FRANCISCA DELANIE BULCAO DE MACEDO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
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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conferenceObject Time Course of Central Precocious Puberty Development Caused by an MKRN3 Gene Mutation: A Prismatic Case(2016) STECCHINI, M.; MACEDO, D.; REIS, A. C.; ABREU, A. P.; MOREIRA, A.; CASTRO, M.; KAISER, U.; LATRONICO, A. C.; ANTONINI, S.conferenceObject Apparently Sporadic Central Precocious Puberty Is Caused By Paternally Inherited Mutations in the Imprinted MKRN3 Gene(2014) ABREU, Ana Paula; MACEDO, Delanie B.; REIS, Ana Claudia Silva; MONTENEGRO, Luciana Ribeiro; DAUBER, Andrew; BENEDUZZI, Diane; CULIER, Priscilla; SILVEIRA, Leticia Gontijo; TELES, Milena Gurgel; CARROLL, Rona S.; GUERRA, Gil; GUARAGNA FILHO, Guilherme; GUCEV, Zoran Spasico; ARNHOLD, Ivo J. P.; CASTRO, Margaret; MOREIRA, Ayrton Custodio; MARTINELLI, Carlos Eduardo; HIRSCHHORN, Joel N.; MENDONASA, Berenice Bilharinho; BRITO, Vinicius N.; ANTONINI, Sonir Roberto; KAISER, Ursula B.; LATRONICO, Ana Claudia- High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic(2017) BESSA, Danielle S.; MACEDO, Delanie B.; BRITO, Vinicius N.; FRANCA, Monica M.; MONTENEGRO, Luciana R.; CUNHA-SILVA, Marina; SILVEIRA, Leticia G.; HUMMEL, Tiago; BERGADA, Ignacio; BRASLAVSKY, Debora; ABREU, Ana Paula; DAUBER, Andrew; MENDONCA, Berenice B.; KAISER, Ursula B.; LATRONICO, Ana ClaudiaBackground/Aims: Recently, loss-of-function mutations in the MKRN3 gene have been implicated in the etiology of familial central precocious puberty (CPP) in both sexes. We aimed to analyze the frequency of MKRN3 mutations in boys with CPP and to compare the clinical and hormonal features of boys with and without MKRN3 mutations. Methods: This was a retrospective review of clinical, hormonal and genetic features of 20 male patients with idiopathic CPP evaluated at an academic medical center. The entire coding regions of MKRN3, KISS1 and KISS1R genes were sequenced. Results: We studied 20 boys from 17 families with CPP. All of them had normal brain magnetic resonance imaging. Eight boys from 5 families harbored four distinct heterozygous MKRN3 mutations predicted to be deleterious for protein function, p.Ala162Glyfs*14, p.Arg213Glyfs*73, p.Arg328Cys and p. Arg365Ser. One boy carried a previously described KISS1-activating mutation (p.Pro74Ser). The frequency of MKRN3 mutations among these boys with idiopathic CPP was significantly higher than previously reported female data (40 vs. 6.4%, respectively, p < 0.001). Boys with MKRN3 mutations had typical clinical and hormonal features of CPP. Notably, they had later pubertal onset than boys without MKRN3 abnormalities (median age 8.2 vs. 7.0 years, respectively, p = 0.033). Conclusion: We demonstrated a high frequency of MKRN3 mutations in boys with CPP, previously classified as idiopathic, suggesting the importance of genetic analysis in this group. The boys with CPP due to MKRN3 mutations had classical features of CPP, but with puberty initiation at a borderline age. (C) 2016 S. Karger AG, Basel
conferenceObject Clinical and Genetic Features of Central Precocious Puberty Associated with Complex Phenotypes(2018) CANTON, Ana; BRITO, Vinicius; MONTENEGRO, Luciana; RAMOS, Carolina; MACEDO, Delanie; BESSA, Danielle; CUNHA, Marina; JORGE, Alexander; MENDONCA, Berenice; LATRONICO, Ana Claudia- Spontaneous fertility in a male patient with testotoxicosis despite suppression of FSH levels(2018) CUNHA-SILVA, M.; BRITO, V. N.; MACEDO, D. B.; BESSA, D. S.; RAMOS, C. O.; LIMA, L. G.; BARROSO, P. S.; ARNHOLD, I. J. P.; SEGALOFF, D. L.; MENDONCA, B. B.; LATRONICO, A. C.Testotoxicosis is a