PRISCILLA CUKIER
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
3 resultados
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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
- Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3(2013) ABREU, Ana Paula; DAUBER, Andrew; MACEDO, Delanie B.; NOEL, Sekoni D.; BRITO, Vinicius N.; GILL, John C.; CUKIER, Priscilla; THOMPSON, Iain R.; NAVARRO, Victor M.; GAGLIARDI, Priscila C.; RODRIGUES, Tania; KOCHI, Cristiane; LONGUI, Carlos Alberto; BECKERS, Dominique; ZEGHER, Francis de; MONTENEGRO, Luciana R.; MENDONCA, Berenice B.; CARROLL, Rona S.; HIRSCHHORN, Joel N.; LATRONICO, Ana Claudia; KAISER, Ursula B.BACKGROUND The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS Deficiency of MKRN3 causes central precocious puberty in humans.