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
10 resultados
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conferenceObject 46,XY Partial gonadal dysgenesis; diagnosis and long-term outcome at puberty(2022) CUCCARO, Rieko Tadokoro; HUGHES, Ieuan; COOLS, Martine; VIJVER, Koen van de; MENDONCA, Berenice Bilharinho de; DOMENICE, Sorahia; BATISTA, Rafael L.; DALLAGO, Renata Thomazini; GOMES, Nathalia Lisboa; COSTA, Elaine F.; MACIEL-GUERRA, Andrea T.; GUERRA-JUNIOR, Gil; ANDRADE, Juliana Gabriel Ribeiro de; LUCAS-HERALD, Angela; BRYCE, Jillian; HANNEMA, Sabine; JUUL, Anders; GLOBA, Eugenia; ELREAVEY, Kenneth M.; BARONIO, Federico; DACAL, Jimena Lopez; DARENDELILER, Feyza; POYRAZOGLU, Sukran; KOLESINSKA, Zofia; NIEDZIELA, Marek; CLAAHSEN, Hedi; AKKER, Erica L. T. van den; HERRMANN, Gloria; ATAPATTU, Navoda; JAIN, Vandana; SHARMA, Rajni; BETTERDORF, Markus; KONRAD, Daniel; HOLTERHUS, Paul Martin; FICA, Simona; SKAE, Mars; RUSSO, Gianni; STANCAMPIANO, Marianna Rita; GAZDAGH, Gabriella; DAVIES, Justin H.; MOHAMED, Zainaba; SENEVIRATNE, Sumudu Nimali; GURAN, Tulay; GUVEN, Ayla; WASNIEWSKA, Malgorzata; MLADENOV, Vilhelm; VERKAUSKAS, Gilvydas; MARKOSYAN, Renata; KORBONITS, Marta; HIORT, Olaf; WAGNER, IsabelViola; AHMED, S. Faisal; THANKAMONY, Ajay- 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.
conferenceObject Gonadal morphology in 46,XY gonadal dysgenesis: I-DSD Registry-based study(2022) TADOKORO-CUCCARO, Rieko; HUGHES, Ieuan; COOLS, Martine; VIJVER, Koen van de; MENDONCA, Berenice Bilharinho de; DOMENICE, Sorahia; BATISTA, Rafael L.; DALLAGO, Renata Thomazini; GOMES, Nathalia Lisboa; COSTA, Elaine F.; MACIEL-GUERRA, Andrea T.; GUERRA-JUNIOR, Gil; ANDRADE, Juliana Gabriel Ribeiro de; LUCAS-HERALD, Angela; BRYCE, Jillian; HANNEMA, Sabine; JUUL, Anders; GLOBA, Eugenia; ELREAVEY, Kenneth M.; BARONIO, Federico; DACAL, Jimena Lopez; DARENDELILER, Feyza; POYRAZOGLU, Sukran; KOLESINSKA, Zofia; NIEDZIELA, Marek; GRINTEN, Hedi L. Claahsen-van der; AKKE, Erica L. T. van den; HERRMANN, Gloria; ATAPATTU, Navoda; JAIN, Vandana; SHARMA, Rajni; BETTENDORF, Markus; KONRAD, Daniel; HOLTERHUS, Paul Martin; FICA, Simona; SKAE, Mars; RUSSO, Gianni; STANCAMPIANO, Marianna Rita; GAZDAGH, Gabriella; DAVIES, Justin H.; MOHAMED, Zainaba; SENEVIRATNE, Sumudu Nimali; GURAN, Tulay; GUVEN, Ayla; WASNIEWSKA, Malgorzata; MLADENOV, Vilhelm; VERKAUSKAS, Gilvydas; MARKOSYAN, Renata; KORBONITS, Marta; AHMED, S. Faisal; HIORT, Olaf; WAGNER, Isabel; THANKAMONY, Ajay- The Molecular Basis of 5 alpha-Reductase Type 2 Deficiency(2022) BATISTA, Rafael L.; MENDONCA, Berenice B.The 5 alpha-reductase type 2 enzyme catalyzes the conversion of testosterone into dihydrotestosterone, playing a crucial role in male development. This enzyme is encoded by the SRD5A2 gene, which maps to chromosome 2 (2p23), consists of 5 exons and 4 introns, and encodes a 254 amino acid protein. Disruptions in this gene are the molecular etiology of a subgroup of differences of sex development (DSD) in 46,XY patients. Affected individuals present a large range of external genitalia undervirilization, ranging from almost typically female external genitalia to predominantly typically male external genitalia with minimal undervirilization, including isolated micropenis. This is an updated review of the implication of the SRD5A2 gene in 5 alpha-reductase type 2 enzyme deficiency. For that, we identified 451 cases from 48 countries of this particular 46,XY DSD from the literature with reported variants in the SRD5A2 gene. Herein, we present the SRD5A2 mutational profile, the SRD5A2 polymorphisms, and the functional studies related to SRD5A2 variants to detail the molecular etiology of this condition. (c) 2022 S. Karger AG, Base
