RAFAEL LOCH BATISTA
Projetos de Pesquisa
Unidades Organizacionais
Instituto de Psiquiatria, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
37 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 37
- Partial androgen insensitivity syndrome due to somatic mosaicism of the androgen receptor(2018) BATISTA, Rafael Loch; RODRIGUES, Andresa De Santi; MACHADO, Aline Zamboni; NISHI, Mirian Yumie; CUNHA, Flavia Siqueira; SILVA, Rosana Barbosa; COSTA, Elaine M. F.; MENDONCA, Berenice B.; DOMENICE, SorahiaBackground: Androgen insensitivity syndrome (AIS) is the most frequent etiology of 46, XY disorders of sex development (DSDs), and it is an X-linked disorder caused by mutations in the androgen receptor (AR) gene. AIS patients present a broad phenotypic spectrum and individuals with a partial phenotype present with different degrees of undervirilized external genitalia. There are more than 500 different AR gene allelic variants reported to be linked to AIS, but the presence of somatic mosaicisms has been rarely identified. In the presence of a wild-type AR gene, a significant degree of spontaneous virilization at puberty can be observed, and it could influence the gender assignment, genetic counseling and the clinical and psychological management of these patients and the psychosexual outcomes of these patients are not known. Case presentation: In this study, we report two patients with AR allelic variants in heterozygous (c.382G>T and c.1769-1G>C) causing a partial AIS (PAIS) phenotype. The first patient was raised as female and she had undergone a gonadectomy at puberty. In both patients there was congruency between gender of rearing and gender identity and gender role. Conclusions: Somatic mosaicism is rare in AIS and nonsense AR variant allelic can cause partial AIS phenotype in this situation. Despite the risk of virilization and prenatal androgen exposure, the gender identity and gender role was concordant with sex of rearing in both cases. A better testosterone response can be expected in male individuals and this should be considered in the clinical management.
- Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life(2019) WISNIEWSKI, Amy B.; BATISTA, Rafael L.; COSTA, Elaine M. F.; FINLAYSON, Courtney; SIRCILI, Maria Helena Palma; DENES, Francisco Tibor; DOMENICE, Sorahia; MENDONCA, Berenice B.Differences/disorders of sex development (DSD) are a heterogeneous group of congenital conditions that result in discordance between an individual's sex chromosomes, gonads, and/or anatomic sex. Advances in the clinical care of patients and families affected by 46,XY DSD have been achieved since publication of the original Consensusmeeting in 2006. The aims of this paper are to review what is known about morbidity and mortality, diagnostic tools and timing, sex of rearing, endocrine and surgical treatment, fertility and sexual function, and quality of life in people with 46,XY DSD. The role for interdisciplinary health care teams, importance of establishing a molecular diagnosis, and need for research collaborations using patient registries to better understand long-term outcomes of specific medical and surgical interventions are acknowledged and accepted. Topics that require further study include prevalence and incidence, understanding morbidity and mortality as these relate to specific etiologies underlying 46,XY DSD, appropriate and optimal options for genitoplasty, long-term quality of life, sexual function, involvement with intimate partners, and optimizing fertility potential.
- Heterozygous Nonsense Mutation in the Androgen Receptor Gene Associated with Partial Androgen Insensitivity Syndrome in an Individual with 47, XXY Karyotype(2017) BATISTA, Rafael L.; RODRIGUES, Andresa S.; NISHI, Mirian Y.; FEITOSA, Alina C. R.; GOMES, Nathalia L. R. A.; JUNIOR, Jose Antonio F.; DOMENICE, Sorahia; COSTA, Elaine M. F.; MENDONCA, Berenice B. deThere are only 2 patients with 47, XXY karyotype and androgen receptor (AR) gene mutation reported in the literature, and both are diagnosed as complete androgen insensitivity syndrome (CAIS). We report a 22-year-old female with 47, XXY karyotype and atypical external genitalia. Sequencing of AR revealed the heterozygous p.Asn849Lys*32 mutation, and extensive X chromosome microsatellite analysis showed homozygosity for Xp and heterozygosity for Xq, suggesting partial X maternal isodisomy. Partial androgen insensitivity syndrome (PAIS) developed in this case, probably because of the presence of the heterozygous AR mutation and random X-inactivation of the healthy allele. This is the first report of a female patient with 47, XXY karyotype and PAIS phenotype. (C) 2017 S.Karger AG, Basel
- 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.
- 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.
- Variants in 46,XY DSD-Related Genes in Syndromic and Non-Syndromic Small for Gestational Age Children with Hypospadias(2022) BRAGA, B. L.; GOMES, N. L.; NISHI, M. Y.; FREIRE, B. L.; BATISTA, R. L.; FARIA JUNIOR, J. A. D.; FUNARI, M. F. A.; BENEDETTI, A. F. F.; NARCIZO, A. De Moraes; CARDOSO, L. Cavalca; LERARIO, A. M.; GUERRA-JUNIOR, G.; COSTA, E. M. F.; DOMENICE, S.; JORGE, A. A. L.; MENDONCA, B. B.Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region H19/IGF2 was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the CUL7 gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in TRIM37 was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition.
