ANA CLAUDIA LATRONICO XAVIER
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
171 resultados
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- Myocardial Inactivation of Thyroid Hormones in Patients with Aortic Stenosis(2017) PAOLINO, Bruno S.; POMERANTZEFF, Pablo M.; DALLAN, Luis Alberto O.; GAIOTTO, Fabio A.; PREITE, Nailliw Z.; LATRONICO, Ana Claudia; NICOLAU, Jose Carlos; BIANCO, Antonio C.; GIRALDEZ, Roberto R. C. V.Objective: The human heart expresses the type 2 deiodinase (D2) that activates thyroxine (T4) to triiodothyronine (T3). At the same time, the inactivating type 3 deiodinase (D3) has been found in a rat model of right ventricular hypertrophy. It is not known whether the human myocardium metabolizes thyroid hormone. This study examined myocardial thyroid hormone metabolism in patients with aortic valve stenosis (AS) undergoing aortic valve replacement and in patients with coronary artery disease (CAD) undergoing coronary artery bypass grafting surgery. Methods: Myocardial thyroid hormone metabolism was assessed by analyzing the difference in serum thyroid hormone levels between the aortic root (incoming blood) and the coronary sinus (outgoing blood) of patients undergoing cardiac surgery. A total of 23 patients with AS and 35 patients with CAD were included. Patients received a pre-surgical echocardiogram, and pre-, during and post-surgical thyroid hormone serum levels were collected in the myocardial and peripheral circulations. Results: Patients with AS exhibited the expected left ventricle (LV) hypertrophy (i.e., 20-30% increase in LV posterior wall and interventricular septum thickness and similar to 10% increase in AS in LV diastolic diameter). Immediately before cardiopulmonary bypass, blood flowing through the AS myocardium exhibited a 4.6% reduction in T3 and 6.9% increase in rT3 levels, decreasing the serum T3/rT3 ratio by 9.6%. T4 and thyrotropin serum levels remained similar between the aortic root and coronary sinus. In contrast, no myocardial thyroid hormone metabolism was observed in CAD patients. Notably, the AS myocardium lost the ability to inactivate thyroid hormone after cardiopulmonary bypass, possibly due to myocardial stunning. Conclusions: There is accelerated thyroid hormone inactivation in the AS myocardium, which is likely the result of D3 expression. No evidence to suggest thyroid hormone activation in the myocardium was obtained in the present study.
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.- KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After Adrenalectomy for Unilateral Primary Aldosteronism(2019) VILELA, Leticia A. P.; RASSI-CRUZ, Marcela; GUIMARAES, Augusto G.; MOISES, Caio C. S.; FREITAS, Thais C.; ALENCAR, Natalia P.; PETENUCI, Janaina; GOLDBAUM, Tatiana S.; MACIEL, Ana Alice W.; PEREIRA, Maria Adelaide A.; V, Giovanio Silva; PIO-ABREU, Andrea; ZERBINI, Maria Claudia N.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; YAMAUCHI, Fernando; SROUGI, Vitor; TANNO, Fabio Y.; CHAMBO, Jose L.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; BORTOLOTTO, Luiz A.; DRAGER, Luciano F.; ALMEIDA, Madson Q.Context: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear. Objective: To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA. Methods: We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases. Results: KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.GIu145GIn (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P= 0.0001), and 64.9% had HT duration <10 years (P= 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004). Conclusion: The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.
- Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma(2023) FAGUNDES, Gustavo F. C.; FREITAS-CASTRO, Felipe; SANTANA, Lucas S.; AFONSO, Ana Caroline F.; PETENUCI, Janaina; FUNARI, Mariana F. A.; GUIMARAES, Augusto G.; LEDESMA, Felipe L.; PEREIRA, Maria Adelaide A.; VICTOR, Carolina R.; FERRARI, Marcela S. M.; COELHO, Fernando M. A.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose L.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; HOFF, Ana O.; ALMEIDA, Madson Q.Context Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. Objective Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. Methods Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. Results Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X-2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. Conclusion The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas.
