76 results on '"Bruno Ferraz-de-Souza"'
Search Results
2. Prevention and treatment of oral adverse effects of antiresorptive medications for osteoporosis – A position paper of the Brazilian Society of Endocrinology and Metabolism (SBEM), Brazilian Society of Stomatology and Oral Pathology (Sobep), and Brazilian Association for Bone Evaluation and Osteometabolism (Abrasso)
- Author
-
Miguel Madeira, André Caroli Rocha, Carolina Aguiar Moreira, Águida Maria Menezes Aguiar, Sergio Setsuo Maeda, Abel Silveira Cardoso, Charlles Heldan de Moura Castro, Catarina Brasil D'Alva, Barbara Campolina Carvalho Silva, Bruno Ferraz-de-Souza, Marise Lazaretti-Castro, Francisco Bandeira, and Sandra R. Torres more...
- Subjects
Osteoporosis ,bisphosphonate ,medication-related osteonecrosis of the jaw ,antifracture therapy ,dental care ,Medicine ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
ABSTRACT Antiresorptive therapy is the main form of prevention of osteoporotic or fragility fractures. Medication-related osteonecrosis of the jaw (MRONJ) is a relatively rare but severe adverse reaction to antiresorptive and antiangiogenic drugs. Physicians and dentists caring for patients taking these drugs and requiring invasive procedures face a difficult decision because of the potential risk of MRONJ. The aim of this study was to discuss the risk factors for the development of MRONJ and prevention of this complication in patients with osteoporosis taking antiresorptive drugs and requiring invasive dental treatment. For this goal, a task force with representatives from three professional associations was appointed to review the pertinent literature and discuss systemic and local risk factors, prevention of MRONJ in patients with osteoporosis, and management of established MRONJ. Although scarce evidence links the use of antiresorptive agents in the context of osteoporosis to the development of MRONJ, these agents are considered a risk factor for this complication. Despite the rare reports of MRONJ in patients with osteoporosis, the severity of symptoms and impact of MRONJ in the patients' quality of life make it imperative for health care professionals to consider this complication when planning invasive dental procedures. more...
- Published
- 2020
- Full Text
- View/download PDF
Catalog
3. Acute and long-term kidney function after parathyroidectomy for primary hyperparathyroidism.
- Author
-
Marcelo Belli, Regina Matsunaga Martin, Marília D'Elboux Guimarães Brescia, Climério Pereira Nascimento, Ledo Mazzei Massoni Neto, Sergio Samir Arap, Bruno Ferraz-de-Souza, Rosa Maria Affonso Moyses, Munro Peacock, and Fábio Luiz de Menezes Montenegro more...
- Subjects
Medicine ,Science - Abstract
BackgroundIn kidney transplant patients, parathyroidectomy is associated with an acute decrease in renal function. Acute and chronic effects of parathyroidectomy on renal function have not been extensively studied in primary hyperparathyroidism (PHPT).MethodsThis retrospective cohort study included 494 patients undergoing parathyroidectomy for PHPT. Acute renal changes were evaluated daily until day 4 post-parathyroidectomy and were stratified according to acute kidney injury (AKI) criteria. Biochemical assessment included serum creatinine, total and ionized calcium, parathyroid hormone (PTH), and 25-hydroxyvitamin D (25OHD). The estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation. We compared preoperative and postoperative renal function up to 5 years of follow-up.ResultsA total of 391 (79.1%) patients were female, and 422 (85.4%) were non-African American. The median age was 58 years old. The median (first and third quartiles) preoperative serum creatinine, PTH and total calcium levels were 0.81 mg/dL (0.68-1.01), 154.5 pg/mL (106-238.5), and 10.9 mg/dL (10.3-11.5), respectively. The median (first and third quartiles) preoperative eGFR was 86 mL/min/1.73 m2 (65-101.3). After surgery, the median acute decrease in the eGFR was 21 mL/min/1.73 m2 (pConclusionThere was significant acute impairment in renal function after parathyroidectomy for PHPT, and almost half of the patients met the criteria for AKI. Significant eGFR recovery was observed during the first month after surgery, but a small permanent reduction may occur. Patients treated for PHPT seemed to present with prominent renal dysfunction compared to patients who underwent thyroidectomy. more...
- Published
- 2020
- Full Text
- View/download PDF
4. 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
- Author
-
Pedro L. F. Costa, Monica M. França, Maria L. Katayama, Eduardo T. Carneiro, Regina M. Martin, Maria A. K. Folgueira, Ana C. Latronico, and Bruno Ferraz-de-Souza
- Subjects
vitamin D ,calcitriol ,microarray ,gene expression ,CYP24A1 ,cell proliferation ,Cytology ,QH573-671 - Abstract
The 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. more...
- Published
- 2019
- Full Text
- View/download PDF
5. 25-Hydroxyvitamin D and TSH as Risk Factors or Prognostic Markers in Thyroid Carcinoma.
- Author
-
Debora Lucia Seguro Danilovic, Bruno Ferraz-de-Souza, Amanda Wictky Fabri, Nathalie Oliveira Santana, Marco Aurelio Kulcsar, Claudio Roberto Cernea, Suemi Marui, and Ana Oliveira Hoff
- Subjects
Medicine ,Science - Abstract
OBJECTIVE:The increasing incidence of thyroid nodules demands identification of risk factors for malignant disease. Several studies suggested the association of higher TSH levels with cancer, but influence of 25-hydroxyvitamin D (25OHD) is controversial. This study aimed to identify the relationship of thyroid cancer with higher TSH levels and hypovitaminosis D and to evaluate their influence on prognostic characteristics of papillary thyroid carcinomas (PTC). METHODS:We retrospectively evaluated 433 patients submitted to thyroidectomy for thyroid nodules. Patients were categorized according to quartiles of TSH and 25OHD levels. Clinicopathological features were analyzed. RESULTS:Subjects with thyroid carcinomas were more frequently male and younger compared to those with benign disease. Their median TSH levels were higher and adjusted odds-ratio (OR) for cancer in the highest-quartile of TSH (> 2.4 mUI/mL) was 2.36 (1.36-4.09). Although vitamin D deficiency/insufficiency was prevalent in our cohort (84%), no significant differences in 25OHD levels or quartile distribution were observed between benign and malignant cases. Among 187 patients with PTC, analyses of prognostic features revealed increased risk of lymph nodes metastases for subjects with highest-quartile TSH levels (OR = 3.7, p = 0.029). Decreased 25OHD levels were not overtly associated with poor prognosis in PTC. CONCLUSIONS:In this cross-sectional cohort, higher TSH levels increased the risk of cancer in thyroid nodules and influenced its prognosis, particularly favoring lymph nodes metastases. On the other hand, no association was found between 25OHD levels and thyroid carcinoma risk or prognosis, suggesting that serum 25OHD determination may not contribute to risk assessment workup of thyroid nodules. more...
- Published
- 2016
- Full Text
- View/download PDF
6. Genetics of osteoporosis: searching for candidate genes for bone fragility
- Author
-
Manuela G. M. Rocha-Braz and Bruno Ferraz-de-Souza
- Subjects
GWAS ,mutation ,fracture ,low bone mass ,bone remodeling ,Medicine ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
ABSTRACT The pathogenesis of osteoporosis, a common disease with great morbidity and mortality, comprises environmental and genetic factors. As with other complex disorders, the genetic basis of osteoporosis has been difficult to identify. Nevertheless, several approaches have been undertaken in the past decades in order to identify candidate genes for bone fragility, including the study of rare monogenic syndromes with striking bone phenotypes (e.g. osteogenesis imperfecta and osteopetroses), the analysis of individuals or families with extreme osteoporotic phenotypes (e.g. idiopathic juvenile and pregnancy-related osteoporosis), and, chiefly, genome-wide association studies (GWAS) in large populations. Altogether, these efforts have greatly increased the understanding of molecular mechanisms behind bone remodelling, which has rapidly translated into the development of novel therapeutic strategies, exemplified by the tales of cathepsin K (CTSK) and sclerostin (SOST). Additional biological evidence of involvement in bone physiology still lacks for several candidate genes arisen from GWAS, opening an opportunity for the discovery of new mechanisms regulating bone strength, particularly with the advent of high-throughput genomic technologies. In this review, candidate genes for bone fragility will be presented in comprehensive tables and discussed with regard to how their association with osteoporosis emerged, highlighting key players such as LRP5, WNT1 and PLS3. Current limitations in our understanding of the genetic contribution to osteoporosis, such as yet unidentified genetic modifiers, may be overcome in the near future with better genotypic and phenotypic characterisation of large populations and the detailed study of candidate genes in informative individuals with marked phenotype. more...
- Full Text
- View/download PDF
7. Diagnosis and treatment of hypoparathyroidism: a position statement from the Brazilian Society of Endocrinology and Metabolism
- Author
-
Sergio Setsuo Maeda, Carolina Aguiar Moreira, Victória Zeghbi Cochenski Borba, Francisco Bandeira, Maria Lucia Fleiuss de Farias, João Lindolfo Cunha Borges, Francisco José Albuquerque de Paula, Felipe Augusto Brasileiro Vanderlei, Fábio Luiz de Menezes Montenegro, Rodrigo Oliveira Santos, Bruno Ferraz-de-Souza, and Marise Lazaretti-Castro more...
- Subjects
Hypoparathyroidism ,hypocalcemia ,calcitriol ,PTH ,guideline ,diagnosis ,treatment ,Medicine ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
ABSTRACT Objective To present an update on the diagnosis and treatment of hypoparathyroidism based on the most recent scientific evidence. Materials and methods The Department of Bone and Mineral Metabolism of the Sociedade Brasileira de Endocrinologia e Metabologia (SBEM; Brazilian Society of Endocrinology and Metabolism) was invited to prepare a document following the rules set by the Guidelines Program of the Associação Médica Brasileira (AMB; Brazilian Medical Association). Relevant papers were retrieved from the databases MEDLINE/PubMed, LILACS, and SciELO, and the evidence derived from each article was classified into recommendation levels according to scientific strength and study type. Conclusion An update on the recent scientific literature addressing hypoparathyroidism is presented to serve as a basis for the diagnosis and treatment of this condition in Brazil. more...
- Full Text
- View/download PDF
8. The evolution of primary hyperparathyroidism
- Author
-
Bruno Ferraz-de-Souza
- Subjects
Medicine ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Full Text
- View/download PDF
9. The elusive clinical significance of osteocalcin actions in energy metabolism in humans
- Author
-
Bruno Ferraz-de-Souza
- Subjects
Medicine ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Full Text
- View/download PDF
10. Guia Prático em Osteometabolismo
- Author
-
Alexandre Hohl, Amanda Moreira Portes, Ana Carla Montenegro, Ana Oliveira Hoff, Bárbara Campolina C. Silva, Bruno Ferraz de Souza, Carolina Aguiar Moreira, Cynthia M. Álvares Brandão, Dalisbor Marcelo Weber Silva, David William Dempster, Débora Meira Ramos Amorim, Eduardo Medeiros Ferreira da Gama, Eliane Naomi Sakane, Elizabete Ribeiro Barros, Érico Higino de Carvalho, Francisco Bandeira, Francisco de Assis Pereira, Francisco José Albuquerque de Paula, Henrique Pierotti Arantes, Ingrid de Lima Carlos, João Lindolfo C. Borges, José Gilberto Henriques Vieira, Júlia Vieira Oberger Marques, Karla Possídio, Katia de Paula Farah, Laís Oliveira Marinho Dias, Leila Caroline Bianchet Zanatta, Leonardo Bandeira, Linda Denise Fernandes Moreira, Lívia Marcela dos Santos, Lucian Batista de Oliveira, Lúcio Henrique Rocha Vieira, Luiz Claudio Gonçalves de Castro, Luiz Henrique Maciel Griz, Marcelo Fernando Ronsoni, Maria Lucia Fleiuss de Farias, Maria Marta Sarquis Soares, Maria Paula Bandeira, Mariana Lima Mascarenhas Moreira, Marise Lazaretti-Castro, Melissa Orlandin Premaor, Miguel Madeira, Mônica Longo de Oliveira, Monique Nakayama Ohe, Narriane Chaves Pereira de Holanda, Patrícia Dreyer, Patrícia Nunes Mesquita, Paulo Gustavo Sampaio Lacativa, Paulo Tannús Jorge, Pedro Paulo Martins Alvarenga, Phelipe Guimarães de Ornellas, Rafaela Martinez Copês Leal, Regina Matsunaga Martin, Rodrigo Nolasco dos Santos, Sergio Setsuo Maeda, Sérgio Luchini Batista, Simone Polonine Silva, Simone van de Sande Lee, Soraya Lopes Sader, Stefani Otoni Murakami Ramos, Sthefanie Pallone, Tatiane Vilaça, Telma Palomo, Thais Gelenske, Vanessa Leão de Medeiros Fabrino, and Victória Zeghbi Cochenski Borba more...
