REGINA MATSUNAGA MARTIN
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Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients(2020) MANTOVANI, Giovanna; BASTEPE, Murat; MONK, David; SANCTIS, Luisa De; THIELE, Susanne; AHMED, S. Faisal; BUFO, Roberto; CHOPLIN, Timothee; FILIPPO, Gianpaolo De; DEVERNOIS, Guillemette; EGGERMANN, Thomas; ELLI, Francesca M.; RAMIREZ, Aurora Garcia; GERMAIN-LEE, Emily L.; GROUSSIN, Lionel; HAMDY, Neveen A. T.; HANNA, Patrick; HIORT, Olaf; JUEPPNER, Harald; KAMENICKY, Peter; KNIGHT, Nina; NORCY, Elvire Le; LECUMBERRI, Beatriz; LEVINE, Michael A.; MAEKITIE, Outi; MARTIN, Regina; MARTOS-MORENO, Gabriel Angel; MINAGAWA, Manasori; MURRAY, Philip; PEREDA, Arrate; PIGNOLO, Robert; REJNMARK, Lars; RODADO, Rebeca; ROTHENBUHLER, Anya; SARAFF, Vrinda; SHOEMAKER, Ashley H.; SHORE, Eileen M.; SILVE, Caroline; TURAN, Serap; WOODS, Philip; ZILLIKENS, M. Carola; NANCLARES, Guiomar Perez de; LINGLART, AgnesPatients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.
- 46,XY disorder of sex development (DSD) due to 17 beta-hydroxysteroid dehydrogenase type 3 deficiency(2017) MENDONCA, Berenice B.; GOMES, Nathalia Lisboa; COSTA, Elaine M. F.; INACIO, Marlene; MARTIN, Regina M.; NISHI, Mirian Y.; CARVALHO, Filomena Marino; TIBOR, Francisco Denes; DOMENICE, Sorahia17 beta-hydroxysteroid dehydrogenase 3 deficiency consists of a defect in the last phase of steroidogenesis, in which androstenedione is converted into testosterone and estrone into estradiol. External genitalia range from female-like to atypical genitalia and most affected males are raised as females. Virilization in subjects with 17 beta-HSD3 deficiency occurs at the time of puberty and several of them change to male social sex. In male social sex patients, testes can be safely maintained, as long as they are positioned inside the scrotum The phenotype of 46,XY DSD due to 17 beta-HSD3 deficiency is extremely variable and clinically indistinguishable from other causes of 46,XY DSD such as partial androgen insensitivity syndrome and 5 alpha-reductase 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio due to high serum levels of androstenedione and low levels of testosterone. The disorder is caused by a homozygous or compound heterozygous mutations in the HSD17B3 gene that encodes the 17 beta-HSD3 isoenzyme leading to an impairment of the conversion of 17-keto into 17-hydroxysteroids. Molecular genetic testing confirms the diagnosis and provides the orientation for genetic counseling. Our proposal in this article is to review-the previously reported cases of 17 beta-HSD3 deficiency adding our own cases. (C) 2016 Published by Elsevier Ltd.