- Genetic and clinical aspects of paediatric pheochromocytomas and paragangliomas(2021) PETENUCI, Janaina; GUIMARAES, Augusto G.; FAGUNDES, Gustavo F. C.; BENEDETTI, Anna Flavia F.; AFONSO, Ana Caroline F.; PEREIRA, Maria Adelaide A.; ZERBINI, Maria Claudia N.; SIQUEIRA, Sheila; YAMAUCHI, Fernando; SOARES, Silvia C.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose L.; I, Roberto Lopes; DENES, Francisco T.; HOFF, Ana O.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; ALMEIDA, Madson Q.Objective Few and conflicting reports have characterized the genetics of paediatric pheochromocytomas and paragangliomas (PPGLs). This study aimed to investigate the clinical and genetic features of Brazilian children with PPGL. Patients and Methods This study included 25 children (52% girls) with PPGL. The median age at diagnosis was 15 years (4-19). The median time of follow-up was 145 months. The genetic investigation was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification and/or target next-generation sequencing panel. Results Of the 25 children with PPGL, 11 (44%), 4 (16%), 2 (8%), 1 (4%) and 7 (28%) had germline VHL pathogenic variants, SDHB, SDHD, RET and negative genetic investigation, respectively. Children with germline VHL missense pathogenic variants were younger than those with SDHB or SDHD genetic defects [median (range), 12 (4-16) vs. 15.5 (14-19) years; P = .027]. Moreover, 10 of 11 cases with VHL pathogenic variants had bilateral pheochromocytoma (six asynchronous and four synchronous). All children with germline SDHB pathogenic variants presented with abdominal paraganglioma (one of them malignant). The two cases with SDHD pathogenic variants presented with head and neck paraganglioma. Among the cases without a genetic diagnosis, 6 and 2 had pheochromocytoma and paraganglioma, respectively. Furthermore, metastatic PPGL was diagnosed in four (16%) of 25 PPGL. Conclusions Most of the paediatric PPGL were hereditary and multifocal. The majority of the affected genes belong to pseudohypoxic cluster 1, with VHL being the most frequently mutated. Therefore, our findings impact surgical management and surveillance of children with PPGL.
- Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations (vol 106, pg 1041, 2021)(2021) SERAPHIM, C. E.; CANTON, A. P. M.; MONTENEGRO, L.; PIOVESAN, M. R.; MACEDO, D. B.; CUNHA, M.; GUIMARAES, A.; RAMOS, C. O.; BENEDETTI, A. F. F.; LEAL, De Castro A.; GAGLIARDI, P. C.; ANTONINI, S. R.; GRYNGARTEN, M.; ARCARI, A. J.; ABREU, A. P.; KAISER, U. B.; SORIANO-GUILLEN, L.; ESCRIBANO-MUNOZ, A.; CORRIPIO, R.; I, J. Labarta; TRAVIESO-SUAREZ, L.; V, N. Ortiz-Cabrera; ARGENTE, J.; MENDONCA, B. B.; BRITO, V. N.; LATRONICO, A. C.
- Normal bone mass and normocalcemia in adulthood despite homozygous vitamin D receptor mutations(2015) DAMIANI, F. M.; MARTIN, R. M.; LATRONICO, A. C.; FERRAZ-DE-SOUZA, B.A Summary Adding to the debate around vitamin D's effects on skeletal health, we report the long-term follow-up of two patients with severe vitamin D receptor mutations, who had normal bone mass acquisition and normalization of calcemia around puberty, suggesting that vitamin D might not be essential for skeletal health in adulthood. Introduction Vitamin D plays a pivotal role in calcium homeostasis, and the consequences of vitamin D insufficiency for skeletal health, as well as the importance of its supplementation, are a matter of great interest. Individuals bearing homozygous vitamin D receptor (VDR) defects present with severe hypocalcemic rickets in early infancy due to vitamin D resistance. Methods Here, we report the follow-up of two patients with hereditary vitamin D-resistant rickets (HVDRR), focusing on bone mass acquisition and evolution of calcemia. Results Patient 1 is a 30-year-old male bearing a homozygous p.Arg30* nonsense mutation in the VDR DNA-binding domain, who presented at 6 months. From 9 years of age, treatment requirement decreased progressively. Follow-up with DXA showed normal bone mass acquisition. In adulthood, he maintains normocalcemia without calcium supplementation and has no signs of bone fragility. Patient 2 is a 37-year-old female with milder HVDRR and alopecia due to a homozygous p.Gly319Val mutation in the VDR ligand-binding domain. Around puberty, hypercalciuria and kidney stones were detected, resulting in suspension of treatment. Follow-up with DXA revealed normal bone mass, and she maintained normocalcemia without supplementation during gestation and lactation. Conclusions The long-term follow-up of HVDRR provides insights into the role of vitamin D in human calcium homeostasis and bone health. The normalization of calcemia and normal bone mass acquisition despite a permanently dysfunctional VDR suggest that vitamin D might not be essential for skeletal health in adulthood. Extrapolation of these findings may have implications in broader clinical settings, especially considering widespread vitamin D supplementation.