- Abstract
A relevância e a abordagem consistente dos temas reunidos no Guia Prático em Osteometabolismo asseguraram a publicação dessa nova edição. Preparada pelos membros do Departamento de Metabolismo Ósseo e Mineral da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) e por seus colaboradores, oferece uma visão ainda mais detalhada sobre condições enfrentadas diariamente por clínicos e especialistas, como diabetes mellitus, osteoporose, hipertireoidismo e hipoparatireoidismo. Com isso, o guia mantém a sua condição como material de consulta e referência para profissionais da Endocrinologia e áreas relacionadas. more...
- Published
- 2022
- Full Text
- View/download PDF
11. Prevention and treatment of oral adverse effects of antiresorptive medications for osteoporosis – A position paper of the Brazilian Society of Endocrinology and Metabolism (SBEM), Brazilian Society of Stomatology and Oral Pathology (Sobep), and Brazilian Association for Bone Evaluation and Osteometabolism (Abrasso)
- Author
-
Marise Lazaretti-Castro, Sergio Setsuo Maeda, Bruno Ferraz-de-Souza, Carolina Aguiar Moreira, Miguel Madeira, Sandra Torres, Catarina Brasil d’Alva, Abel Silveira Cardoso, André Caroli Rocha, Águida Maria Menezes Aguiar, Charlles Heldan de Moura Castro, Barbara C. Silva, and Francisco Bandeira more...
- Subjects
medicine.medical_specialty ,bisphosphonate ,Endocrinology, Diabetes and Metabolism ,Oral Medicine ,Osteoporosis ,Context (language use) ,Diseases of the endocrine glands. Clinical endocrinology ,Quality of life ,Health care ,Oral and maxillofacial pathology ,medicine ,Humans ,medication-related osteonecrosis of the jaw ,Risk factor ,Adverse effect ,Intensive care medicine ,Bone Density Conservation Agents ,Diphosphonates ,business.industry ,medicine.disease ,RC648-665 ,Pathology, Oral ,Quality of Life ,antifracture therapy ,Medicine ,Bisphosphonate-Associated Osteonecrosis of the Jaw ,dental care ,business ,Osteonecrosis of the jaw ,Brazil - Abstract
Antiresorptive therapy is the main form of prevention of osteoporotic or fragility fractures. Medication-related osteonecrosis of the jaw (MRONJ) is a relatively rare but severe adverse reaction to antiresorptive and antiangiogenic drugs. Physicians and dentists caring for patients taking these drugs and requiring invasive procedures face a difficult decision because of the potential risk of MRONJ. The aim of this study was to discuss the risk factors for the development of MRONJ and prevention of this complication in patients with osteoporosis taking antiresorptive drugs and requiring invasive dental treatment. For this goal, a task force with representatives from three professional associations was appointed to review the pertinent literature and discuss systemic and local risk factors, prevention of MRONJ in patients with osteoporosis, and management of established MRONJ. Although scarce evidence links the use of antiresorptive agents in the context of osteoporosis to the development of MRONJ, these agents are considered a risk factor for this complication. Despite the rare reports of MRONJ in patients with osteoporosis, the severity of symptoms and impact of MRONJ in the patients' quality of life make it imperative for health care professionals to consider this complication when planning invasive dental procedures. more...
- Published
- 2020
12. Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years’ Experience in the UK
- Author
-
Bruno Ferraz-de-Souza, Katrin Koehler, Elizabeth Crowne, Charles R. Buchanan, Nils Krone, Jeremy Allgrove, Edward T Andrews, P. K. Shah, N. Simon Thomas, Jenifer P. Suntharalingham, Tony Hulse, Angela Huebner, John C. Achermann, Adrian J. L. Clark, Peter E. Clayton, John Gregory, Tim Cheetham, Louise A. Metherell, Rathi Prasad, Avinaash Maharaj, M Guftar Shaikh, Peter C. Hindmarsh, Mehul T. Dattani, Catherine Roberts, Li F. Chan, Claire Hughes, Justin H Davies, Younus Qamar, Lin Lin, and Federica Buonocore more...
- Subjects
0301 basic medicine ,Candidate gene ,Pediatrics ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Context (language use) ,Primary Adrenal Insufficiency ,03 medical and health sciences ,0302 clinical medicine ,Adrenal insufficiency ,medicine ,Congenital adrenal hyperplasia ,genetics ,Exome sequencing ,Clinical Research Articles ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Addison disease ,medicine.disease ,030104 developmental biology ,adrenal ,NGS ,Etiology ,business ,adrenal insufficiency ,030217 neurology & neurosurgery ,AcademicSubjects/MED00250 - Abstract
Context Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood. Objective We investigated genetic causes of PAI in children and young people over a 25 year period. Design, Setting and Participants Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers. Intervention and Outcome Measurements Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018). Results A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1/steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause. Conclusions PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved. more...
- Published
- 2021
13. Comprehensive Genetic Analysis of 128 Candidate Genes in a Cohort With Idiopathic, Severe, or Familial Osteoporosis
- Author
-
Adriana M. Fernandes, Evelin Aline Zanardo, Antonio M. Lerario, Lucas Santos de Santana, Manuela G. M. Rocha-Braz, Bruno Ferraz-de-Souza, Leslie Domenici Kulikowski, Monica M. França, Regina Matsunaga Martin, and Berenice B. Mendonca more...
- Subjects
idiopathic osteoporosis ,0301 basic medicine ,Candidate gene ,Endocrinology, Diabetes and Metabolism ,Genome-wide association study ,Context (language use) ,genetic analysis ,030105 genetics & heredity ,Bioinformatics ,Genetic analysis ,03 medical and health sciences ,symbols.namesake ,Commentaries ,familial osteoporosis ,Genetic predisposition ,Medicine ,Clinical Research Articles ,Sanger sequencing ,Massive parallel sequencing ,business.industry ,massively parallel sequencing ,targeted massively parallel sequencing ,bone fragility ,030104 developmental biology ,symbols ,candidate genes ,business ,AcademicSubjects/MED00250 ,SNP array - Abstract
Context The genetic bases of osteoporosis (OP), a disorder with high heritability, are poorly understood at an individual level. Cases of idiopathic or familial OP have long puzzled clinicians as to whether an actionable genetic cause could be identified. Objective We performed a genetic analysis of 28 cases of idiopathic, severe, or familial osteoporosis using targeted massively parallel sequencing. Design Targeted sequencing of 128 candidate genes was performed using Illumina NextSeq. Variants of interest were confirmed by Sanger sequencing or SNP array. Patients and Setting Thirty-seven patients in an academic tertiary hospital participated (54% male; median age, 44 years; 86% with fractures), corresponding to 28 sporadic or familial cases. Main Outcome Measure The identification of rare stop-gain, indel, splice site, copy-number, or nonsynonymous variants altering protein function. Results Altogether, we identified 28 variants of interest, but only 3 were classified as pathogenic or likely pathogenic variants: COL1A2 p.(Arg708Gln), WNT1 p.(Gly169Asp), and IDUA p.(His82Gln). An association of variants in different genes was found in 21% of cases, including a young woman with severe OP bearing WNT1, PLS3, and NOTCH2 variants. Among genes of uncertain significance analyzed, a potential additional line of evidence has arisen for GWAS candidates GPR68 and NBR1, warranting further studies. Conclusions While we hope that continuing efforts to identify genetic predisposition to OP will lead to improved and personalized care in the future, the likelihood of identifying actionable pathogenic variants in intriguing cases of idiopathic or familial osteoporosis is seemingly low. more...
- Published
- 2020
- Full Text
- View/download PDF
14. MON-333 Cutaneous Skeletal Hypophosphatemic Syndrome (Cshs) Caused by Somatic HRAS p.G13R Mutation: Long Follow-Up of Two Brazilian Women
- Author
-
Marcelo Bordalo Rodrigues, Bruna L Freire, Regina Matsunaga Martin, André Caroli Rocha, Hially R Cabral, Caio Santiago Moises, Thamiris Freitas Maia, Vanda Jorgetti, Andresa De Santi Rodrigues, Alexander A. L. Jorge, and Bruno Ferraz de Souza more...
- Subjects
Somatic cell ,business.industry ,Endocrinology, Diabetes and Metabolism ,Bone and Mineral Metabolism ,Bone and Mineral Case Reports II ,Mutation (genetic algorithm) ,Cancer research ,Medicine ,HRAS ,business ,AcademicSubjects/MED00250 - Abstract
BACKGROUND CSHS refers to the association of epidermal nevus syndrome (ENS), skeletal dysplasia, and hypophosphatemic osteomalacia (OM) mediated by FGF23 resulting from post zygotic mutations in RAS signaling pathway, with known by relationship with human cancers. CLINICAL CASE Patient 1 presented ENS since birth at right hemibody. At 1.6-yr-old, she underwent treatment for a left inguinal rhabdomyosarcoma. At 3-yr-old, she had an atraumatic right femur fracture associated with muscle weakness, and laboratory data and X-rays suggesting OM. Phosphate and calcitriol were initiated, but with poor adherence, and no improvement; skeletal deformities got worse and the girl became wheelchair user at 13-yr-old. Skeletal CT scan at age 17 showed dysplastic lesions with lytic changes at right dimidium (skull, jaw, ribs, pelvis and femur) with systemic OM signs confirmed by bone biopsy. The progressive enlargement of the jaw lesion required surgical removal after 2 years; histopathology revealed giant cell tumor. Patient 2 also had congenital ENS on the right dimidium with complaint of bone pain and muscle weakness since 2-yr-old. She evolved with bone fractures and deformities at 4-yr-old, becoming wheelchair user after 2 years. Iliac crest biopsy confirmed OM, already suspected based on laboratorial and X-rays findings at age 7. She had few improvements with phosphate and calcitriol treatment also due to low compliance. During follow-up, symptomatic nephrolithiasis occurred and, in regions affected by EN, multiple basal cell carcinomas (BCCs) emerged requiring excisions. Skeletal CT scan at age 36 showed dysplastic lesions at right hemibody (skull, ribs, pelvis, and limbs) with diffuse bone rarefaction and signs of OM. Sanger sequencing of DNA from EN and jaw tumor samples of patient 1 and from EN and BCC samples of patient 2 disclosed heterozygous HRAS p.G13R mutation, and this mutation was absent in leukocytes DNA from both patients confirming CSHS mosaicism. Owing to the CSHS associated increase risk of cancer, screening with thyroid and breast ultrasound, mammography, CT of skull, chest, abdomen, and pelvis ruled out presence of tumors in patient 1. Patient 2 is waiting for similar screening. Nowadays, patient 1 is 25-yr-old and patient 2 is 36-yr-old; both women have maintenance of OM, characterized by persistent hypophosphatemia with elevated bone formation makers despite treatment with phosphate and calcitriol. CONCLUSION CHSC is a very rare syndrome with less than 10 cases with molecular characterization in literature. Although Collins et al suggest an age-dependent improvement in mineral abnormalities, we reported two women without OM recovery probably because of extensive bone dysplasia. These cases also reinforce association of CSHS with neoplasms, including first descriptions of patients with rhabdomyosarcoma and giant cell tumor of jaw and the longest follow-ups described until. more...
