per se has no deleterious effect on the gonadotropic axis in adulthood. (c) 2017 S. Karger AG, Basel
conferenceObject ANTHROPOMETRIC, METABOLIC AND REPRODUCTIVE OUTCOME OF PATIENTS WITH CENTRAL PRECOCIOUS PUBERTY DUE TO HYPOTHALAMIC HAMARTOMA IN ADULT LIFE(2017) RAMOS, Carolina O.; LATRONICO, Ana Claudia; CUKIER, Priscila; MACEDO, Delanie; BESSA, Danielle S.; SILVA, Marina C.; ARNHOLD, Ivo J.; MENDONCA, Berenice B.; BRITO, Vinicius N.- Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3(2014) MACEDO, Delanie B.; ABREU, Ana Paula; REIS, Ana Claudia S.; MONTENEGRO, Luciana R.; DAUBER, Andrew; BENEDUZZI, Daiane; CUKIER, Priscilla; SILVEIRA, Leticia F. G.; TELES, Milena G.; CARROLL, Rona S.; GUERRA JUNIOR, Gil; GUARAGNA FILHO, Guilherme; GUCEV, Zoran; ARNHOLD, Ivo J. P.; CASTRO, Margaret de; MOREIRA, Ayrton C.; MARTINELLI JR., Carlos Eduardo; HIRSCHHORN, Joel N.; MENDONCA, Berenice B.; BRITO, Vinicius N.; ANTONINI, Sonir R.; KAISER, Ursula B.; LATRONICO, Ana ClaudiaContext: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. Objectives: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. Setting and Participants: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. Main Outcome Measures: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. Results: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. Conclusions: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.