- The Use of Genetics for Reaching a Diagnosis in XY DSD(2022) AHMED, S. Faisal; ALIMUSINA, Malika; BATISTA, Rafael L.; DOMENICE, Sorahia; GOMES, Nathalia Lisboa; MCGOWAN, Ruth; PATJAMONTRI, Supitcha; MENDONCA, Berenice B.Reaching a firm diagnosis is vital for the long-term management of a patient with a difference or disorder of sex development (DSD). This is especially the case in XY DSD where the diagnostic yield is particularly low. Molecular genetic technology is playing an increasingly important role in the diagnostic process, and it is highly likely that it will be used more often at an earlier stage in the diagnostic process. In many cases of DSD, the clinical utility of molecular genetics is unequivocally clear, but in many other cases there is a need for careful exploration of the benefit of genetic diagnosis through long-term monitoring of these cases. Furthermore, the incorporation of molecular genetics into the diagnostic process requires a careful appreciation of the strengths and weaknesses of the evolving technology, and the interpretation of the results requires a clear understanding of the wide range of conditions that are associated with DSD.
- Elevated plasma miR-210 expression is associated with atypical genitalia in patients with 46,XY differences in sex development(2022) ELIAS, Felipe Martins; NISHI, Mirian Yumi; SIRCILI, Maria Helena Palma; BASTISTA, Rafael Loch; GOMES, Nathalia Lisboa; FERRARI, Maria Tereza Martins; COSTA, Elaine Maria Frade; DENES, Francisco Tibor; MENDONCA, Berenice Bilharinho; DOMENICE, SorahiaBackground: Differences of sex development (DSD) is a term used for conditions in which the chromosomal, gonadal or phenotypical sex is atypical. 46,XY DSD patients frequently present undervirilized external genitalia. The expression of different miRNAs in many organs of the male genital system has been reported, and these miRNAs have been associated with testicular function and its disorders, but no description has been related to DSD conditions. This study aimed to evaluate the plasma expression of miR-210 in 46,XY DSD patients who presented atypical genitalia at birth. Methods: Eighteen 46,XY DSD patients who presented atypical genitalia (undescended testis and/or hypospadias, bifid scrotum or micropenis) at birth and 36 male control individuals were selected. Plasma levels of miR-210 and reference miR-23a were measured using RT-qPCR and the data were analysed by the 2(-Delta Ct) method. Results: MiR-210 plasma levels were significantly higher in 46,XY DSD patients with atypical genitalia than in male control subjects (p = 0.0024). A positive association between miR-210 levels and the presence of cryptorchidism and hypospadias (p = 0.0146 and p = 0.0223) was found in these patients. Significantly higher levels of miR-210 were observed in patients with 46,XY DSD and cryptorchidism than in control subjects (p = 0.0118). These results are in agreement with previous literature reports, in which increased levels of miR-210 expression were observed in human testicular tissue from adult males with undescended testes in comparison with samples of descended testes. Conclusion: Our study showed a positive association between the presence of atypical genitalia and plasma levels of miR-210 expression in the group of patients with 46,XY DSD of unknown aetiology studied. These findings contribute to reveal a new perspective on the role of miRNAs in the development of male external genitalia and the broad spectrum of phenotypes presented by patients with 46,XY DSD.
- WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease(2022) FERRARI, M. T. M.; WATANABE, A.; SILVA, T. E. Da; GOMES, N. L.; BATISTA, R. L.; NISHI, M. Y.; PAULA, L. C. P. De; COSTA, E. C.; COSTA, E. M. F.; CUKIER, P.; ONUCHIC, L. F.; MENDONCA, B. B.; DOMENICE, S.Wilms' tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms' tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs∗14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.