- Published
- 2020
15. Acute and long-term kidney function after parathyroidectomy for primary hyperparathyroidism
- Author
-
Munro Peacock, Climerio Pereira do Nascimento, Bruno Ferraz-de-Souza, Sérgio Samir Arap, Regina Matsunaga Martin, Marcelo Belli, Rosa M.A. Moysés, Fábio Luiz de Menezes Montenegro, Ledo Mazzei Massoni Neto, and Marília D'Elboux Guimarães Brescia more...
- Subjects
Male ,medicine.medical_treatment ,urologic and male genital diseases ,Biochemistry ,chemistry.chemical_compound ,Postoperative Complications ,0302 clinical medicine ,Chronic Kidney Disease ,Medicine and Health Sciences ,030212 general & internal medicine ,Vitamin D ,Aged, 80 and over ,Univariate analysis ,Multidisciplinary ,Acute kidney injury ,Acute Kidney Injury ,Middle Aged ,Hyperparathyroidism, Primary ,Adenomas ,Oncology ,Parathyroid Hormone ,Nephrology ,Creatinine ,Medicine ,Female ,Anatomy ,Glomerular Filtration Rate ,Research Article ,Adult ,Parathyroidectomy ,medicine.medical_specialty ,Endocrine System Procedures ,Adolescent ,Science ,Urology ,Renal function ,Surgical and Invasive Medical Procedures ,030209 endocrinology & metabolism ,03 medical and health sciences ,Renal Diseases ,medicine ,Humans ,Aged ,Hyperparathyroidism ,business.industry ,Thyroidectomy ,Biology and Life Sciences ,Cancers and Neoplasms ,Kidneys ,Renal System ,medicine.disease ,Otolaryngological Procedures ,chemistry ,business ,Biomarkers ,Primary hyperparathyroidism - Abstract
Background In kidney transplant patients, parathyroidectomy is associated with an acute decrease in renal function. Acute and chronic effects of parathyroidectomy on renal function have not been extensively studied in primary hyperparathyroidism (PHPT). Methods This retrospective cohort study included 494 patients undergoing parathyroidectomy for PHPT. Acute renal changes were evaluated daily until day 4 post-parathyroidectomy and were stratified according to acute kidney injury (AKI) criteria. Biochemical assessment included serum creatinine, total and ionized calcium, parathyroid hormone (PTH), and 25-hydroxyvitamin D (25OHD). The estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation. We compared preoperative and postoperative renal function up to 5 years of follow-up. Results A total of 391 (79.1%) patients were female, and 422 (85.4%) were non-African American. The median age was 58 years old. The median (first and third quartiles) preoperative serum creatinine, PTH and total calcium levels were 0.81 mg/dL (0.68–1.01), 154.5 pg/mL (106–238.5), and 10.9 mg/dL (10.3–11.5), respectively. The median (first and third quartiles) preoperative eGFR was 86 mL/min/1.73 m2 (65–101.3). After surgery, the median acute decrease in the eGFR was 21 mL/min/1.73 m2 (p Conclusion There was significant acute impairment in renal function after parathyroidectomy for PHPT, and almost half of the patients met the criteria for AKI. Significant eGFR recovery was observed during the first month after surgery, but a small permanent reduction may occur. Patients treated for PHPT seemed to present with prominent renal dysfunction compared to patients who underwent thyroidectomy. more...
- Published
- 2020
16. Real-world impact of glucocorticoid replacement therapy on bone mineral density: retrospective experience of a large single-center CAH cohort spanning 24 years
- Author
-
Fernanda C. Costa, Berenice B Mendonca, Regina Matsunaga Martin, Bruno Ferraz-de-Souza, T S Bachega, Mirela C Miranda, and L L Iervolino
- Subjects
0301 basic medicine ,Adult ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Fludrocortisone ,Population ,Urology ,030209 endocrinology & metabolism ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Absorptiometry, Photon ,Bone Density ,medicine ,Humans ,Congenital adrenal hyperplasia ,education ,Child ,Glucocorticoids ,Dexamethasone ,Femoral neck ,Retrospective Studies ,Bone mineral ,education.field_of_study ,Adrenal Hyperplasia, Congenital ,business.industry ,medicine.disease ,Regimen ,medicine.anatomical_structure ,Cohort ,030101 anatomy & morphology ,business ,medicine.drug - Abstract
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. 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. 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. 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/m2, 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 more...
- Published
- 2019
17. OR13-5 The Molecular Landscape of Osteogenesis Imperfecta in a Brazilian Tertiary Service Cohort
- Author
-
Regina Matsunaga Martin, Bruno Ferraz-de-Souza, Berenice B Mendonca, Simões, Adriana M. Fernandes, Monica M. França, and Manuela G. M. Rocha-Braz
- Subjects
Service (business) ,medicine.medical_specialty ,Osteogenesis imperfecta ,business.industry ,Bone and Mineral Metabolism ,Endocrinology, Diabetes and Metabolism ,Family medicine ,Cohort ,medicine ,Rare Bone Diseases and Mineral Metabolism ,medicine.disease ,business - Abstract
Osteogenesis imperfecta (OI) is clinically and genetically heterogeneous. Defects in collagen type 1 are reportedly the main cause of OI (85-90%), but most available data has arisen from developed countries. Massively parallel sequencing (MPS) technologies now allow for systematic and comprehensive analysis of OI genes simultaneously. Our objective was to obtain the molecular diagnosis of OI through targeted MPS in a single tertiary center cohort of Brazilian adults with OI. After informed consent, DNA samples were obtained from 52 cases of OI (9 families and 43 sporadic; total of 64 sequenced individuals, 96% adults). Sixty-nine percent of the cohort had moderate to severe OI, and consanguinity was common (22%). 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 captured with Agilent SureSelectXT and sequenced in Illumina NextSeq. Identified variants were classified according to ACMG/AMP guidelines and those considered to be disease-causing were confirmed by Sanger sequencing. Segregation analysis was pursued when familial samples were available. A molecular diagnosis was obtained in 92% of cases. Altogether, 55 variants were identified, 21 of which had never been previously reported in international databases. Variants in COL1A1 or COL1A2 were identified in 77%, whereas 23% had variants in other candidate genes. Amongst these, variants in SERPINF1, FKBP10 and PLOD2 were more prevalent. Only one case had the previously described IFITM5 c.-14C>T variant. A peculiar combination of four heterozygous P3H1 and WNT1 variants was detected in a non-consanguineous case, where one variant in each gene was inherited from each parent. In two cases, potentially modifier variants in LRP5 were identified. Surprisingly, in four consanguineous families the molecular cause was still related to COL1A1 or COL1A2, and two non-consanguineous cases had compound heterozygous PLOD2 variants. In conclusion, targeted MPS has effectively allowed establishing the molecular basis of OI in this Brazilian cohort, unraveling novel disease-causing variants in 29% of cases, and potentially reflecting new aspects of OI pathogenesis in Brazil. Non-collagen defects were found in 23% of cases, with a higher prevalence of P3H1, FKBP10, PLOD2 and SERPINF1 defects, with potential digenic interactions, and a lower prevalence of IFITM5-related OI. Inferring the molecular diagnosis from a family history of consanguinity was misleading in this setting. Obtaining a precise diagnosis of OI in underrepresented populations allows expanding our understanding of its molecular landscape and may lead to improved personalized care in the future. more...
- Published
- 2019
- Full Text
- View/download PDF
18. SUN-359 Preserved Bone Mineral Density In Adults With Classical Forms Of Congenital Adrenal Hyperplasia Submitted To Long-term Low Glucocorticoid Doses
- Author
-
Fernanda C. Costa, Luiz Iervolino, Bruno Ferraz-de-Souza, Berenice B. Mendonca, Regina Matsunaga Martin, and Tania A. S. S. Bachega
- Subjects
Bone mineral ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.disease ,Endocrinology ,Internal medicine ,Adrenal Tumors and Hyperplasia ,medicine ,Congenital adrenal hyperplasia ,Adrenal ,business ,Glucocorticoid ,medicine.drug - Abstract
The impact of long-term and supposedly physiological doses of corticosteroids on bone mineral density (BMD) in congenital adrenal hyperplasia (CAH) remains unknown. There are few studies with discordant results performed with mixed clinical forms and glucocorticoid (GC) regimens. Additionally, the effect of mineralocorticoid (MC) therapy has rarely been evaluated. Objective: To evaluate the BMD in adults with classical forms of CAH receiving the same GC regimen and to correlate with cumulative GC and MC doses since diagnosis. Methods: 34 adults (20 simple virilizing-SV/ 21 females) with good compliance (normal serum androgens levels for sex/age), who used cortisone acetate during childhood (16±3.3mg/m2/d) and dexamethasone after final height achievement (0.19±0.07mg/m2/d). The cumulative cortisone acetate, dexamethasone, total GC and MC doses (mg/m2) were calculated from diagnosis until the last evaluation. BMD was evaluated by z-scores (z) in the first and last densitometry. Physical activity and calcium intake were assessed by questionnaires; PTH and 25OH-Vitamin D levels were measured in the latter evaluation. GC/MC doses, clinical/laboratory data were correlated with z scores by linear regression, chi-square and t-tests. Results: The mean age in the last evaluation was 26±6yrs, duration of cortisone acetate therapy in the salt-wasting (SW) and SV forms was 14.8±4.2 and 10.5±4.3 yrs, respectively (p more...
- Published
- 2019
- Full Text
- View/download PDF
19. Nonspecific binding of a frequently used vitamin D receptor (VDR) antibody: important implications for vitamin D research in human health
- Author
-
Bruno Ferraz-de-Souza, Pedro L. F. Costa, and Monica M. França
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Calcitriol receptor ,Antibodies ,03 medical and health sciences ,Human health ,0302 clinical medicine ,Endocrinology ,Diabetes mellitus ,Internal medicine ,medicine ,Vitamin D and neurology ,Humans ,Nonspecific binding ,biology ,business.industry ,Fibroblasts ,medicine.disease ,030104 developmental biology ,biology.protein ,Receptors, Calcitriol ,Binding Sites, Antibody ,Antibody ,business - Published
- 2016
- Full Text
- View/download PDF
20. The elusive clinical significance of osteocalcin actions in energy metabolism in humans
- Author
-
Bruno Ferraz-de-Souza
- Subjects
medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Osteocalcin ,Energy metabolism ,lcsh:Medicine ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Bone and Bones ,Cachexia ,Bone remodeling ,Osteogenesis ,Internal medicine ,medicine ,Humans ,Clinical significance ,Hyperparathyroidism ,lcsh:RC648-665 ,biology ,business.industry ,lcsh:R ,medicine.disease ,Endocrinology ,Osteogenesis imperfecta ,biology.protein ,business ,Energy Metabolism ,Homeostasis - Abstract
In spite of its stagnant gross appearance, the skeleton is a highly metabolically active organ. The continuous process of bone remodeling, allowing homeostatic availability of calcium and renovation of the important structural material of bone, requires ample energy supply (). Extreme examples of such energy demand had been noticed a long time ago in high bone turnover states, for instance in the cachexia accompanying severe hyperparathyroidism or in slender children with osteogenesis imperfecta, but lacked an explanation. Therefore, when the [...] more...
