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
63 resultados
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- Genotype analysis of the human endostatin variant p.D104N in benign and malignant adrenocortical tumors(2012) MARIANI, Beatriz Marinho de Paula; TRARBACH, Ericka Barbosa; RIBEIRO, Tamaya Castro; PEREIRA, Maria Adelaide Albergaria; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson VillaresOBJECTIVE: Endostatin is a potent endogenous inhibitor of angiogenesis. It is derived from the proteolytic cleavage of collagen XVIII, which is encoded by the COL18A1 gene. A polymorphic COL18A1 allele encoding the functional polymorphism p.D104N impairs the activity of endostatin, resulting in a decreased ability to inhibit angiogenesis. This polymorphism has been previously analyzed in many types of cancer and has been considered a phenotype modulator in some benign and malignant tumors. However, these data are controversial, and different results have been reported for the same tumor types, such as prostate and breast cancer. The purpose of this study was to genotype the p.D104N variant in a cohort of pediatric and adult patients with adrenocortical tumors and to determine its possible association with the biological behavior of adrenocortical tumors. METHODS: DNA samples were obtained from 38 pediatric and 56 adult patients (0.6-75 yrs) with adrenocortical tumors. The DNA samples were obtained from peripheral blood, frozen tissue or paraffin-embedded tumor blocks when blood samples or fresh frozen tissue samples were unavailable. Restriction fragment length polymorphism analysis was used to genotype the patients and 150 controls. The potential associations of the p.D104N polymorphism with clinical and histopathological features and oncologic outcome (age of onset, tumor size, malignant tumor behavior, and clinical syndrome) were analyzed. RESULTS: Both the patient group and the control group were in Hardy-Weinberg equilibrium. The frequencies of the p.D104N polymorphism in the patient group were 81.9% (DD), 15.9% (DN) and 2.2% (NN). In the controls, these frequencies were 80.6%, 17.3% and 2.0%, respectively. We did not observe any association of this variant with clinical or histopathological features or oncologic outcome in our cohort of pediatric and adult patients with adrenocortical tumors.
- International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia: data from the I-CAH registry(2021) BACILA, Irina; FREEMAN, Nicole; DANIEL, Eleni; SANDRK, Marija; BRYCE, Jillian; ALI, Salma Rashid; ABALI, Zehra Yavas; ATAPATTU, Navoda; BACHEGA, Tania A.; BALSAMO, Antonio; BIRKEBAEK, Niels; BLANKENSTEIN, Oliver; BONFIG, Walter; COOLS, Martine; COSTA, Eduardo Correa; DARENDELILER, Feyza; EINAUDI, Silvia; ELSEDFY, Heba Hassan; FINKEN, Martijn; GEVERS, Evelien; GRINTEN, Hedi L. Claahsen-van der; GURAN, Tulay; GUVEN, Ayla; HANNEMA, Sabine E.; HIGHAM, Claire E.; IOTOVA, Violeta; KAMP, Hetty J. van der; KORBONITS, Marta; KRONE, Ruth E.; LICHIARDOPOL, Corina; LUCZAY, Andrea; MENDONCA, Berenice Bilharinho; MILENKOVIC, Tatjana; MIRANDA, Mirela C.; MOHNIKE, Klaus; NEUMANN, Uta; ORTOLANO, Rita; POYRAZOGLU, Sukran; THANKAMONY, Ajay; TOMLINSON, Jeremy W.; VIEITES, Ana; VRIES, Liat de; AHMED, S. Faisal; ROSS, Richard J.; KRONE, Nils P.Objective: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. Design: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International CAH Registry. Methods: Data were collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits. Results: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0-14.5) mg/m(2)/day at age 1-8 years and the highest dose of 14.0 (11.6-17.4) mg/m(2)/day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (P < 0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. Conclusions: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.