- Central adrenal insufficiency: who, when, and how? From the evidence to the controversies - an exploratory review(2022) BITENCOURT, Mariana Rechia; BATISTA, Rafael Loch; BISCOTTO, Isabela; CARVALHO, Luciani R.Central adrenal insufficiency (CAI) is a life-threatening disorder. This occurs when ACTH production is insufficient, leading to low cortisol levels. Since corticosteroids are crucial to many metabolic responses under organic stress and inflammatory conditions, CAI recognition and prompt treatment are vital. However, the diagnosis of CAI is challenging. This is not only because its clinical presentation is usually oligosymptomatic, but also because the CAI laboratory investigation presents many pitfalls. Thus, the clarification of when to use each test could be helpful in many contexts. The CAI challenge is also involved in treatment: Several formulations of synthetic steroids exist, followed by the lack of a biomarker for glucocorticoid replacement. This review aims to access all available literature to synthesize important topics about who should investigate CAI, when it should be suspected, and how CAI must be treated. Arch Endocrinol Metab. 2022;66(4):541-50
- Contribution of Clinical and Genetic Approaches for Diagnosing 209 Index Cases With 46,XY Differences of Sex Development(2022) GOMES, Nathalia Lisboa; BATISTA, Rafael Loch; NISHI, Mirian Y.; LERARIO, Antonio Marcondes; SILVA, Thatiana E.; NARCIZO, Amanda de Moraes; BENEDETTI, Anna Flavia Figueredo; FUNARI, Mariana Ferreira de Assis; FARIA JUNIOR, Jose Antonio; MORAES, Daniela Rodrigues; QUINTAO, Lia Mesquita Lousada; MONTENEGRO, Luciana Ribeiro; FERRARI, Maria Teresa Martins; JORGE, Alexander A.; ARNHOLD, Ivo J. P.; COSTA, Elaine Maria Frade; DOMENICE, Sorahia; MENDONCA, Berenice BilharinhoContext Massively parallel sequencing (MPS) technologies have emerged as a first-tier approach for diagnosing several pediatric genetic syndromes. However, MPS has not been systematically integrated into the diagnostic workflow along with clinical/biochemical data for diagnosing 46,XY differences of sex development (DSD). Objective To analyze the contribution of phenotypic classification either alone or in association with genetic evaluations, mainly MPS, for diagnosing a large cohort of 46,XY DSD patients. Design/patients 209 nonsyndromic 46,XY DSD index cases from a Brazilian DSD center were included. Patients were initially classified into 3 subgroups according to clinical and biochemical data: gonadal dysgenesis (GD), disorders of androgen secretion/action, and DSD of unknown etiology. Molecular genetic studies were performed by Sanger sequencing and/or MPS. Results Clinical/biochemical classification into either GD or disorders of hormone secretion/action was obtained in 68.4% of the index cases. Among these, a molecular diagnosis was obtained in 36% and 96.5%, respectively. For the remainder 31.6% classified as DSD of clinically unknown etiology, a molecular diagnosis was achieved in 31.8%. Overall, the molecular diagnosis was achieved in 59.3% of the cohort. The combination of clinical/biochemical and molecular approaches diagnosed 78.9% of the patients. Clinical/biochemical classification matched with the genetic diagnosis in all except 1 case. DHX37 and NR5A1 variants were the most frequent genetic causes among patients with GD and DSD of clinical unknown etiology, respectively. Conclusions The combination of clinical/biochemical with genetic approaches significantly improved the diagnosis of 46,XY DSD. MPS potentially decreases the complexity of the diagnostic workup as a first-line approach for diagnosing 46,XY DSD.
- Mild Androgen Insensitivity Syndrome: The Current Landscape(2022) BATISTA, Rafael Loch; CRAVEIRO, Flora Ladeira; RAMOS, Raquel Martinez; MENDONCA, Berenice BilharinhoObjective: Mild androgen insensitivity syndrome (MAIS) belongs to the androgen insensitivity syndrome (AIS) spectrum, an X-linked genetic disease that is the most common cause of differences in sex development. Unfortunately, AIS studies mainly focus on the partial and complete phenotypes, and the mild phenotype (MAIS) has been barely reported. Our purpose is to explore the MAIS facets, clinical features, and molecular aspects. Methods: We collected all reported MAIS cases in the medical literature and presented them based on the phenotype and molecular diagnosis. Results: We identified 49 different androgen receptor (AR) mutations in 69 individuals in the literature. We compared the AR mutations presented in individuals with MAIS with AR mutations previously re-ported in other AIS phenotypes (partial and complete) regarding the type, location, genotype-phenotype correlation, and functional studies. Conclusion: This review provides a landscape of the mild phenotype of AIS. Most patients with MAIS present with male factor infertility. Therefore, AR gene sequencing should be considered during male factor infertility investigation, even in males with typically male external genitalia. In addition, MAIS can be part of other medical conditions, such as X-linked spinal and bulbar muscular atrophy (Kennedy disease).