- Published
- 2018
21. Diagnosis and treatment of hypoparathyroidism: a position statement from the Brazilian Society of Endocrinology and Metabolism
- Author
-
Bruno Ferraz-de-Souza, Carolina Aguiar Moreira, Maria Lucia Fleiuss Farias, Marise Lazaretti-Castro, Sergio Setsuo Maeda, João Lindolfo C. Borges, Francisco Bandeira, Felipe Augusto Brasileiro Vanderlei, Victoria Zeghbi Cochenski Borba, Fábio Luiz de Menezes Montenegro, Rodrigo Oliveira Santos, and Francisco José Albuquerque de Paula more...
- Subjects
SciELO ,Position statement ,calcitriol ,medicine.medical_specialty ,Hypoparathyroidism ,diagnosis ,Endocrinology, Diabetes and Metabolism ,MEDLINE ,lcsh:Medicine ,030209 endocrinology & metabolism ,Scientific literature ,hypocalcemia ,VITAMINA D ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Scientific evidence ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Societies, Medical ,Evidence-Based Medicine ,lcsh:RC648-665 ,treatment ,business.industry ,lcsh:R ,Evidence-based medicine ,Guideline ,medicine.disease ,Endocrinology ,030220 oncology & carcinogenesis ,business ,guideline ,Brazil ,PTH - Abstract
Objective To present an update on the diagnosis and treatment of hypoparathyroidism based on the most recent scientific evidence. Materials and methods The Department of Bone and Mineral Metabolism of the Sociedade Brasileira de Endocrinologia e Metabologia (SBEM; Brazilian Society of Endocrinology and Metabolism) was invited to prepare a document following the rules set by the Guidelines Program of the Associação Médica Brasileira (AMB; Brazilian Medical Association). Relevant papers were retrieved from the databases MEDLINE/PubMed, LILACS, and SciELO, and the evidence derived from each article was classified into recommendation levels according to scientific strength and study type. Conclusion An update on the recent scientific literature addressing hypoparathyroidism is presented to serve as a basis for the diagnosis and treatment of this condition in Brazil. more...
- Published
- 2018
22. Normal bone mass and normocalcemia in adulthood despite homozygous vitamin D receptor mutations
- Author
-
F. M. Damiani, Ana Claudia Latronico, Bruno Ferraz-de-Souza, and Regina Matsunaga Martin
- Subjects
Adult ,Male ,Vitamin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Nonsense mutation ,Rickets ,Calcitriol receptor ,chemistry.chemical_compound ,Bone Density ,Internal medicine ,medicine ,Vitamin D and neurology ,Humans ,Hypercalciuria ,Calcium metabolism ,business.industry ,medicine.disease ,Pedigree ,Endocrinology ,chemistry ,Mutation ,Hypercalcemia ,Receptors, Calcitriol ,Calcium ,Female ,Kidney stones ,business ,Follow-Up Studies - Abstract
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. 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. 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. 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. 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. more...
- Published
- 2015
- Full Text
- View/download PDF
23. 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
- Author
-
Maria Aparecida Azevedo Koike Folgueira, Ana Claudia Latronico, Monica M. França, Bruno Ferraz-de-Souza, Eduardo T. Carneiro, Regina Matsunaga Martin, Maria L. Katayama, and Pedro L. F. Costa
- Subjects
calcitriol ,0301 basic medicine ,Transcription, Genetic ,Calcitriol ,Down-Regulation ,vitamin D ,030209 endocrinology & metabolism ,Biology ,Calcitriol receptor ,Article ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,CYP24A1 ,Human Umbilical Vein Endothelial Cells ,Transcriptional regulation ,medicine ,Vitamin D and neurology ,Humans ,Receptor ,lcsh:QH301-705.5 ,Molecular Sequence Annotation ,General Medicine ,Fibroblasts ,Cell cycle ,Up-Regulation ,Cell biology ,cell proliferation ,030104 developmental biology ,lcsh:Biology (General) ,Mutation ,gene expression ,Receptors, Calcitriol ,lipids (amino acids, peptides, and proteins) ,microarray ,medicine.drug - Abstract
The 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. more...
- Published
- 2019
- Full Text
- View/download PDF
24. Diagnóstico e tratamento da doença de Paget dos ossos: uma minirrevisão
- Author
-
Bruno Ferraz-de-Souza and Pedro Henrique Silveira Corrêa
- Subjects
medicine.medical_specialty ,Pediatrics ,Endocrinology, Diabetes and Metabolism ,ácido zoledrônico ,Disease ,Zoledronic Acid ,Asymptomatic ,Bone remodeling ,Diagnosis, Differential ,Doença de Paget dos ossos ,zoledronic acid ,medicine ,Deformity ,Humans ,antiresorptive treatment ,Vitamin D ,Bone pain ,bisphosphonates ,Bone Density Conservation Agents ,Diphosphonates ,medicine.diagnostic_test ,business.industry ,Imidazoles ,tratamento antirreabsortivo ,General Medicine ,Alkaline Phosphatase ,Osteitis Deformans ,medicine.disease ,Surgery ,Radiography ,Paget's disease of bone ,Zoledronic acid ,Bone scintigraphy ,Asymptomatic Diseases ,osteoclast ,Calcium ,bifosfonatos ,medicine.symptom ,business ,medicine.drug - Abstract
Paget's disease of bone (PDB) is a chronic progressive disorder of bone metabolism that may go undetected for many years, and endocrinologists should be alert to its clinical signs and promptly diagnose and treat PDB before it results in irreversible complications, such as deformity, fracture or neurological sequelae. Most commonly, PDB is suspected upon the incidental finding of elevated serum alkaline phosphatase levels or a radiographic abnormality in an otherwise healthy individual above 55 years of age. Some of these individuals may have symptoms such as bone pain or enlargement with increased warmth. In general, a basic laboratory evaluation of bone metabolism, plain radiographies of affected bones and bone scintigraphy are sufficient to corroborate the diagnosis. Antiresorptive therapy with bisphosphonates is the mainstay of treatment of symptomatic PDB, and intravenous zoledronic acid has emerged as an effective and safe treatment option, leading to sustained remission and improved quality of life. It is extremely important, though, to ensure calcium and vitamin D sufficiency before and during treatment in order to prevent hypocalcemia. The benefit of treating all asymptomatic patients is not clear, but treatment is warranted if the pagetic lesion is located in a site where progression to fracture, deformity, or compression would significantly impair the patient quality of life. This mini-review focuses on important aspects of the diagnosis and treatment of PDB. A doença de Paget dos ossos (PDB) é uma doença progressiva e crônica do metabolismo ósseo que pode passar despercebida por muitos anos. Os endocrinologistas devem ficar alertas aos seus sinais clínicos e diagnosticar e tratar a PDB imediatamente, antes que ela gere complicações irreversíveis, como deformidade, fratura ou sequelas neurológicas. Mais comumente, suspeita-se da PBD após o achado incidental de níveis elevados de fosfatase alcalina no soro, ou anormalidades radiográficas em indivíduos aparentemente saudáveis com mais de 55 anos de idade. Alguns desses indivíduos podem apresentar sintomas, como a dor ou aumento ósseo com temperatura aumentada. Em geral, a avaliação laboratorial básica de metabolismo ósseo, radiografias simples dos ossos afetados e cintilografia óssea são suficientes para corroborar o diagnóstico. O tratamento antirreabsortivo com bifosfonatos é o principal tratamento da PDB sintomática, e o ácido zoledrônico intravenoso passou a ser uma opção de tratamento segura e eficiente, levando à manutenção da remissão e à melhora da qualidade de vida. É extremamente importante, entretanto, garantir níveis adequados de cálcio e vitamina D antes e durante o tratamento para se evitar a hipocalcemia. O benefício de se tratar todos os pacientes assintomáticos não está claro, mas o tratamento é recomendado se a localização da lesão pagética sugerir progressão para fratura, deformidade ou compressão que comprometam a qualidade de vida. Esta minirrevisão concentra-se em importantes aspectos do diagnóstico e tratamento da PDB. more...
- Published
- 2013
- Full Text
- View/download PDF
25. Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals
- Author
-
Sorahia, Domenice, Aline Zamboni, Machado, Frederico Moraes, Ferreira, Bruno, Ferraz-de-Souza, Antonio Marcondes, Lerario, Lin, Lin, Mirian Yumie, Nishi, Nathalia Lisboa, Gomes, Thatiana Evelin, da Silva, Rosana Barbosa, Silva, Rafaela Vieira, Correa, Luciana Ribeiro, Montenegro, Amanda, Narciso, Elaine Maria Frade, Costa, John C, Achermann, and Berenice Bilharinho, Mendonca more...
- Subjects
Adult ,Male ,endocrine system ,gonadal dysgenesis ,Adolescent ,disorders of sex development ,Gonadal Disorders ,Infant ,Reviews ,Review ,Primary Ovarian Insufficiency ,Steroidogenic Factor 1 ,ovotestis ,Phenotype ,Child, Preschool ,Mutation ,NR5A1 gene ,Humans ,Female ,Child ,adrenal insufficiency ,Brazil ,primary ovarian failure - Abstract
Steroidogenic 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 Müllerian 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. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc. more...
- Published
- 2016
26. Effects of Type 1 Insulin-Like Growth Factor Receptor Silencing in a Human Adrenocortical Cell Line
- Author
-
Tamaya C. Ribeiro, Madson Q. Almeida, Mirian Yumie Nishi, Alexander A. L. Jorge, Bruno Ferraz-de-Souza, Ana Claudia Latronico, Berenice B. Mendonca, and Luciana Ribeiro Montenegro
- Subjects
medicine.medical_specialty ,Small interfering RNA ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Down-Regulation ,030209 endocrinology & metabolism ,Apoptosis ,Biology ,medicine.disease_cause ,Biochemistry ,Cell Line ,Receptor, IGF Type 1 ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Growth factor receptor ,Downregulation and upregulation ,Internal medicine ,medicine ,Gene silencing ,Humans ,Gene Silencing ,RNA, Messenger ,RNA, Small Interfering ,Insulin-like growth factor 1 receptor ,Cell Proliferation ,Cell growth ,Biochemistry (medical) ,General Medicine ,Molecular biology ,Cell culture ,030220 oncology & carcinogenesis ,Adrenal Cortex ,Carcinogenesis - Abstract
Type 1 insulin-like growth factor receptor (IGF-1R) is overexpressed in a variety of human cancers, including adrenocortical tumors. The aim of the work was to investigate the effects of IGF-1R downregulation in a human adrenocortical cell line by small interfering RNA (siRNA). The human adrenocortical tumor cell line NCI H295R was transfected with 2 specific IGF1R siRNAs (# 1 and # 2) and compared with untreated cells and a negative control siRNA. IGF1R expression was determined by quantitative reverse-transcription PCR (qRTPCR) and Western blot. The effects of IGF-1R downregulation on cell proliferation and apoptosis were assessed. IGF-1R levels were significantly decreased in cells treated with IGF-1R siRNA # 1 or # 2. Relative expression of IGF1R mRNA decreased approximately 50% and Western blot analysis revealed a 30% of reduction in IGF-1R protein. Downregulation of this gene resulted in 40% reduction in cell growth in vitro and 45% increase in apoptosis using siRNA # 2. These findings demonstrate that decreasing IGF-1R mRNA and protein expression in NCI H295R cells can partially inhibit adrenal tumor cell growth in vitro. Targeting IGF1R is a promising therapy for pediatric malignant adrenocortical tumor and can still be an option for adult adrenocortical cancer based on personalized genomic tumor profiling. more...
