BERENICE BILHARINHO DE MENDONCA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
34 resultados
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- Combined pituitary hormone deficiency caused by PROP1 mutations: update 20 years post-discovery(2019) CORREA, Fernanda A.; NAKAGUMA, Marilena; MADEIRA, Joao L. O.; NISHI, Mirian Y.; ABRAO, Milena G.; JORGE, Alexander A. L.; CARVALHO, Luciani R.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.The first description of patients with combined pituitary hormone deficiencies (CPHD) caused by PROP1 mutations was made 20 years ago. Here we updated the clinical and genetic characteristics of patients with PROP1 mutations and summarized the phenotypes of 14 patients with 7 different pathogenic PROP1 mutations followed at the Hospital das Clinicas of the University of Sao Paulo. In addition to deficiencies in GH, TSH, PRL and gonadotropins some patients develop late ACTH deficiency. Therefore, patients with PROP1 mutations require permanent surveillance. On magnetic resonance imaging, the pituitary stalk is normal, and the posterior lobe is in the normal position. The anterior lobe in patients with PROP1 mutations is usually hypoplastic but may be normal or even enlarged. Bi-allelic PROP1 mutations are currently the most frequently recognized genetic cause of CPHD worldwide. PROP1 defects occur more frequently among offspring of consanguineous parents and familial cases, but they also occur in sporadic cases, especially in countries in which the prevalence of PROP1 mutations is relatively high. We classified all reported PROP1 variants described to date according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines: 29 were pathogenic, 2 were likely pathogenic, and 2 were of unknown significance. An expansion of the phenotype of patients with PROP1 mutations was observed since the first description 20 years ago: variable anterior pituitary size, different pathogenic mutations, and late development of ACTH deficiency. PROP1 mutations are the most common cause of autosomal recessive CPHD with a topic posterior pituitary lobe.
- Adult Height of Patients with SHOX Haploinsufficiency with or without GH Therapy: A Real-World Single-Center Study(2022) DANTAS, Naiara C. B.; FUNARI, Mariana F. A.; VASQUES, Gabriela A.; ANDRADE, Nathalia L. M.; REZENDE, Raissa C.; BRITO, Vinicius; SCALCO, Renata C.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.; JORGE, Alexander A. L.Introduction: Isolated SHOX haploinsufficiency is a common monogenic cause of short stature. Few studies compare untreated and rhGH-treated patients up to adult height (AH). Our study highlights a growth pattern from childhood to AH in patients with SHOX haploinsufficiency and analyzes the real-world effectiveness of rhGH alone or plus GnRH analog (GnRHa). Methods: Forty-seven patients (18 untreated and 29 rhGH-treated) with SHOX haploinsufficiency were included in a longitudinal retrospective study. Adult height was attained in 13 untreated and 18 rhGH-treated (rhGH alone [n = 8] or plus GnRHa [n = 10]) patients. Results: The untreated group decreased height SDS from baseline to AH (-0.8 [-1.1; -0.4]), with an increase in the prevalence of short stature from 31% to 77%. Conversely, the rhGH-treated group had an improvement in height SDS from baseline to AH (0.6 [0.2; 0.6]; p < 0.001), with a reduction in the prevalence of short stature (from 61% to 28%). AH in the rhGH-treated patients was 1 SD (6.3 cm) taller than in untreated ones. Regarding the use of GnRHa, the subgroups (rhGH alone or plus GnRHa) attained similar AH, despite the higher prevalence of pubertal patients and worse AH prediction at the start of rhGH treatment in patients who used combined therapy. Conclusion: The use of rhGH treatment improves AH in patients with SHOX haploinsufficiency, preventing the loss of height potential during puberty. In peripubertal patients, the addition of GnRHa to rhGH allows AH attainment similar to the AH of patients who start rhGH alone in the prepubertal age. (C) 2022 S. Karger AG, Basel
- Homozygous Inactivating Mutation in NANOS3 in Two Sisters with Primary Ovarian Insufficiency(2014) SANTOS, Mariza G.; MACHADO, Aline Z.; MARTINS, Conceicao N.; DOMENICE, Sorahia; COSTA, Elaine M. F.; NISHI, Mirian Y.; FERRAZ-DE-SOUZA, Bruno; JORGE, Soraia A. C.; PEREIRA, Carlos A.; SOARDI, Fernanda C.; MELLO, Maricilda P. de; MACIEL-GUERRA, Andrea T.; GUERRA-JUNIOR, Gil; MENDONCA, Berenice B.Despite the increasing understanding of female reproduction, the molecular diagnosis of primary ovarian insufficiency (POI) is seldom obtained. The RNA-binding protein NANOS3 poses as an interesting candidate gene for POI since members of the Nanos family have an evolutionarily conserved function in germ cell development and maintenance by repressing apoptosis. We performed mutational analysis of NANOS3 in a cohort of 85 Brazilian women with familial or isolated POI, presenting with primary or secondary amenorrhea, and in ethnically-matched control women. A homozygous p.Glu120Lysmutation in NANOS3 was identified in two sisters with primary amenorrhea. The substituted amino acid is located within the second C2HC motif in the conserved zinc finger domain of NANOS3 and in silico molecular modelling suggests destabilization of protein-RNA interaction. In vitro analyses of apoptosis through flow cytometry and confocal microscopy show that NANOS3 capacity to prevent apoptosis was impaired by this mutation. The identification of an inactivating missense mutation in NANOS3 suggests a mechanism for POI involving increased primordial germ cells (PGCs) apoptosis during embryonic cell migration and highlights the importance of NANOS proteins in human ovarian biology.