rare cause of peripheral precocious puberty in boys caused by constitutively activating mutations of the LHCG receptor. Affected males usually have normal gonadotropin profiles and fertility in their adult life. Here, we described the long-term follow-up of a 24-year-old young man with severe testotoxicosis due to a de novo activating mutation in the third transmembrane helix of the LHCGR (p. Leu457Arg). This patient was treated with different medications, including medroxyprogesterone acetate, ketoconazole, cyproterone acetate and aromatase inhibitor from age 2.5 to 9.5 years. His basal and GnRH-stimulated gonadotropin levels were continually suppressed during and after medical treatment. At adulthood, extremely high serum testosterone levels (>35 nmol/L), undetectable gonadotropin levels (LH < 0.15 IU/L and FSH < 0.6 IU/L) and oligozoospermia were evidenced. Despite his suppressed FSH levels and an unfavorable spermogram, the patient fathered a healthy girl and biological paternity was confirmed through analysis of microsatellites. Spontaneous fertility in a young man with severe testotoxicosis and chronic suppression of FSH levels reinforces the key role of high intratesticular testosterone levels in human spermatogenesis.
- Methylome profiling of healthy and central precocious puberty girls(2018) BESSA, Danielle S.; MASCHIETTO, Mariana; AYLWIN, Carlos Francisco; CANTON, Ana P. M.; BRITO, Vinicius N.; MACEDO, Delanie B.; CUNHA-SILVA, Marina; PALHARES, Heloisa M. C.; RESENDE, Elisabete A. M. R. de; BORGES, Maria de Fatima; MENDONCA, Berenice B.; NETCHINE, Irene; KREPISCHI, Ana C. V.; LOMNICZI, Alejandro; OJEDA, Sergio R.; LATRONICO, Ana ClaudiaBackgroundRecent studies demonstrated that changes in DNA methylation (DNAm) and inactivation of two imprinted genes (MKRN3 and DLK1) alter the onset of female puberty. We aimed to investigate the association of DNAm profiling with the timing of human puberty analyzing the genome-wide DNAm patterns of peripheral blood leukocytes from ten female patients with central precocious puberty (CPP) and 33 healthy girls (15 pre- and 18 post-pubertal). For this purpose, we performed comparisons between the groups: pre- versus post-pubertal, CPP versus pre-pubertal, and CPP versus post-pubertal.ResultsAnalyzing the methylome changes associated with normal puberty, we identified 120 differentially methylated regions (DMRs) when comparing pre- and post-pubertal healthy girls. Most of these DMRs were hypermethylated in the pubertal group (99%) and located on the X chromosome (74%). Only one genomic region, containing the promoter of ZFP57, was hypomethylated in the pubertal group. ZFP57 is a transcriptional repressor required for both methylation and imprinting of multiple genomic loci. ZFP57 expression in the hypothalamus of female rhesus monkeys increased during peripubertal development, suggesting enhanced repression of downstream ZFP57 target genes. Fourteen other zinc finger (ZNF) genes were related to the hypermethylated DMRs at normal puberty. Analyzing the methylome changes associated with CPP, we demonstrated that the patients with CPP exhibited more hypermethylated CpG sites compared to both pre-pubertal (81%) and pubertal (89%) controls. Forty-eight ZNF genes were identified as having hypermethylated CpG sites in CPP.ConclusionMethylome profiling of girls at normal and precocious puberty revealed a widespread pattern of DNA hypermethylation, indicating that the pubertal process in humans is associated with specific changes in epigenetically driven regulatory control. Moreover, changes in methylation of several ZNF genes appear to be a distinct epigenetic modification underlying the initiation of human puberty.
- Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region (vol 107, pg 127, 2018)(2018) MACEDO, D. B.; FRANCA, M. M.; MONTENEGRO, L. R.; CUNHA-SILVA, M.; BESSA, D. S.; ABREU, A. P.; KAISER, U. B.; MENDONCA, B. B.; JORGE, A. A. L.; BRITO, V. N.; LATRONICO, A. N.
- A boy with Prader-Willi syndrome: unmasking precocious puberty during growth hormone replacement therapy(2016) LUDWIG, Natasha G.; RADAELI, Rafael F.; SILVA, Mariana M. X.; ROMERO, Camila M.; CARRILHO, Alexandre J. F.; BESSA, Danielle; MACEDO, Delanie B.; OLIVEIRA, Maria L.; LATRONICO, Ana Claudia; MAZZUCO, Tânia L.SUMMARY Prader-Willi syndrome (PWS) is a genetic disorder frequently characterized by obesity, growth hormone deficiency, genital abnormalities, and hypogonadotropic hypogonadism. Incomplete or delayed pubertal development as well as premature adrenarche are usually found in PWS, whereas central precocious puberty (CPP) is very rare. This study aimed to report the clinical and biochemical follow-up of a PWS boy with CPP and to discuss the management of pubertal growth. By the age of 6, he had obesity, short stature, and many clinical criteria of PWS diagnosis, which was confirmed by DNA methylation test. Therapy with recombinant human growth hormone (rhGH) replacement (0.15 IU/kg/day) was started. Later, he presented psychomotor agitation, aggressive behavior, and increased testicular volume. Laboratory analyses were consistent with the diagnosis of CPP (gonadorelin-stimulated LH peak 15.8 IU/L, testosterone 54.7 ng/dL). The patient was then treated with gonadotropin-releasing hormone analog (GnRHa). Hypothalamic dysfunctions have been implicated in hormonal disturbances related to pubertal development, but no morphologic abnormalities were detected in the present case. Additional methylation analysis (MS-MLPA) of the chromosome 15q11 locus confirmed PWS diagnosis. We presented the fifth case of CPP in a genetically-confirmed PWS male. Combined therapy with GnRHa and rhGH may be beneficial in this rare condition of precocious pubertal development in PWS.
conferenceObject PATERNALLY INHERITED DLK1 DELETION AS A NOVEL CAUSE OF FAMILIAL CENTRAL PRECOCIOUS PUBERTY(2017) DAUBER, Andrew; CUNHA-SILVA, Marina; MACEDO, Delanie; BRITO, Vinicius; ABREU, Ana Paula; ROBERTS, Stephanie; MONTENEGRO, Luciana; ANDREW, Melissa; KRIBY, Andrew; WEIRAUCH, Matthew; LABILLOY, Guillaume; BESSA, Danielle; CARROLL, Rona; JACOBS, Dakota; CHAPPELL, Patrick; MENDONCA, Berenice B.; HAIG, David; KAISER, Ursula; LATRONICO, Ana Claudia- New Causes of Central Precocious Puberty: The Role of Genetic Factors(2014) MACEDO, Delanie Bulcao; BRITO, Vinicius Nahime; LATRONICO, Ana ClaudiaA pivotal event in the onset of puberty in humans is the reemergence of the pulsatile release of the gonadotropin-releasing hormone (GnRH) from hypothalamic neurons. Pathways governing GnRH ontogeny and physiology have been discovered by studying animal models and humans with reproductive disorders. Recent human studies implicated the activation of kisspeptin and its cognate receptor (KISS1 / KISS1R) and the inactivation of MKRN3 in the premature reactivation of GnRH secretion, causing central precocious puberty (CPP). MKRN3, an imprinted gene located on the long arm of chromosome 15, encodes makorin ring finger protein 3, which is involved in ubiquitination and cell signaling. The MKRN3 protein is derived only from RNA transcribed from the paternally inherited copy of the gene due to maternal imprinting. Currently, MKRN3 defects represent the most frequent known genetic cause of familial CPP. In this review, we explored the clinical, hormonal and genetic aspects of children with sporadic or familial CPP caused by mutations in the kisspeptin and MKRN3 systems, essential genetic factors for pubertal timing. (C) 2014 S. Karger AG, Basel
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