- Published
- 2016
27. Symptomatic intracranial hypertension and prolonged hypocalcemia following treatment of Paget’s disease of the skull with zoledronic acid
- Author
-
Bruno Ferraz-de-Souza, Regina Matsunaga Martin, and Pedro Henrique Silveira Corrêa
- Subjects
medicine.medical_specialty ,Calcitriol ,Endocrinology, Diabetes and Metabolism ,Urinary incontinence ,Basilar invagination ,Zoledronic Acid ,Endocrinology ,medicine ,Humans ,Orthopedics and Sports Medicine ,Radionuclide Imaging ,Intracranial pressure ,Platybasia ,Diphosphonates ,Hypocalcemia ,business.industry ,Skull ,Imidazoles ,General Medicine ,Middle Aged ,Osteitis Deformans ,medicine.disease ,Hydrocephalus ,Surgery ,Zoledronic acid ,Paget's disease of bone ,Female ,Intracranial Hypertension ,medicine.symptom ,Tomography, X-Ray Computed ,business ,medicine.drug - Abstract
Skull involvement in Paget's disease of bone can lead to neurological symptoms, prompting treatment. Intravenous zoledronic acid (ZA) has emerged as an effective and safe treatment option for patients with Paget's, leading to sustained remission and improved quality of life. A previously untreated 61-year-old female presented with 2-year history of facial asymmetry with progressive hearing impairment. Serum calcium levels were normal with upper normal levels of PTH and low 25OHD levels. Serum alkaline phosphatase was markedly increased and bone scan showed extensive pagetic involvement of the skull. Head CT and MRI revealed hydrocephalus with cerebellar tonsillar herniation, platybasia and basilar invagination. In the absence of clinical signs or symptoms of intracranial hypertension, she was treated with intravenous ZA after 15-day supplementation with calcium and vitamin D. Twelve hours after the infusion, the patient became confused, agitated and disoriented and developed urinary incontinence; cortical sulci became effaced on CT indicating increased intracranial pressure. Over the following days, she developed frank hypocalcemia requiring intravenous calcium infusion and calcitriol. Neurological status returned to normal within 24 h of onset, except for urinary incontinence. Nine months later she remained incontinent and still required calcitriol to maintain normocalcemia. Zoledronic acid is a first-line option for the treatment of Paget's disease, yet there can be complications in particular clinical scenarios such as pagetic hydrocephalus, as seen in this case. Plentiful supplementation of calcium and vitamin D before bisphosphonate therapy is paramount in order to minimize the risk of prolonged post-treatment hypocalcemia. more...
- Published
- 2012
- Full Text
- View/download PDF
28. Mutations in the PCNA-binding domain of CDKN1C cause IMAGE Syndrome
- Author
-
Hane Lee, Imilce A. Rodriguez-Fernandez, John C. Achermann, Esteban C. Dell'Angelica, Bruno Ferraz-de-Souza, Eric Vilain, Abhik Banerjee, Valerie A. Arboleda, Stanley F. Nelson, Ignacio Bergadá, Julian A. Martinez-Agosto, Alice Fleming, Debora Braslavsky, Emmanuèle Délot, and Rahul Parnaik more...
- Subjects
Male ,Hypoadrenocorticism ,Beckwith-Wiedemann Syndrome ,Beckwith–Wiedemann syndrome ,Medical and Health Sciences ,Congenital ,Familial ,0302 clinical medicine ,Missense mutation ,Pair 11 ,IMAGe Syndrome ,Cell Line, Transformed ,Pediatric ,Genetics ,0303 health sciences ,Fetal Growth Retardation ,Genetic Diseases, X-Linked ,Exons ,Biological Sciences ,Metaphyseal dysplasia ,Genetic Diseases ,030220 oncology & carcinogenesis ,Drosophila ,Female ,Human ,Protein Binding ,Protein Structure ,Locus (genetics) ,Biology ,Osteochondrodysplasias ,Chromosomes ,Article ,Cell Line ,03 medical and health sciences ,Rare Diseases ,Proliferating Cell Nuclear Antigen ,X-linked adrenal hypoplasia congenita ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Adrenal Hyperplasia ,Cyclin-Dependent Kinase Inhibitor p57 ,030304 developmental biology ,Adrenal Hyperplasia, Congenital ,Chromosomes, Human, Pair 11 ,X-Linked ,medicine.disease ,Molecular biology ,Protein Structure, Tertiary ,HEK293 Cells ,Transformed ,Genetic Loci ,Hypoadrenocorticism, Familial ,Overgrowth syndrome ,Mutation ,Congenital Structural Anomalies ,Genomic imprinting ,Tertiary ,Developmental Biology ,Adrenal Insufficiency - Abstract
IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) is an undergrowth developmental disorder with life-threatening consequences. An identity-by-descent analysis in a family with IMAGe syndrome identified a 17.2-Mb locus on chromosome 11p15 that segregated in the affected family members. Targeted exon array capture of the disease locus, followed by high-throughput genomic sequencing and validation by dideoxy sequencing, identified missense mutations in the imprinted gene CDKN1C (also known as P57KIP2) in two familial and four unrelated patients. A familial analysis showed an imprinted mode of inheritance in which only maternal transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits cell-cycle progression, and we found that targeted expression of IMAGe-associated CDKN1C mutations in Drosophila caused severe eye growth defects compared to wild-type CDKN1C, suggesting a gain-of-function mechanism. All IMAGe-associated mutations clustered in the PCNA-binding domain of CDKN1C and resulted in loss of PCNA binding, distinguishing them from the mutations of CDKN1C that cause Beckwith-Wiedemann syndrome, an overgrowth syndrome. © 2012 Nature America, Inc. All rights reserved. more...
- Published
- 2012
- Full Text
- View/download PDF
29. Sterol O-Acyltransferase 1 (SOAT1, ACAT) Is a Novel Target of Steroidogenic Factor-1 (SF-1, NR5A1, Ad4BP) in the Human Adrenal
- Author
-
Rahul Parnaik, Mike Hubank, Mehul T. Dattani, John C. Achermann, Bruno Ferraz-de-Souza, Rebecca E. Hudson-Davies, and Lin Lin
- Subjects
Steroidogenic factor 1 ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Steroidogenic Factor 1 ,Biochemistry ,0403 veterinary science ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Adrenal Glands ,Cluster Analysis ,RNA, Small Interfering ,Cells, Cultured ,Regulation of gene expression ,0303 health sciences ,SOAT1 ,Adrenal cortex ,030302 biochemistry & molecular biology ,Gene Expression Regulation, Developmental ,04 agricultural and veterinary sciences ,General Medicine ,Cholesterol ,medicine.anatomical_structure ,Translational Highlights from JCEM ,030220 oncology & carcinogenesis ,Steroids ,endocrine system ,medicine.medical_specialty ,040301 veterinary sciences ,Sterol O-acyltransferase ,030209 endocrinology & metabolism ,Biology ,Models, Biological ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Stress, Physiological ,Internal medicine ,medicine ,Endocrine Research ,Humans ,Molecular Biology ,030304 developmental biology ,Microarray analysis techniques ,Gene Expression Profiling ,Biochemistry (medical) ,Embryo, Mammalian ,Microarray Analysis ,chemistry ,Nuclear receptor ,Brief Reports ,Sterol O-Acyltransferase - Abstract
We used up- and down-regulation of the nuclear receptor steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) to identify new components of adrenal function and steroidogenesis., Context: Steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) is a master regulator of adrenal development and steroidogenesis. Defects in several known targets of SF-1 can cause adrenal disorders in humans. Objective: We aimed to identify novel targets of SF-1 in the human adrenal. These factors could be important regulators of adrenal development and steroidogenesis and potential candidates for adrenal dysfunction. Design: A gene discovery strategy was developed based on bidirectional manipulation of SF-1. Overexpression or knockdown of SF-1 in NCI-H295R human adrenocortical cells was used to identify a subset of positively-regulated SF-1 targets. Results: This approach identified well-established SF-1 target genes (STAR, CYP11A) and several novel genes (VSNL1, ZIM2, PEG3, SOAT1, and MTSS1). Given its role in cholesterol metabolism, sterol O-acyltransferase 1 (SOAT1, previously referred to as acyl-Coenzyme A:cholesterol acyltransferase 1, ACAT) was studied further and found to be expressed in the developing human fetal adrenal cortex. We hypothesized that impaired SOAT1 activity could result in adrenal insufficiency through reduced cholesteryl ester reserves or through toxic destruction of the adrenal cells during development. Therefore, mutational analysis of SOAT1 in a cohort of 43 patients with unexplained adrenal insufficiency was performed but failed to reveal significant coding sequence changes. Conclusions: Our reverse discovery approach led to the identification of novel SF-1 targets and defined SOAT1 as an important factor in human adrenal steroidogenesis. SF-1–dependent up-regulation of SOAT1 may be important for maintaining readily-releasable cholesterol reserves needed for active steroidogenesis and during episodes of recurrent stress. more...
- Published
- 2011
- Full Text
- View/download PDF
30. ChIP‐on‐chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor‐1 (SF‐1, NR5A1) in the human adrenal gland
- Author
-
Mehul T. Dattani, Mike Hubank, Sonia Shah, Nipurna Jina, John C. Achermann, Bruno Ferraz-de-Souza, and Lin Lin
- Subjects
Steroidogenic factor 1 ,Chromatin Immunoprecipitation ,Adrenal Gland Neoplasm ,Adrenal Gland Neoplasms ,Adenocarcinoma ,Biology ,Steroidogenic Factor 1 ,Biochemistry ,Research Communications ,Angiopoietin-2 ,angiogenesis ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Adrenal Glands ,Gene expression ,Genetics ,Transcriptional regulation ,medicine ,Humans ,transcriptional regulation ,Molecular Biology ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Adrenal gland ,adrenal tumorigenesis ,ChIP-on-chip ,Repressor Proteins ,medicine.anatomical_structure ,Nuclear receptor ,030220 oncology & carcinogenesis ,NCI-H295R adrenocortical cells ,Trans-Activators ,adrenal development ,Cancer research ,Chromatin immunoprecipitation ,Biotechnology - Abstract
The nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) is a key regulator of adrenal and gonadal biology. Disruption of SF-1 can lead to disorders of adrenal development, while increased SF-1 dosage has been associated with adrenocortical tumorigenesis. We aimed to identify a novel subset of SF-1 target genes in the adrenal by using chromatin immunoprecipitation (ChIP) microarrays (ChIP-on-chip) combined with systems analysis. SF-1 ChIP-on-chip was performed in NCI-H295R human adrenocortical cells using promoter tiling arrays, leading to the identification of 445 gene loci where SF-1-binding regions were located from 10 kb upstream to 3 kb downstream of a transcriptional start. Network analysis of genes identified as putative SF-1 targets revealed enrichment for angiogenic process networks. A 1.1-kb SF-1-binding region was identified in the angiopoietin 2 (Ang2, ANGPT2) promoter in a highly repetitive region, and SF-1-dependent activation was confirmed in luciferase assays. Angiogenesis is paramount in adrenal development and tumorigenesis, but until now a direct link between SF-1 and vascular remodeling has not been established. We have identified Ang2 as a potentially important novel target of SF-1 in the adrenal gland, indicating that regulation of angiogenesis might be an important additional mechanism by which SF-1 exerts its actions in the adrenal gland.—Ferraz-de-Souza, B., Lin, L., Shah, S., Jina, N., Hubank, M., Dattani, M. T., Achermann, J. C. ChIP-on-chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor-1 (SF-1, NR5A1) in the human adrenal gland. more...