- Mutational Analysis of the Genes Encoding RFAmide-Related Peptide-3, the Human Orthologue of Gonadotrophin-Inhibitory Hormone, and its Receptor (GPR147) in Patients with Gonadotrophin-Releasing Hormone-Dependent Pubertal Disorders(2014) LIMA, C. J. G.; CARDOSO, S. C.; LEMOS, E. F. L.; ZINGLER, E.; CAPANEMA, C.; MENEZES, L. D.; VOGADO, G.; SANTOS, B. T. A. dos; MORAES, O. L. de; DUARTE, E. F.; BRITO, V. N. de; LATRONICO, A. C.; LOFRANO-PORTO, A.RFamide-related peptide-3 (RFRP-3), the orthologue of avian gonadotrophin-inhibitory hormone, and its receptor GPR147 have been recently identified in the human hypothalamus, and their roles in the regulation of reproductive axis has been studied. The present study aimed to investigate whether the presence of variants in the genes encoding human RFRP-3 (NPVF gene) and its receptor, GPR147 (NPFFR1 gene), is associated with the occurrence of gonadotrophin-releasing hormone-dependent pubertal disorders. Seventy-eight patients with idiopathic central precocious puberty (CPP) and 51 with normosmic isolated hypogonadotrophic hypogonadism (nIHH) were investigated. Fifty healthy subjects comprised the control group. The coding sequences of the NPVF and NPFFR1 genes were amplified and sequenced. Odds ratios (OR) were used to estimate the likelihood of CPP or nIHH in the presence of the described polymorphisms. All such polymorphisms have already been registered in the National Center for Biotechnology Information database. A three-nucleotide in frame deletion was identified in the NPVF gene (p.I71_K72), with a smaller proportion in the CPP (5%) compared to the nIHH (15%) group (P=0.06). This results in the deletion of the isoleucine at position 71, adjacent to lysine at an endoproteolytic cleavage site of the precursor peptide. This polymorphism was associated with a lower risk of CPP (OR=0.33; 95% confidence interval=0.08-0.88); interestingly, only two men with nIHH were homozygotes for this variant. A total of five missense polymorphisms were found in the NPFFR1 gene, which encodes GPR147, with similar frequencies among groups and no association with pubertal timing. Our data suggest that RFRP-3/GPR147 may play secondary, modulatory roles on the regulation of pubertal development; a restraining modulatory effect of the NPVF p.I71_K72 variant on the activation of the gonadotrophic axis cannot be ruled out and deserves further investigation.
- Transcriptomic Response to 1,25-Dihydroxyvitamin D in Human Fibroblasts with or without a Functional Vitamin D Receptor (VDR): Novel Target Genes and Insights into VDR Basal Transcriptional Activity(2019) COSTA, Pedro L. F.; FRANCA, Monica M.; KATAYAMA, Maria L.; CARNEIRO, Eduardo T.; MARTIN, Regina M.; FOLGUEIRA, Maria A. K.; LATRONICO, Ana C.; FERRAZ-DE-SOUZA, BrunoThe vitamin D receptor (VDR) mediates vitamin D actions beyond bone health. While VDR activation by 1,25-dihydroxyvitamin D (1,25D) leads to robust transcriptional regulation, less is known about VDR actions in the absence of 1,25D. We analyzed the transcriptomic response to 1,25D in fibroblasts bearing a severe homozygous hereditary vitamin D resistant rickets-related p.Arg30* VDR mutation (MUT) and in control fibroblasts (CO). Roughly 4.5% of the transcriptome was regulated by 1,25D in CO fibroblasts, while MUT cells without a functional VDR were insensitive to 1,25D. Novel VDR target genes identified in human fibroblasts included bone and cartilage factors CILP, EFNB2, and GALNT12. Vehicle-treated CO and MUT fibroblasts had strikingly different transcriptomes, suggesting basal VDR activity. Indeed, oppositional transcriptional effects in basal conditions versus after 1,25D activation were implied for a subset of target genes mostly involved with cell cycle. Cell proliferation assays corroborated this conjectured oppositional basal VDR activity, indicating that precise 1,25D dosage in target tissues might be essential for modulating vitamin D actions in human health.
conferenceObject X-Linked Central Precocious Puberty Associated with MECP2 defects(2022) CANTON, Ana; TINANO, Flavia; GUASTI, Leonardo; MONTENEGRO, Luciana; RYAN, Fiona; SHEARS, Deborah; MELO, Maria Edna; GOMES, Larissa; PIANA, Mariana; BRAUNER, Raja; ESPINO, Rafael; ESCRIBANO-MUNOZ, Arancha; PAGANONI, Alyssa; KORBONITS, Marta; SERAPHIM, Carlos Eduardo; FARIA, Aline; COSTA, Silvia; KREPISCHI, Ana Cristina; JORGE, Alexander; DAVID, Alessia; ARGENTE, Jesus; MENDONCA, Berenice; BRITO, Vinicius; HOWARD, Sasha; LATRONICO, Ana Claudia