- Association between KISS1 rs5780218 promoter polymorphism and onset of growth hormone secreting pituitary adenoma(2019) AMORIM, Paulo V. G. H.; GRANDE, Isabella P. P.; BATISTA, Rafael L.; SILVEIRA, Leticia F. G.; FREIRE, Ane Caroline T. B.; BRONSTEIN, Marcello D.; JALLAD, Raquel S.; TRARBACH, Ericka B.Objectives. - This study analyzed the KISS1 c.-145delA (rs5780218) promoter polymorphism in a cohort of patients with growth hormone secreting pituitary adenoma (somatotropinoma) and controls, to investigate its role in the incidence of acromegaly and to assess patient/tumor characteristics. Material and methods rs5780218 allelic and genotypic distributions were compared between 49 somatotropinoma patients and 167 healthy controls. rs5780218 was also assessed in relation to patient characteristics and tumor aggressiveness, as characterized by tumor invasion and resistance to conventional therapy. The relationship between KISS1 mRNA expression and the rs5780218 genotype was also assessed in available pituitary tumor samples. Results. - The homozygous -/- variant genotype was associated with high rates of somatotropinoma (P < 0.01), but not with tumor invasiveness, patient characteristics or hormonal remission. KISS1 mRNA expression was much lower in somatotropinomas carrying the deleted allele than in homozygous wild type AA. Conclusions. - In this pilot study, the rs5780218 promoter polymorphism was evaluated in pituitary adenoma, and showed a possible association with the incidence of somatotropinoma but not with tumor progression.
- Fructosamine and glycated hemoglobin as biomarkers of glycemic control in people with type 2 diabetes mellitus and cancer (GlicoOnco study)(2023) TOYOSHIMA, Marcos Tadashi Kakitani; CUKIER, Priscilla; DAMASCENA, Aline Santos; BATISTA, Rafael Loch; CORREA, Fernanda de Azevedo; KAWAHARA, Eduardo Zanatta; MINANNI, Carlos Andre; HOFF, Ana O.; NERY, MarciaIntroduction: Glycemic control is important to avoid diabetes complications in individuals with cancer. There is no evidence for HbA1c and fructosamine as reliable biomarkers in these conditions. There are particularities in caring for patients with diabetes and cancer that can alter these biomarkers.Objective: The aim of this study was to evaluate HbA1c and fructosamine as glycemic biomarkers in people with type 2 diabetes and cancer, undergoing clinical or surgical oncological treatment. Methods: The authors conducted a single-center, retrospective analysis with people who have cancer and diabetes. Comparison of glycemic biomarkers (HbA1c, fructosamine, and Self-Monitoring of Blood Glucose [SMBG]) was performed including evaluation in individuals undergoing chemotherapy, using glucocorticoids, with anemia, hypoproteinemia or with reduced estimated Glomerular Filtration Rate (eGFR).Results: There was a strong positive correlation between fructosamine and HbA1c (n = 318, r = 0.66, p < 0.001) in people with diabetes and cancer even in those under chemotherapy (n = 101, r = 0.61, p < 0.001) or using glucocorticoids (n = 96, r = 0.67, p<0.001). There was a strong correlation between HbA1c and fructosamine in subjects with anemia (n = 111, r = 0.66, p < 0.001), hypoproteinemia (n = 54, r = 0.67, p < 0.001), or with eGFR & GE; 60 mL/min/1.73 m2 (n = 189, r = 0.70, p < 0.001), and moderate correlation with hypoalbuminemia (n = 21, r = 0.54, p = 0.001) and with reduced eGFR (n = 67, r = 0.57, p < 0.001). The correlations between fructosamine and HbA1c with SMBG were moderate (n = 164, r = 0.49, p < 0.001; n = 111, r = 0.55, p < 0.001, respectively), strong in subjects undergoing chemotherapy, with hypoalbuminemia or hypoproteinemia, and at least moderate, if eGFR < 60 mL/min/1.73 m2 or with anemia. Conclusions: Fructosamine and HbA1c can be used as glycemic biomarkers in people with diabetes and cancer, even in those with anemia, hypoproteinemia, or undergoing chemotherapy.
- Cabergoline in the Management of Residual Nonfunctioning Pituitary Adenoma A Single-Center, Open-Label, 2-Year Randomized Clinical Trial(2019) BATISTA, Rafael L.; MUSOLINO, Nina R. C.; CESCATO, Valter A. S.; SILVA, Gilberto O. da; MEDEIROS, Raphael S. S.; HERKENHOFF, Clarissa G. B.; TRARBACH, Ericka B.; CUNHA-NETO, Malebranche B.Background: Complete tumor removal by transsphenoidal surgery is usually difficult for large nonfunctioning pituitary adenomas (NFPAs). A validated medical treatment may be useful for their management. This study evaluates the clinical efficacy of the dopaminergic agonist cabergoline for residual NFPA. Design, Setting, and Participants: We conducted a randomized, parallel, open-label clinical trial that compared cabergoline with nonintervention in patients with residual NFPA after transsphenoidal surgery over 2 years. The primary outcome was clinical efficacy (tumor reduction). The secondary outcome was the relationship between tumor dopamine D2 receptor (D2R) expression and clinical responsiveness. Tumor measurements and clinical evaluations were performed every 6 months. Results: In total, 59 and 57 individuals were randomly assigned to the study and control groups, respectively. At the end of the study, residual tumor shrinkage, stabilization, and enlargement were observed in 28.8%, 66.1%, and 5.1% of patients, respectively, in the medical-therapy group and in 10.5%, 73.7%, and 15.8% of patients, respectively, in the control group (P=0.01). The progression-free survival rate was 23.2 and 20.8 months for the study and control groups, respectively (P=0.01). D2R was not associated with cabergoline responsiveness. No major side effects were related to cabergoline use. Conclusions: Cabergoline was an effective drug for treating residual NFPA, and its use was associated with a high rate of tumor shrinkage ( NCT03271918).
- Clinically nonfunctioning pituitary adenoma growth after radiosurgery(2012) BATISTA, Rafael Loch; TOSCANINI, Andrea Cecilia; GLEZER, Andrea; SIQUEIRA, Mario Gilberto; BENABOU, Salomon; FONOFF, Erick Talamoni; TAVARES, Wagner Malago; TEIXEIRA, Manoel Jacobsen; CUNHA NETO, Malebranche Berardo Carneiro da