- Published
- 2010
- Full Text
- View/download PDF
31. CBP/p300-Interacting Transactivator, with Glu/Asp-Rich C-Terminal Domain, 2, and Pre-B-Cell Leukemia Transcription Factor 1 in Human Adrenal Development and Disease
- Author
-
Patricia Cogram, Bruno Ferraz-de-Souza, Yves Morel, Dianne Gerrelli, Franziska Martin, Felix Beuschlein, Angela Huebner, John C. Achermann, Lin Lin, Delphine Mallet, and Rebecca E. Hudson-Davies
- Subjects
Male ,Steroidogenic factor 1 ,medicine.medical_specialty ,Adrenal disorder ,Receptors, Retinoic Acid ,Endocrinology, Diabetes and Metabolism ,DNA Mutational Analysis ,Clinical Biochemistry ,Adrenal Gland Diseases ,Biology ,Steroidogenic Factor 1 ,Transfection ,Biochemistry ,Transactivation ,Endocrinology ,Proto-Oncogene Proteins ,Internal medicine ,Adrenal Glands ,medicine ,Humans ,Pre-B-Cell Leukemia Transcription Factor 1 ,Transcription factor ,Cells, Cultured ,DAX-1 Orphan Nuclear Receptor ,Adrenal hypoplasia ,Biochemistry (medical) ,Gene Expression Regulation, Developmental ,Adrenal Cortex Neoplasm ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,Mutation ,Trans-Activators ,Original Article ,Female ,DAX1 - Abstract
Context: Disorders of adrenal development result in significant morbidity and mortality. However, the molecular basis of human adrenal development, and many forms of disease, is still poorly understood.Objectives: We evaluated the role of two new candidate genes, CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2 (CITED2), and pre-B-cell leukemia transcription factor 1 (PBX1), in human adrenal development and disease.Design: CITED2 and PBX1 expression in early human fetal adrenal development was assessed using RT-PCR and in situ hybridization. The regulation of CITED2 and PBX1 by steroidogenic factor-1 (SF-1) and dosage-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome, gene-1 (DAX1) was evaluated in NCI-H295R human adrenocortical tumor cells by studying promoter regulation. Finally, mutational analysis of CITED2 and PBX1 was performed in patients with primary adrenal disorders.Results: CITED2 and PBX1 are expressed in the human fetal adrenal gland during early development. Both genes are activated by SF-1 in a dose-dependent manner in NCI-H295R cells, and, surprisingly, PBX1 is synergistically activated by SF-1 and DAX1. Mutational analysis failed to reveal significant coding sequence changes in individuals with primary adrenal disorders.Conclusions: CITED2 and PBX1 are likely to be important mediators of adrenal development and function in humans, but mutations in these genes are not common causes of adrenal failure in patients in whom a molecular diagnosis remains unknown. The positive interaction between DAX1 and SF-1 in regulating PBX1 may be an important mechanism in this process. more...
- Published
- 2009
- Full Text
- View/download PDF
32. Heterozygous Missense Mutations in Steroidogenic Factor 1 (SF1/Ad4BP, NR5A1) Are Associated with 46,XY Disorders of Sex Development with Normal Adrenal Function
- Author
-
Ieuan A. Hughes, J. Larry Jameson, Charles Sultan, Lin Lin, Assunta Albanese, Bruno Ferraz-de-Souza, Tessa Homfray, Neil J. Sebire, Pascal Philibert, Mehul T. Dattani, Gerard S. Conway, Silvia Einaudi, Daniel Kelberman, John C. Achermann, and Veruska Molini more...
- Subjects
Male ,Steroidogenic factor 1 ,Heterozygote ,endocrine system ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Molecular Sequence Data ,Clinical Biochemistry ,Mutation, Missense ,Receptors, Cytoplasmic and Nuclear ,Context (language use) ,CHO Cells ,Biology ,Steroidogenic Factor 1 ,Biochemistry ,Gonadal Agenesis ,Article ,XY gonadal dysgenesis ,Cricetulus ,Endocrinology ,Cricetinae ,Internal medicine ,Adrenal Glands ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Disorders of sex development ,Gonadal Dysgenesis, 46,XY ,Homeodomain Proteins ,Sequence Homology, Amino Acid ,Sexual Development ,Liver receptor homolog-1 ,Biochemistry (medical) ,Infant ,medicine.disease ,DNA-Binding Proteins ,Developmental disorder ,Female ,Mutant Proteins ,Haploinsufficiency ,Transcription Factors - Abstract
Context: Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure. Objective: Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46,XY gonadal dysgenesis/impaired androgenization (now termed 46,XY disorders of sex development) with normal adrenal function. Methods and Patients: The study included mutational analysis of NR5A1 in 30 individuals with 46,XY disorders of sex development, followed by functional studies of SF1 activity. Results: Heterozygous missense mutations in NR5A1 were found in four individuals (four of 30, 13%) with this phenotype. These mutations (V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding (V15M, M78I, G91S), altered subnuclear localization (V15M, M78I), or disruption of the putative ligand-binding pocket (L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change. Conclusions: These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46,XY individuals. more...
- Published
- 2007
- Full Text
- View/download PDF
33. Five novel mutations in steroidogenic factor 1 (SF1,NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency
- Author
-
Heike Biebermann, Peter Heidemann, John C. Achermann, Bruno Ferraz-de-Souza, Vanessa Schröder, Lin Lin, Peter Wieacker, Birgit Köhler, Annette Grüters, and Dirk Schnabel
- Subjects
Adult ,Steroidogenic factor 1 ,endocrine system ,medicine.medical_specialty ,Adolescent ,Nonsense mutation ,NR5A1 ,Gonadal dysgenesis ,Biology ,Steroidogenic Factor 1 ,medicine.disease_cause ,Frameshift mutation ,Cohort Studies ,Internal medicine ,Adrenal Glands ,Genetics ,medicine ,Adrenal insufficiency ,Humans ,Missense mutation ,nuclear receptor ,Child ,steroidogenic factor-1 ,Genetics (clinical) ,Gonadal Dysgenesis, 46,XY ,Mutation ,gonadal dysgenesis ,disorders of sex development (DSD) ,medicine.disease ,SF1 ,Endocrinology ,male pseudohermaphroditism ,Child, Preschool ,Female ,Haploinsufficiency ,Adrenal Insufficiency ,Research Article - Abstract
Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in two 46,XY female patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 27 patients with 46,XY disorders of sex development (DSD) from the German network of DSD. Heterozygous SF1 mutations were found in 5 out of 27 (18.5%) of cases. Four patients with SF1 mutations presented with the similar phenotype of mild gonadal dysgenesis, severe underandrogenization, and absent Müllerian structures. Of these, two patients harbored missense mutations within the DNA-binding region of SF1 (p.C33S, p.R84H), one patient had a nonsense mutation (p.Y138X) and one patient had a frameshift mutation (c.1277dupT) predicted to disrupt RNA stability or protein function. One additional patient ([c.424_427dupCCCA]+[p.G146A]) displayed a more marked phenotype of severe gonadal dysgenesis, normal female external genitalia, and Müllerian structures. Functional studies of the missense mutants (p.C33S, p.R84H) and of one nonsense mutant (p.Y138X) revealed impaired transcriptional activation of SF1-responsive target genes. To date, adrenal insufficiency has not occurred in any of the patients. Thus, SF1 mutations are a relatively frequent cause of 46,XY DSD in humans. more...
- Published
- 2007
- Full Text
- View/download PDF
34. POD-1/TCF21 Reduces SHP Expression, Affecting LRH-1 Regulation and Cell Cycle Balance in Adrenocortical and Hepatocarcinoma Tumor Cells
- Author
-
Claudimara Ferini Pacicco Lotfi, Maria Candida Barisson Villares Fragoso, Monica M. França, Antonio M. Lerario, and Bruno Ferraz-de-Souza
- Subjects
Cyclin E ,Carcinoma, Hepatocellular ,Article Subject ,Molecular Sequence Data ,Repressor ,Down-Regulation ,Receptors, Cytoplasmic and Nuclear ,lcsh:Medicine ,Biology ,General Biochemistry, Genetics and Molecular Biology ,E-Box Elements ,Mice ,Downregulation and upregulation ,Cell Line, Tumor ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Humans ,RNA, Messenger ,CARCINOMA HEPATOCELULAR ,Regulation of gene expression ,General Immunology and Microbiology ,Base Sequence ,Cell Cycle ,Liver Neoplasms ,lcsh:R ,Reproducibility of Results ,General Medicine ,Transfection ,Cell cycle ,Molecular biology ,Adrenal Cortex Neoplasms ,Chromatin ,Cell biology ,Gene Expression Regulation, Neoplastic ,Cyclin E1 ,Nuclear receptor ,Research Article ,Protein Binding - Abstract
POD-1/TCF21may play a crucial role in adrenal and gonadal homeostasis and repressesSf-1/SF-1 expression in adrenocortical tumor cells. SF-1 and LRH-1 are members of the Fzt-F1 subfamily of nuclear receptors. LRH-1 is involved in several biological processes, and both LRH-1 and its repressor SHP are involved in many types of cancer. In order to assess whether POD-1 can regulate LRH-1 via the same mechanism that regulates SF-1, we analyzed the endogenous mRNA levels ofPOD-1,SHP, andLRH-1in hepatocarcinoma and adrenocortical tumor cells using qRT-PCR. Hereafter, these tumor cells were transiently transfected with pCMVMycPod-1, and the effect of POD-1 overexpression on E-box elements in theLRH-1andSHPpromoter region were analyzed by ChIP assay. Also, Cyclin E1 protein expression was analyzed to detect cell cycle progression. We found that POD-1 overexpression significantly decreasedSHP/SHP mRNA and protein levels through POD-1 binding to the E-box sequence in theSHPpromoter. DecreasedSHPexpression affectedLRH-1regulation and increased Cyclin E1. These findings show that POD-1/TCF21regulates SF-1 and LRH-1 by distinct mechanisms, contributing to the understanding of POD-1 involvement and its mechanisms of action in adrenal and liver tumorigenesis, which could lead to the discovery of relevant biomarkers. more...
- Published
- 2015
35. Feocromocitoma
- Author
-
Maria Adelaide A. Pereira, Bruno Ferraz de Souza, Daniel Soares Freire, and Antonio Marmo Lucon
- Subjects
Endocrinology, Diabetes and Metabolism ,General Medicine - Abstract
Apresentamos a experiência do Hospital das Clínicas da FMUSP, com o diagnóstico clínico, laboratorial e topográfico e com o tratamento do feocromocitoma. Embora novos testes bioquímicos, como as determinações de metanefrinas plasmáticas, tenham maior sensibilidade no diagnóstico desse tumor, testes mais disponíveis, como as determinações de metanefrinas urinárias e catecolaminas plasmáticas e urinárias ainda demonstram grande valor no diagnóstico. Eventuais falso-negativos e falso-positivos podem ser identificados com os testes de estímulo e depressão e com a exclusão do uso de droga. A ressonância magnética é o método mais sensível na identificação topográfica do tumor. O tratamento do tumor, exceto quando houver contraindicações, é sempre cirúgico e deve ser precedido pelo tratamento clínico. A identificação desse tumor é de fundamental importância no sentido de se prevenir a ocorrência de eventos com alta morbidade e mortalidade, bem como na identificação de outras síndromes neoplásicas que podem estar associadas a ele. more...