- The molecular landscape of osteogenesis imperfecta in a Brazilian tertiary service cohort(2020) FERNANDES, A. M.; ROCHA-BRAZ, M. G. M.; FRANCA, M. M.; LERARIO, A. M.; SIMOES, V. R. F.; ZANARDO, E. A.; KULIKOWSKI, L. D.; MARTIN, R. M.; MENDONCA, B. B.; FERRAZ-DE-SOUZA, B.We have sought the molecular diagnosis of OI in 38 Brazilian cases through targeted sequencing of 15 candidate genes. While 71% had type 1 collagen-related OI, defects in FKBP10, PLOD2 and SERPINF1, and a potential digenic P3H1/WNT1 interaction were prominent causes of OI in this underrepresented population. Introduction Defects in type 1 collagen reportedly account for 85-90% of osteogenesis imperfecta (OI) cases, but most available molecular data has derived from Sanger sequencing-based approaches in developed countries. Massively parallel sequencing (MPS) allows for systematic and comprehensive analysis of OI genes simultaneously. Our objective was to obtain the molecular diagnosis of OI in a single Brazilian tertiary center cohort. Methods Forty-nine individuals (84% adults) with a clinical diagnosis of OI, corresponding to 30 sporadic and 8 familial cases, were studied. Sixty-three percent had moderate to severe OI, and consanguinity was common (26%). Coding regions and 25-bp boundaries of 15 OI genes (COL1A1, COL1A2, IFITM5 [plus 5 ' UTR], SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, PLOD2, BMP1, SP7, TMEM38B, WNT1, CREB3L1) were analyzed by targeted MPS and variants of interest were confirmed by Sanger sequencing or SNP array. Results A molecular diagnosis was obtained in 97% of cases. COL1A1/COL1A2 variants were identified in 71%, whereas 26% had variants in other genes, predominantly FKBP10, PLOD2, and SERPINF1. A potential digenic interaction involving P3H1 and WNT1 was identified in one case. Phenotypic variability with collagen defects could not be explained by evident modifying variants. Four consanguineous cases were associated to heterozygous COL1A1/COL1A2 variants, and two nonconsanguineous cases had compound PLOD2 heterozygosity. Conclusions Novel disease-causing variants were identified in 29%, and a higher proportion of non-collagen defects was seen. Obtaining a precise diagnosis of OI in underrepresented populations allows expanding our understanding of its molecular landscape, potentially leading to improved personalized care in the future.
- 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.
bookPart Hipercalcemia e hiperparatireoidismo primário(2022) MARTIN, Regina Matsunaga- Time to Recurrence as a Prognostic Factor in Parathyroid Carcinoma(2023) MAGNABOSCO, Felipe Ferraz; BRESCIA, Marilia D'Elboux Guimaraes; NASCIMENTO JUNIOR, Climerio Pereira; MASSONI NETO, Ledo Mazzei; ARAP, Sergio Samir; CASTRO JUNIOR, Gilberto de; LEDESMA, Felipe Lourenco; ALVES, Venancio Avancini Ferreira; KOWALSKI, Luiz Paulo; MARTIN, Regina Matsunaga; MONTENEGRO, Fabio Luiz de MenezesBackground Parathyroid carcinoma (PC) is a rare and challenging disease without clearly understood prognostic factors. Adequate management can improve outcomes. Characteristics of patients treated for PC over time and factors affecting prognosis were analyzed. Methods Retrospective cohort study including surgically treated patients for PC between 2000 and 2021. If malignancy was suspected, free-margin resection was performed. Demographic, clinical, laboratory, surgical, pathological, and follow-up characteristics were assessed. Results Seventeen patients were included. Mean tumor size was 32.5 mm, with 64.7% staged as pT1/pT2. None had lymph node involvement at admission, and 2 had distant metastases. Parathyroidectomy with ipsilateral thyroidectomy was performed in 82.2%. Mean postoperative calcium levels were different between patients who developed recurrence vs those who did not (P = .03). Six patients (40%) had no recurrence during follow-up, 2 (13.3%) only regional, 3 (20%) only distant, and 4 (26.6%) both regional and distant. At 5 and 10 years, 79% and 56% of patients were alive, respectively. Median disease-free survival was 70 months. Neither Tumor, Nodule, Metastasis system nor largest tumor dimension (P = .29 and P = .74, respectively) were predictive of death. En bloc resection was not superior to other surgical modalities (P = .97). Time between initial treatment and development of recurrence negatively impacted overall survival rate at 36 months (P = .01). Conclusion Patients with PC can survive for decades and have indolent disease course. Free margins seem to be the most important factor in initial surgery. Recurrence was common (60%), but patients with disease recurrence within 36 months of initial surgery had a lower survival rate.
- 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.