- Amplification of the Insulin-Like Growth Factor 1 Receptor Gene Is a Rare Event in Adrenocortical Adenocarcinomas: Searching for Potential Mechanisms of Overexpression(2014) RIBEIRO, Tamaya Castro; JORGE, Alexander Augusto; ALMEIDA, Madson Q.; MARIANI, Beatriz Marinho de Paula; NISHI, Mirian Yumi; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson Villares; LATRONICO, Ana ClaudiaContext. IGF1R overexpression appears to be a prognostic biomarker of metastatic pediatric adrenocortical tumors. However, the molecular mechanisms that are implicated in its upregulation remain unknown. Aim. To investigate the potential mechanisms involved in IGF1R overexpression. Patients and Methods. We studied 64 adrenocortical tumors. IGF1R copy number variation was determined in all patients using MLPA and confirmed using real time PCR. In a subgroup of 32 patients, automatic sequencing was used to identify IGF1R allelic variants and the expression of microRNAs involved in IGF1R regulation by real time PCR. Results. IGF1R amplification was detected in an adrenocortical carcinoma that was diagnosed in a 46-year-old woman with Cushing's syndrome and virilization. IGF1R overexpression was demonstrated in this case. In addition, gene amplification of other loci was identified in this adrenocortical malignant tumor, but no IGF1R copy number variation was evidenced in the remaining cases. Automatic sequencing revealed three known polymorphisms but they did not correlate with its expression. Expression of miR-100, miR-145, miR-375, and miR-126 did not correlate with IGF1R expression. Conclusion. We demonstrated amplification and overexpression of IGF1R gene in only one adrenocortical carcinoma, suggesting that these combined events are uncommon. In addition, IGF1R polymorphisms and abnormal microRNA expression did not correlate with IGF1R upregulation in adrenocortical tumors.
- Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide(2020) BATISTA, Rafael Loch; MENDONCA, Berenice BilharinhoIntroduction: The conversion of testosterone into dihydrotestosterone is catalyzed by the 5 alpha-reductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the SRD5A2 gene. Allelic variants in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported in the early 70s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge on the molecular bases of androgen milieu. Methods: We searched for SRD5A2 allelic variants (AV) in the literature (PubMed, Embase, MEDLINE) and websites (ensembl, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous or compound heterozygous were included. The included cases were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender reassignment, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using the CONSURF platform. For categorical variables, we used X2 test and Cramer's V. Continuous variables were analyzed by t test or ANOVA. Concordance was estimated by Kappa. Results: We identified 434 cases of 5ARD2 deficiencies from 44 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). Sixty-nine percent were assigned as female. There were 70% of homozygous allelic variants and 30% compound heterozygous. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along with all exons with exon 1 (33%) and exon 4 (25%) predominance. Allelic variants in the exon 4 (NADPH-binding domain) resulted in lower virilization (p<0.0001). The codons 55, 65, 196, 235 and 246 are hotspots making up 25% of all allelic variants. Most of them (76%) were located at conserved aa. However, allelic variants at non-conserved aa were more frequently indels (28% vs 6%; p<0.01). The overall rate of gender change from female to male ranged from 16% to 70%. The lowest rate of gender change from female to male occurred in Turkey and the highest in Brazil. External genitalia virilization was similar between those who changed and those who kept their assigned gender. The gender change rate was significantly different across the countries (V=0.44; p<0.001) even with similar virilization scores. Conclusion: 5ARD2 deficiency has a worldwide distribution. Allelic variants at the NADPH-ligand region cause lower virilization. Genitalia virilization influenced sex assignment but not gender change which was influenced by cultural aspects across the countries. Molecular diagnosis influenced on sex assignment, favoring male sex assignment in newborns with 5 alpha-reductase type 2 deficiency.
- Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals(2016) DOMENICE, Sorahia; MACHADO, Aline Zamboni; FERREIRA, Frederico Moraes; FERRAZ-DE-SOUZA, Bruno; LERARIO, Antonio Marcondes; LIN, Lin; NISHI, Mirian Yumie; GOMES, Nathalia Lisboa; SILVA, Thatiana Evelin da; SILVA, Rosana Barbosa; CORREA, Rafaela Vieira; MONTENEGRO, Luciana Ribeiro; NARCISO, Amanda; COSTA, Elaine Maria Frade; ACHERMANN, John C.; MENDONCA, Berenice BilharinhoSteroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Mullerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309-320, 2016. (c) 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.