- Published
- 2004
- Full Text
- View/download PDF
36. Homozygous inactivating mutation in NANOS3 in two sisters with primary ovarian insufficiency
- Author
-
Fernanda Caroline Soardi, Mirian Yumie Nishi, Aline Zamboni Machado, Maricilda Palandi de Mello, Soraia Attie Calil Jorge, Conceição N. Martins, Carlos Eduardo Pereira, Gil Guerra-Júnior, Berenice B. Mendonca, Sorahia Domenice, Andréa Trevas Maciel-Guerra, Mariza Gerdulo Santos, Elaine Maria Frade Costa, and Bruno Ferraz-de-Souza more...
- Subjects
Adult ,Candidate gene ,Article Subject ,Adolescent ,In silico ,lcsh:Medicine ,RNA-binding protein ,Apoptosis ,Biology ,APOPTOSE ,Primary Ovarian Insufficiency ,General Biochemistry, Genetics and Molecular Biology ,Young Adult ,Chlorocebus aethiops ,medicine ,Missense mutation ,Animals ,Humans ,Amenorrhea ,Zinc finger ,Genetics ,Microscopy, Confocal ,General Immunology and Microbiology ,lcsh:R ,Homozygote ,RNA-Binding Proteins ,Zinc Fingers ,General Medicine ,Flow Cytometry ,Embryonic stem cell ,medicine.anatomical_structure ,Case-Control Studies ,COS Cells ,Mutation ,RNA ,Female ,Germ cell ,Brazil ,Protein Binding ,Research Article - Abstract
Despite the increasing understanding of female reproduction, the molecular diagnosis of primary ovarian insufficiency (POI) is seldom obtained. The RNA-binding protein NANOS3 poses as an interesting candidate gene for POI since members of the Nanos family have an evolutionarily conserved function in germ cell development and maintenance by repressing apoptosis. We performed mutational analysis ofNANOS3in a cohort of 85 Brazilian women with familial or isolated POI, presenting with primary or secondary amenorrhea, and in ethnically-matched control women. A homozygous p.Glu120Lys mutation inNANOS3was identified in two sisters with primary amenorrhea. The substituted amino acid is located within the second C2HC motif in the conserved zinc finger domain of NANOS3 andin silicomolecular modelling suggests destabilization of protein-RNA interaction.In vitroanalyses of apoptosis through flow cytometry and confocal microscopy show that NANOS3 capacity to prevent apoptosis was impaired by this mutation. The identification of an inactivating missense mutation inNANOS3suggests a mechanism for POI involving increased primordial germ cells (PGCs) apoptosis during embryonic cell migration and highlights the importance of NANOS proteins in human ovarian biology. more...
- Published
- 2014
37. POD-1 binding to the E-box sequence inhibits SF-1 and StAR expression in human adrenocortical tumor cells
- Author
-
Ana Claudia Latronico, Antonio M. Lerario, Bruno Ferraz-de-Souza, Gary D. Hammer, Rork Kuick, Maria Candida Barisson Villares Fragoso, Mariza Gerdulo Santos, Claudimara Ferini Pacicco Lotfi, and Monica M. França more...
- Subjects
endocrine system ,Chromatin Immunoprecipitation ,Transcription, Genetic ,E-box ,Biology ,Steroidogenic Factor 1 ,Biochemistry ,Article ,E-Box Elements ,Mice ,Endocrinology ,Cell Line, Tumor ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Adrenocortical carcinoma ,Animals ,Humans ,Promoter Regions, Genetic ,Molecular Biology ,Reporter gene ,Expression vector ,Steroidogenic acute regulatory protein ,Transfection ,medicine.disease ,Phosphoproteins ,Molecular biology ,Adrenal Cortex Neoplasms ,Cell culture ,Chromatin immunoprecipitation ,REAÇÃO EM CADEIA POR POLIMERASE - Abstract
Pod-1/Tcf21 is expressed at epithelial-mesenchymal interaction sites during development of many organs. Different approaches have demonstrated that Pod-1 transcriptionally inhibits Sf-1/NR5A1 during gonadal development. Disruption of Sf-1 can lead to disorders of adrenal development, while increased dosage of SF-1 has been related to increased adrenal cell proliferation and tumorigenesis. In this study, we analyzed whether POD-1 overexpression inhibits the endogenous Sf-1 expression in human and mouse adrenocortical tumor cells. Cells were transiently transfected with luciferase reporter gene under the control of Sf-1 promoter and with an expression vector encoding Pod-1. Pod-1 construct inhibited the transcription of the Sf1/Luc reporter gene in a dose-dependent manner in mouse Y-1 adrenocortical carcinoma (ACC) cells, and inhibited endogenous SF-1 expression in the human H295R and ACC-T36 adrenocortical carcinoma cells. These results were validated by chromatin immunoprecipitation assay with POD-1-transfected H295R cells using primers specific to E-box sequence in SF-1 promoter region, indicating that POD-1 binds to the SF-1 E-box promoter. Moreover, POD-1 over-expression resulted in a decrease in expression of the SF-1 target gene, StAR (Steroidogenic Acute Regulatory Protein). Lastly, while the induced expression of POD-1 did not affect the cell viability of H295R/POD-1 or ACC-T36/POD-1 cells, the most significantly enriched KEGG pathways for genes negatively correlated to POD-1/TCF21 in 33 human ACCs were those associated with cell cycle genes. more...
- Published
- 2012
38. Potential effects of alendronate on fibroblast growth factor 23 levels and effective control of hypercalciuria in an adult with Jansen's metaphyseal chondrodysplasia
- Author
-
Berenice B. Mendonca, Bruno Ferraz-de-Souza, Regina Matsunaga Martin, Laura Onuchic, and Pedro Henrique Silveira Corrêa
- Subjects
musculoskeletal diseases ,Fibroblast growth factor 23 ,Adult ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Sodium Chloride Symporter Inhibitors ,Clinical Biochemistry ,Hypercalciuria ,Context (language use) ,urologic and male genital diseases ,Fibroblast growth factor ,Osteochondrodysplasias ,Biochemistry ,Asymptomatic ,Severity of Illness Index ,Endocrinology ,Internal medicine ,Severity of illness ,medicine ,Humans ,Alendronate ,Bone Density Conservation Agents ,business.industry ,Biochemistry (medical) ,medicine.disease ,Jansen's metaphyseal chondrodysplasia ,PROLIFERAÇÃO CELULAR ,Fibroblast Growth Factors ,Fibroblast Growth Factor-23 ,Treatment Outcome ,Cardiovascular Diseases ,Hypercalcemia ,Drug Therapy, Combination ,Female ,medicine.symptom ,business ,hormones, hormone substitutes, and hormone antagonists ,Hypophosphatemia - Abstract
Jansen's metaphyseal chondrodysplasia (JMC) is a rare autosomal dominant disorder caused by activating mutations in the PTH 1 receptor (PTH1R; PTH/PTHrP receptor), leading to chronic hypercalcemia and hypercalciuria. Hypophosphatemia is also a hallmark of JMC, and recently, increased fibroblast growth factor 23 (FGF23) levels have been reported in this syndrome. Hypercalcemia has been associated with increased cardiovascular risk; however, cardiovascular disease has not been extensively investigated in JMC patients.The aim of the study was to describe the long-term follow-up of a JMC patient with regard to the management of hypercalciuria, the evaluation of FGF23 levels under bisphosphonate treatment, and the investigation of cardiovascular repercussion of chronic hypercalcemia.The diagnosis of JCM was confirmed by molecular analysis (p.H223R mutation in PTH1R). The patient was followed from 5 to 27 yr of age. Asymptomatic nephrolithiasis was diagnosed at 18 yr of age, prompting pharmacological management of hypercalciuria. Treatment with alendronate reduced hypercalciuria; however, normocalciuria was only obtained with the association of thiazide diuretic. Serum FGF23 levels, measured under alendronate treatment, were repeatedly within the normal range. Subclinical cardiovascular disease was investigated when the patient was 26 yr old, after 19 yr of sustained mild hypercalcemia; carotid and vertebral artery ultrasonography was normal, as well as coronary computed tomography angiography (calcium score = 0).The long-term follow-up of our JMC patient has provided insight on therapeutic strategies to control hypercalciuria, on the potential effects of alendronate on FGF23 levels, and on the lack of detectable cardiovascular disease at young adulthood after prolonged exposure to hypercalcemia. more...
- Published
- 2012
39. Novel Interacting Proteins for Steroidogenic Factor-1 (SF-1, NR5A1, Ad4BP) in the Developing Human Adrenal Gland
- Author
-
Lin Lin, Rahul Parnaik, Bruno Ferraz-de-Souza, and John C Achermann
- Published
- 2011
- Full Text
- View/download PDF
40. Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal function
- Author
-
Ranna, El-Khairi, Alejandro, Martinez-Aguayo, Bruno, Ferraz-de-Souza, Lin, Lin, and John C, Achermann
- Subjects
Male ,Phenotype ,DAX-1 Orphan Nuclear Receptor ,Adrenal Glands ,Animals ,Humans ,Female ,Steroidogenic Factor 1 ,Models, Biological - Abstract
The nuclear receptor transcription factors DAX-1 (NR0B1) and SF-1 (NR5A1) regulate many aspects of adrenal and reproductive development and function. Disruption of the genes encoding these factors can be associated with pediatric adrenal disease. DAX-1 mutations are classically associated with X-linked adrenal hypoplasia congenita, hypogonadotropic hypogonadism and impaired spermatogenesis. However, other phenotypes are also being reported, such as isolated mineralocorticoid insufficiency, premature sexual development, primary adrenal insufficiency in a 46, XX patient and late-onset X-linked adrenal hypoplasia congenita and/or hypogonadotropic hypogonadism. SF-1 mutations have also been associated with primary adrenal insufficiency, together with 46, XY disorders of sex development. However it is emerging that SF-1 changes are a relatively rare cause of primary adrenal failure in humans, and most individuals with SF-1 mutations have a spectrum of 46, XY disorders of sex development phenotypes. These conditions range from 46, XY females with streak gonads and müllerian structures, through children with ambiguous genitalia and inguinal testes, to severe penoscrotal hypospadias with undescended testes. Therefore, the human gonad appears to be more sensitive than the adrenal gland to loss of SF-1 function. This review will focus on the expanding range of phenotypes associated with DAX-1 and SF-1 mutations. more...
- Published
- 2010
41. Role of DAX-1 (NR0B1) and Steroidogenic Factor-1 (NR5A1) in Human Adrenal Function
- Author
-
John C. Achermann, Ranna El-Khairi, Lin Lin, Bruno Ferraz-de-Souza, and Alejandro Martinez-Aguayo
- Subjects
Steroidogenic factor 1 ,medicine.medical_specialty ,Gonad ,Adrenal gland ,business.industry ,medicine.disease ,Primary Adrenal Insufficiency ,medicine.anatomical_structure ,Endocrinology ,Hypogonadotropic hypogonadism ,X-linked adrenal hypoplasia congenita ,Internal medicine ,medicine ,DAX1 ,Disorders of sex development ,business - Abstract
The nuclear receptor transcription factors DAX-1 (NR0B1) and SF-1 (NR5A1) regulate many aspects of adrenal and reproductive development and function. Disruption of the genes encoding these factors can be associated with pediatric adrenal disease. DAX-1 mutations are classically associated with X-linked adrenal hypoplasia congenita, hypogonadotropic hypogonadism and impaired spermatogenesis. However, other phenotypes are also being reported, such as isolated mineralocorticoid insufficiency, premature sexual development, primary adrenal insufficiency in a 46, XX patient and late-onset X-linked adrenal hypoplasia congenita and/or hypogonadotropic hypogonadism. SF-1 mutations have also been associated with primary adrenal insufficiency, together with 46, XY disorders of sex development. However it is emerging that SF-1 changes are a relatively rare cause of primary adrenal failure in humans, and most individuals with SF-1 mutations have a spectrum of 46, XY disorders of sex development phenotypes. These conditions range from 46, XY females with streak gonads and mullerian structures, through children with ambiguous genitalia and inguinal testes, to severe penoscrotal hypospadias with undescended testes. Therefore, the human gonad appears to be more sensitive than the adrenal gland to loss of SF-1 function. This review will focus on the expanding range of phenotypes associated with DAX-1 and SF-1 mutations. more...