bookPart Biologia molecular dos tumores endócrinos(2013) LERARIO, Antonio Marcondes; FRAGOSO, Maria Candida Barisson; BRITO, Luciana Pinto; MARTIN, Regina Matsunaga; TRARBACH, Erika Barbosa; MARUI, Suemi; TOLEDO, Rodrigo de Almeida; DOMENICE, Sorahia; MENDONçA, Berenice Bilharinho de- Oral and maxillofacial manifestations of chronic kidney disease-mineral and bone disorder: a multicenter retrospective study(2018) PONTES, Flavia Sirotheau Correa; LOPES, Marcio Ajudarte; SOUZA, Lucas Lacerda de; REZENDE, Diogo dos Santos da Mata; SANTOS-SILVA, Alan Roger; JORGE JR., Jacks; SILVA, Wagner Gomes da; PIRES, Fabio Ramoa; ROCHA, Andre Caroli; CAMPOS, Wladimir Gushiken de; CALDATO, Milena Coelho Fernandes; MARTIN, Regina Matsunaga; FONSECA, Felipe Paiva; PONTES, Helder Antonio RebeloObjective. To describe the oral and maxillofacial manifestations of patients diagnosed with chronic kidney disease-mineral and bone disorders. Study Design. Over a 13-year period, clinicopathologic data of patients diagnosed with CKD-MBD who had oral and maxillofacial alterations were retrieved from the files of 4 Brazilian institutions. Data included clinical, radiographic, microscopic, and biochemical findings; treatment employed; and follow-up status. Results. Twenty-one cases were identified, with 13 patients diagnosed as brown tumor of hyperparathyroidism (BTH) and 8 as osteitis fibrosa/renal osteodystrophy (OF/RO) (4 of them clinically consistent with Sagliker syndrome). The mean age was 32.7 years, and the mandible was the most affected site (42.8%). OF/RO had an ill-defined ""ground glass"" radiographic appearance, and BTH produced well-defined radiolucent images. Biochemically the following mean values were obtained: parathormone 1511.07 pg/mL, calcium 9.25 mg/dL, phosphorus 5.19 mg/dL, alkaline phosphatase 941.55 U/L, urea 125.42 mg/dL, and creatinine 7.14 mg/dL. Treatment comprised vitamin D and calcium intake, parathyroidectomy, hemodialysis, renal transplantation, and local surgery. During follow-up, 5 patients with BTH were free of lesions, whereas 2 affected by OF/RO/Sagliker syndrome died. Conclusions. Oral and maxillofacial manifestations of BTH and OF/RO are uncommon, but they can be associated with an important life-threatening scenario.
- Real-world impact of glucocorticoid replacement therapy on bone mineral density: retrospective experience of a large single-center CAH cohort spanning 24 years(2020) IERVOLINO, L. L.; FERRAZ-DE-SOUZA, B.; MARTIN, R. M.; COSTA, F. C.; MIRANDA, M. C.; MENDONCA, B. B.; BACHEGA, T. S.The congenital adrenal hyperplasia population seems to have an intrinsic tendency to a high frequency of low bone mass. However in this single-center and long-term evaluated cohort, the simplified corticoid regimen, with exclusive dexamethasone single dose reposition during adulthood, did not represent a risk factor for decrease in bone health. Introduction The impact of long-term and supposedly physiological doses of gluco and mineralocorticoid (GC/MC) on bone mineral density (BMD) in congenital adrenal hyperplasia (CAH) remains discordant among studies, which contain different clinical forms and corticoid regimens. Our aim was to evaluate the BMD in CAH adults receiving similar GC regimen since childhood and to correlate it with GC/MC cumulative doses. Methods Only patients with good compliance, who used cortisone acetate (CA) during childhood and dexamethasone after the final height achievement. Cumulative GC/MC doses were calculated from diagnosis until last evaluation. BMD was analyzed by the first and last energy X-ray absorptiometry (DXA) scans performed. Results Twenty simple virilizing (SV) and 14 salt wasting (WS) whose mean age was 26 +/- 6 years, mean CA, dexamethasone, and fludrocortisone cumulative doses were 63,813 +/- 32,767, 812 +/- 558, and 319 +/- 325 mg/m(2), respectively. Based on the last DXA, low BMD was observed in 11% of patients, total hip Z-score was lower in the SW than SV form (p = 0.04). Cumulative CA dose had an inverse correlation with femoral neck Z-score (p < 0.01). Total cumulative GC and MC doses had an inverse correlation with total hip Z-score (p < 0.01). In the analysis of sequential BMD during dexamethasone therapy, no association was observed among cumulative GC/MC doses, clinical forms, sex, and lumbar Z-score delta. Conclusions Even though a low CA regimen during growth periods in addition to MC replacement appears to have an influence on BMD at femoral sites, interestingly a low dexamethasone one does not seem to be deleterious for bone health in adulthood.