- Cytogenomic Investigation of Syndromic Brazilian Patients with Differences of Sexual Development(2023) JR, Jose Antonio Diniz Faria; MORAES, Daniela R.; KULIKOWSKI, Leslie Domenici; BATISTA, Rafael Loch; GOMES, Nathalia Lisboa; NISHI, Mirian Yumie; ZANARDO, Evelin; NONAKA, Carolina Kymie Vasques; SOUZA, Bruno Solano de Freitas; MENDONCA, Berenice Bilharinho; DOMENICE, SorahiaBackground: Cytogenomic methods have gained space in the clinical investigation of patients with disorders/differences in sexual development (DSD). Here we evaluated the role of the SNP array in achieving a molecular diagnosis in Brazilian patients with syndromic DSD of unknown etiology. Methods: Twenty-two patients with DSD and syndromic features were included in the study and underwent SNP-array analysis. Results: In two patients, the diagnosis of 46,XX SRY + DSD was established. Additionally, two deletions were revealed (3q29 and Xp22.33), justifying the syndromic phenotype in these patients. Two pathogenic CNVs, a 10q25.3-q26.2 and a 13q33.1 deletion encompassing the FGFR2 and the EFNB2 gene, were associated with genital atypia and syndromic characteristics in two patients with 46,XY DSD. In a third 46,XY DSD patient, we identified a duplication in the 14q11.2-q12 region of 6.5 Mb associated with a deletion in the 21p11.2-q21.3 region of 12.7 Mb. In a 46,XY DSD patient with delayed neuropsychomotor development and congenital cataracts, a 12 Kb deletion on chromosome 10 was found, partially clarifying the syndromic phenotype, but not the genital atypia. Conclusions: The SNP array is a useful tool for DSD patients, identifying the molecular etiology in 40% (2/5) of patients with 46,XX DSD and 17.6% (3/17) of patients with 46,XY DSD.
conferenceObject DEAH-Box Helicase 37defects (DXH37) Defects Are a Novel Cause of 46,XY Gonadal Dysgenesis(2018) GOMES, Nathalia; SILVA, Thatiana; LERARIO, Antonio; BATISTA, Rafael Loch; FARIA JUNIOR, Jose Antonio; MORAES, Daniela; COSTA, Elaine Maria Frade; NISHI, Mirian; CARVALHO, Luciani Renata; FORCLAZ, Maria Veronica; PAPAZIAN, Regina; MARTINEZ-AGUAYO, Alejandro; PAULA, Leila Pedroso de; CARVALHO, Filomena Marino; VILAIN, Erick; BARSEGHYAN, Hayk Barseghyan; KEEGAN, Catherine; DOMENICE, Sorahia; MENDONCA, Berenice Bilharinho- Genetics of ovarian insufficiency and defects of folliculogenesis(2022) FRANCA, Monica Malheiros; MENDONCA, Berenice BilharinhoPrimary ovarian insufficiency (POI) is determined by exhaustion of follicles in the ovaries, which leads to infertility before the age of 40 years. It is characterized by a strong familial and heterogeneous genetic background. Therefore, we will mainly discuss the genetic basis of POI in this review. We identified 107 genes related to POI etiology in mammals described by several independent groups. Thirty-four of these genes (AARS2, AIRE, ANTXR1, ATM, BMPR1B, CLPP, CYP17A1, CYP19A1, DCAF17, EIF2B, ERAL1, FANCA, FANCC, FMR1, FOXL2, GALT, GNAS, HARS2, HSD17B4, LARS2, LMNA, MGME1, NBN, PMM2, POLG, PREPL, RCBTB1, RECQL2/3/4, STAR, TWNK, and XRCC4/9) have been linked to syndromic POI and are mainly implicated in metabolism function and meiosis/DNA repair. In addition, the majority of genes associated with nonsyndromic POI, widely