- SDHB large deletions are associated with absence of MIBG uptake in metastatic lesions of malignant paragangliomas(2021) PETENUCI, Janaina; FAGUNDES, Gustavo F. C.; BENEDETTI, Anna Flavia F.; GUIMARAES, Augusto G.; AFONSO, Ana Caroline F.; MOTA, Flavia T.; MAGALHAES, Aurea Luiza F.; COURA-FILHO, George B.; ZERBINI, Maria Claudia N.; SIQUEIRA, Sheila; MONTENEGRO, Fabio L. M.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose Luis; FERRARI, Marcela S. S.; BEZERRA NETO, Joao Evangelista; PEREIRA, Maria Adelaide A.; LATRONICO, Ana Claudia; FRAGOSO, Maria Candida B. V.; MENDONCA, Berenice B.; HOFF, Ana O.; ALMEIDA, Madson Q.
- High-throughput Sequencing to Identify Monogenic Etiologies in a Preselected Polycystic Ovary Syndrome Cohort(2022) CRESPO, Raiane P.; ROCHA, Thais P.; MONTENEGRO, Luciana R.; NISHI, Mirian Y.; JORGE, Alexander A. L.; MACIEL, Gustavo A. R.; BARACAT, Edmund; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; GOMES, Larissa G.Context: Polycystic ovary syndrome (PCOS) etiology remains to be elucidated, but familial clustering and twin studies have shown a strong heritable component. Objective: The purpose of this study was to identify rare genetic variants that are associated with the etiology of PCOS in a preselected cohort. Methods: This prospective study was conducted among a selected group of women with PCOS. The study's inclusion criteria were patients with PCOS diagnosed by the Rotterdam criteria with the following phenotypes: severe insulin resistance (IR), normoandrogenic-normometabolic phenotype, adrenal hyperandrogenism, primary amenorrhea, and familial PCOS. Forty-five patients were studied by target sequencing, while 8 familial cases were studied by whole exome sequencing. Results: Patients were grouped according to the inclusion criteria with the following distribution: 22 (41.5%) with severe IR, 13 (24.5%) with adrenal hyperandrogenism, 7 (13.2%) with normoandrogenic phenotype, 3 (5.7%) with primary amenorrhea, and 8 (15.1%) familial cases. DNA sequencing analysis identified 1 pathogenic variant in LMNA, 3 likely pathogenic variants in INSR, PIK3R1, and DLK1, and 6 variants of uncertain significance level with interesting biologic rationale in 5 genes (LMNA, GATA4, NR5A1, BMP15, and FSHR). LMNA was the most prevalent affected gene in this cohort (3 variants). Conclusion: Several rare variants in genes related to IR were identified in women with PCOS. Although IR is a common feature of PCOS, patients with extreme or atypical phenotype should be carefully evaluated to rule out monogenic conditions.
- 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
- 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.
- Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism(2021) RASSI-CRUZ, Marcela; MARIA, Andrea G.; FAUCZ, Fabio R.; LONDON, Edra; VILELA, Leticia A. P.; SANTANA, Lucas S.; BENEDETTI, Anna Flavia F.; GOLDBAUM, Tatiana S.; TANNO, Fabio Y.; SROUGI, Vitor; CHAMBO, Jose L.; PEREIRA, Maria Adelaide A.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; BORTOLOTTO, Luiz A.; DRAGER, Luciano F.; LERARIO, Antonio M.; LATRONICO, Ana Claudia; V, Maria Candida B. Fragoso; MENDONCA, Berenice B.; ZERBINI, Maria Claudia N.; STRATAKIS, Constantine A.; ALMEIDA, Madson Q.Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, 'sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of gene tic etiologies of PA.
- 46,XY Disorders of Sex Development (46,XY DSD) due to Androgen Receptor Defects: Androgen Insensitivity Syndrome(2011) ARNHOLD, Ivo J. P.; MELO, Karla; COSTA, Elaine M. F.; DANILOVIC, Debora; INACIO, Marlene; DOMENICE, Sorahia; MENDONCA, Berenice B.