- Published
- 2010
- Full Text
- View/download PDF
42. Steroidogenic factor-1 (SF-1, NR5A1) and human disease
- Author
-
John C. Achermann, Lin Lin, and Bruno Ferraz-de-Souza
- Subjects
Infertility ,Steroidogenic factor 1 ,medicine.medical_specialty ,Anorchia ,Endometriosis ,NR5A1 ,Gonadal dysgenesis ,Steroidogenic factor-1 (SF-1) ,POI, primary ovarian insufficiency ,Review ,Biology ,Steroidogenic Factor 1 ,AMH, anti-Müllerian hormone (also known as Müllerian-inhibiting substance) ,Biochemistry ,Polymorphism, Single Nucleotide ,46,XY disorders of sex development (DSD) ,Endocrinology ,LBD, ligand-binding domain ,Internal medicine ,medicine ,Adrenal insufficiency ,Animals ,Humans ,DSD, disorders of sex development ,Disease ,Disorders of sex development ,ACT, adrenocortical tumor ,Molecular Biology ,Adrenocortical tumor ,Endocrine disease ,medicine.disease ,Primary ovarian insufficiency (POI) ,Phenotype ,DBD, DNA-binding domain ,Adrenal failure - Abstract
Steroidogenic factor-1 (SF-1, Ad4BP, encoded by NR5A1) is a key regulator of adrenal and reproductive development and function. Based upon the features found in Nr5a1 null mice, initial attempts to identify SF-1 changes in humans focused on those rare individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis and Mullerian structures. Although alterations affecting DNA-binding of SF-1 were found in two such cases, disruption of SF-1 is not commonly found in patients with adrenal failure. In contrast, it is emerging that variations in SF-1 can be found in association with a range of human reproductive phenotypes such as 46,XY disorders of sex development (DSD), hypospadias, anorchia, male factor infertility, or primary ovarian insufficiency in women. Overexpression or overactivity of SF-1 is also reported in some adrenal tumors or endometriosis. Therefore, the clinical spectrum of phenotypes associated with variations in SF-1 is expanding and the importance of this nuclear receptor in human endocrine disease is now firmly established. more...
- Published
- 2010
43. Adrenals
- Author
-
Bruno Ferraz-de-Souza, Lin Lin, and John C. Achermann
- Published
- 2009
- Full Text
- View/download PDF
44. Disorders of adrenal development
- Author
-
Bruno, Ferraz-de-Souza and John C, Achermann
- Subjects
Models, Molecular ,Adrenocorticotropic Hormone ,Adrenal Glands ,Adrenal Gland Diseases ,Animals ,Humans ,Syndrome ,Adrenal Insufficiency - Abstract
Human adrenal development is a complex and relatively poorly understood process. However, significant insight into some of the mechanisms regulating adrenal development and function is being obtained through the analysis of individuals and families with adrenal hypoplasia. Adrenal hypoplasia can occur: (1) secondary to defects in pituitary adrenocorticotropin (ACTH) synthesis, processing and release (secondary adrenal hypoplasia; e.g. HESX1, LHX4, SOX3, TPIT, pituitary POMC, PC1); (2) as part of several ACTH resistance syndromes (e.g. MC2R/ACTHR, MRAP, Alacrima, Achalasia, Addison disease), or as (3) a primary defect in the development of the adrenal gland itself (primary adrenal hypoplasia; e.g. DAX1/NR0B1 - dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome 1). Indeed, the X-linked form of primary adrenal hypoplasia due to deletions or mutations in the orphan nuclear receptor DAX1 occurs in around half of male infants presenting with a salt-losing adrenal crisis, where no obvious steroidogenic defect (e.g. 21-hydroxylase deficiency), metabolic abnormality (e.g. neonatal adrenoleukodystrophy) or physical cause (e.g. adrenal haemorrhage) is found. Establishing the underlying basis of adrenal failure can have important implications for investigating associated features, the likely long-term approach to treatment, and for counselling families about the risk of other children being affected. more...
- Published
- 2008
45. Disorders of Adrenal Development
- Author
-
Bruno Ferraz-de-Souza and John C. Achermann
- Subjects
endocrine system ,medicine.medical_specialty ,Adrenal gland ,business.industry ,Adrenal hypoplasia ,Adrenal crisis ,Adrenocorticotropic hormone ,medicine.disease ,Alacrima ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,X-linked adrenal hypoplasia congenita ,medicine ,Adrenal insufficiency ,DAX1 ,medicine.symptom ,business - Abstract
Human adrenal development is a complex and relatively poorly understood process. However, significant insight into some of the mechanisms regulating adrenal development and function is being obtained through the analysis of individuals and families with adrenal hypoplasia. Adrenal hypoplasia can occur: (1) secondary to defects in pituitary adrenocorticotropin (ACTH) synthesis, processing and release (secondary adrenal hypoplasia; e.g. HESX1, LHX4, SOX3, TPIT, pituitary POMC, PC1); (2) as part of several ACTH resistance syndromes (e.g. MC2R/ACTHR, MRAP, Alacrima, Achalasia, Addison disease), or as (3) a primary defect in the development of the adrenal gland itself (primary adrenal hypoplasia; e.g. DAX1/NR0B1 - dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome 1). Indeed, the X-linked form of primary adrenal hypoplasia due to deletions or mutations in the orphan nuclear receptor DAX1 occurs in around half of male infants presenting with a salt-losing adrenal crisis, where no obvious steroidogenic defect (e.g. 21-hydroxylase deficiency), metabolic abnormality (e.g. neonatal adrenoleukodystrophy) or physical cause (e.g. adrenal haemorrhage) is found. Establishing the underlying basis of adrenal failure can have important implications for investigating associated features, the likely long-term approach to treatment, and for counselling families about the risk of other children being affected. more...
- Published
- 2008
- Full Text
- View/download PDF
46. Adrenals
- Author
-
Bruno Ferraz-de-Souza, Lin Lin, and John C. Achermann
- Published
- 2008
- Full Text
- View/download PDF
47. Genetic disorders involving adrenal development
- Author
-
Lin, Lin, Bruno, Ferraz-de-Souza, and John C, Achermann
- Subjects
Adrenocorticotropic Hormone ,Adrenal Glands ,Adrenal Gland Diseases ,Drug Resistance ,Genetic Diseases, Inborn ,Humans ,Syndrome ,Models, Biological - Abstract
The past decade has seen significant advances in our understanding of the genetic aetiology of several forms of adrenal failure that present in infancy or childhood. Several of these disorders affect adrenal development and are termed 'adrenal hypoplasia'. These conditions can be broadly divided into: (1) secondary forms of adrenal hypoplasia due to panhypopituitarism (e.g. HESX1, LHX4, SOX3) or abnormalities in ACTH synthesis (TPIT) or processing (e.g. POMC or PC1); (2) adrenal hypoplasia as part of an ACTH resistance syndrome [MC2R/ACTH receptor, MRAP, AAAS (triple A syndrome)], and (3) primary defects in the development of the adrenal gland itself (primary adrenal hypoplasia). Primary adrenal hypoplasia most commonly occurs in an X-linked form due to mutations in the nuclear receptor DAX1 (NR0B1) but can occur in a poorly understood recessive form or as part of the IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, genitourinary anomalies) syndrome. Defining the molecular basis of these conditions can have significant clinical implications for management, counselling and presymptomatic diagnosis, as well as providing fascinating insight into normal and abnormal mechanisms of adrenal development in humans. more...
- Published
- 2007
48. Reproductive Endocrinology
- Author
-
Bruno Ferraz-de-Souza, Lin Lin, Teresa K. Woodruff, and John C. Achermann
- Published
- 2007
- Full Text
- View/download PDF
49. Diagnóstico molecular na prática clínica: visão do endocrinologista
- Author
-
Bruno Ferraz-de-Souza
- Subjects
Sanger sequencing ,Massive parallel sequencing ,medicine.diagnostic_test ,General Medicine ,Dna variants ,Biology ,Bioinformatics ,Gene dosage ,symbols.namesake ,Genetic marker ,medicine ,symbols ,Multiplex ligation-dependent probe amplification ,Restriction fragment length polymorphism ,Genetic testing - Abstract
Endocrinology is one of several medical specialities that have been gradually transformed by a deeper understanding of the molecular bases of disorders. Genetic testing with the purposes of defining a precise molecular diagnosis has increasingly gained space in the routine assessment of patients with endocrinopathies, and the advent of massive parallel sequencing (MPS) is boosting the incorporation of molecular information in the clinic. The main benefit of genetic testing is diagnostic precision, resulting in improved and individualized care for patients and family members, and better disease prevention. However, genetic tests are not infallible and may bear several potential risks, being thus indicated when clinical suspicion is strong and the benefit of determining a molecular diagnosis is unambiguous. In this review, these evolving concepts and current indications for molecular diagnosis in endocrinology will be explored. Molecular tools will be revised and contextualised, including those aimed at identifying changes in gene dosage (karyotpe, FISH, MLPA, aCGH, SNParray) or in the DNA nucleotide sequence (allele-specific PCR, RFLP, Sanger sequencing, MPS or NGS). Finally, matters surrounding the complex attribution of biologically relevant functional impact to identified DNA variants will be explored, together with the challenges brought by high throughput molecular analysis. These are exciting times for molecular endocrinology, and hopefully soon a translation to multiple benefits for patients will be self-evident. more...
- Published
- 2015
- Full Text
- View/download PDF
50. Steroidogenic factor-1 (SF-1) and its relevance to pediatric endocrinology
- Author
-
Bruno Ferraz, de-Souza, Lin, Lin, and John C, Achermann
- Subjects
Homeodomain Proteins ,Endocrinology ,Animals ,Humans ,Receptors, Cytoplasmic and Nuclear ,Child ,Endocrine System Diseases ,Gonadal Dysgenesis ,Steroidogenic Factor 1 ,Pediatrics ,Transcription Factors - Abstract
Steroidogenic factor-1 (SF-1) (NR5A1) is a member of the nuclear receptor superfamily that is expressed widely throughout the adrenal and reproductive axes during development and plays a central role in the function of these endocrine systems in post-natal and adult life. Much has been learned about the role of this transcription factor since its initial cloning in 1992, largely due to the creation of an Sf-1 (FtzF1) knockout mouse model, in vitro studies of nuclear receptor function and, more recently, following identification and characterization of patients with naturally-occurring SF-1 mutations. In this review, we will summarize how our knowledge of SF-1 in endocrine development and disease evolved to its current state, focusing on the spectrum of phenotypes associated with mutations in this transcription factor in patients who might present to a pediatric endocrinologist. more...
- Published
- 2006
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.