expanded by high-throughput techniques over the last decade, have been implicated in ovarian development and meiosis/DNA repair pathways (ATG7, ATG9, ANKRD31, BMP8B, BMP15, BMPR1A, BMPR1B, BMPR2, BNC1, BRCA2, CPEB1, C14ORF39, DAZL, DIAPH2, DMC1, ERCC6, FANCL, FANCM, FIGLA, FSHR, GATA4, GDF9, GJA4, HELQ, HSF2BP, HFM1, INSL3, LHCGR, LHX8, MCM8, MCM9, MEIOB, MSH4, MSH5, NANOS3, NOBOX, NOTCH2, NR5A1, NUP107, PGRMC1, POLR3H, PRDM1, PRDM9, PSMC3IP, SOHLH1, SOHLH2, SPIDR, STAG3, SYCE1, TP63, UBR2, WDR62, and XRCC2), whereas a few are related to metabolic functions (EIF4ENIF1, KHDRBS1, MRPS22, POLR2C). Some genes, such as STRA8, FOXO3A, KIT, KITL, WNT4, and FANCE, have been shown to cause ovarian insufficiency in rodents, but mutations in these genes have yet to be elucidated in women affected by POI. Lastly, some genes have been rarely implicated in its etiology (AMH, AMHR2, ERRC2, ESR1, INHA, LMN4, POF1B, POU5F1, REC8, SMC1B). Considering the heterogeneous genetic and familial background of this disorder, we hope that an overview of literature data would reinforce that genetic screening of those patients is worthwhile and helpful for better genetic counseling and patient management.
- High 18F-FDG uptake in PMAH correlated with normal expression of Glut1, HK1, HK2, and HK3(2016) CAVALCANTE, Isadora Pontes; ZERBINI, Maria Claudia Nogueira; ALENCAR, Guilherme Asmar; MARIANI, Beatriz de Paula; BUCHPIGUEL, Carlos Alberto; ALMEIDA, Madson Queiroz; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson VillaresBackground Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, characterized by functioning adrenal macronodules and variable cortisol production. Recently, we demonstrated a high 18F-FDG uptake in PMAH, an unexpected finding for a benign disorder. Purpose To investigate whether there is a correlation between 18F-FDG high uptake and the expression levels of the glycolytic pathway components GLUT1, HK1, HK2, and HK3 in PMAH. Material and Methods We selected 12 patients undergoing surgery for PMAH who had preoperatively undergone 18F-FDG PET/CT. mRNA and protein expression of the selected genes were evaluated in the adrenal nodules from patients who underwent surgery through quantitative RT-PCR and by immunohistochemistry, respectively. Results SUVmax in PMAH was in the range of 3.3-8.9 and the adrenal size was in the range of 3.5-15cm. A strong correlation between 18F-FDG uptake and largest adrenal diameter was observed in patients with PMAH. However, no correlation between 18F-FDG uptake and GLUT1, HK1, HK2, HK3 mRNA, and protein expression was observed. Conclusion High 18F-FDG uptake is observed in the majority of PMAH cases. However, 18F-FDG uptake in PMAH is independent of the expression levels of GLUT1, HK1, HK2, and HK3. Further investigation is required to elucidate the molecular mechanisms underlying increased 18F-FDG uptake in PMAH.
conferenceObject Clinical, psychological, and molecular aspects of a large androgen insensitivity syndrome cohort(2023) BATISTA, Rafael Loch; INACIO, Marlene; AFONSO, Ane Caroline; CARVALHO, Filomena; RAMOS, Raquel; CRAVEIRO, Flora; DALLAGO, Renata; FERRARI, Maria Tereza; BATATINHA, Julio; NISHI, Miriam; DOMENICE, Sorahia; MENDONCA, Berenice Bilharinho