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ABSTRACT: We report a case of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to a novel DAX1 mutation. A 19-month-old boy with hyperpigmentation and failure to thrive came to our service for investigation. Three brothers of the patient had died due to adrenal failure, and a maternal cousin had adrenal insufficiency. Adrenoleukodystrophy was excluded. MRI showed normal pituitary and hypothalamus. Plasma hormone evaluation revealed high ACTH (up to 2,790 pg/mL), and low levels of androstenedione, DHEA-S, 11-deoxycortisol, and cortisol. At 14 years of age the patient was still prepubescent, his weight was 43.6 kg (SDS: -0.87) and his height was 161 cm (SDS: -0.36), with normal body proportions. In the GnRH test, basal and maximum values of LH and FSH were respectively 0.6/2.1 and < 1.0/< 1.0 U/L. Molecular investigation identified a novel mutation that consists of a deletion of codon 372 (AAC; asparagine) in exon 1 of DAX1. This mutation was not found in a study of 200 alleles from normal individuals. Prediction site analysis indicated that this alteration, located in the DAX1 ligand-binding domain, may damage DAX1 protein. We hypothesize that the novel (p.Asp372del) DAX1 mutation might be able to cause a disruption of DAX1 function, and is probably involved in the development of AHC and HH in this patient. Arq Bras Endocrinol Metab. 2012;56(8):496-500.
Arquivos brasileiros de endocrinologia e metabologia 11/2012; 56(8):496-500. · 0.68 Impact Factor
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André F Reis,
Caroline Kannengiesser,
Farida Jennane, Thais Della Manna,
Nadir Cheurfa,
Claire Oudin,
Roberta Diaz Savoldelli,
Carolina Oliveira,
Bernard Grandchamp,
Fernando Kok,
Gilberto Velho
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ABSTRACT: Wolcott-Rallison syndrome (WRS, OMIM 226980) is a rare autosomal recessive disorder characterized by permanent neonatal diabetes mellitus, epiphyseal dysplasia, and other multisystemic clinical manifestations. We described two novel mutations in the EIF2AK3 gene in two consanguineous families with WRS from Brazil and Morocco. We have observed in case 1 a homozygous C > T replacement at base pair c.1192 at exon 7, generating a stop codon at position 398 (Gln398Stop). Both of his parents were found to be heterozygous for the mutation. We detected in both parents of case 2, a deceased Moroccan girl, a duplication of base pair c.851A at exon 5 (c.851dupA) leading to a frameshift and a stop codon at position 285 (p.Pro285AlafsX3). Both cases 1 and 2 had neonatal diabetes mellitus, multiple epiphyseal dysplasia, and growth delay, and presented episodes of acute hepatic dysfunction. Case 1 presented central hypothyroidism, developmental delay, and mild mental retardation. Case 2 presented a fatal episode of acute renal failure. The clinical phenotype associated with the syndrome can be variable, but a combination of infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, and hepatic and/or renal dysfunction is the mainstay of diagnosis.
Pediatric Diabetes 05/2011; 12(3 Pt 1):187-91. · 2.16 Impact Factor
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ABSTRACT: MCT8 is a cellular transporter of thyroid hormones important in their action and metabolization. We report a male patient with the novel inactivating mutation 630insG in the coding region in exon 1 of MCT8. He was characterized clinically by severe neurologic impairment (initially with global hypotonia, later evolving with generalized hypertonia), normal growth during infancy, reduced weight gain, and absence of typical signs and symptoms of hypothyroidism, while the laboratory evaluation disclosed elevated T3, low total and free T4, and mildly elevated TSH serum levels. Treatment with levothyroxine improved thyroid hormone profile but was not able to alter the clinical picture of the patient. These data reinforce the concept that the role of MCT8 is tissue-dependent: while neurons are highly dependent on MCT8, bone tissue, adipose tissue, muscle, and liver are less dependent on MCT8 and, therefore, may suffer the consequences of the exposition to high serum T3 levels.
Arquivos brasileiros de endocrinologia e metabologia 02/2011; 55(1):60-6. · 0.68 Impact Factor
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Maria Regina R Gasparin,
Felipe Crispim,
Sílvia L Paula,
Maria Beatriz S Freire,
Ivaldir S Dalbosco, Thais Della Manna,
João Eduardo N Salles,
Fábio Gasparin,
Aléxis Guedes,
João M Marcantonio,
Márcio Gambini,
Camila P Salim,
Regina S Moisés
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ABSTRACT: Wolfram syndrome (WS) is a rare, progressive, neurodegenerative disorder with an autosomal recessive pattern of inheritance. The gene for WS, WFS1, was identified on chromosome 4p16 and most WS patients carry mutations in this gene. However, some studies have provided evidence for genetic heterogeneity and the genotype-phenotype relationships are not clear. Our aim was to ascertain the spectrum of WFS1 mutations in Brazilian patients with WS and to examine the phenotype-genotype relationships in these patients.
Clinical characterization and analyses of the WFS1 gene were performed in 27 Brazilian patients with WS from 19 families.
We identified 15 different mutations in the WFS1 gene in 26 patients, among which nine are novel. All mutations occurred in exon 8, except for one missense mutation which was located in exon 5. Although we did not find any clear phenotype-genotype relationship in patients with mutations in exon 8, the homozygous missense mutation in exon 5 was associated with a mild phenotype: onset of diabetes mellitus and optic atrophy during adulthood with good metabolic control being achieved with low doses of sulfonylurea.
Our data show that WFS1 is the major gene involved in WS in Brazilian patients and most mutations are concentrated in exon 8. Also, our study increases the spectrum of WFS1 mutations. Although no clear phenotype-genotype relationship was found for mutations in exon 8, a mild phenotype was associated with a homozygous missense mutation in exon 5.
European Journal of Endocrinology 12/2008; 160(2):309-16. · 3.42 Impact Factor
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ABSTRACT: Heterozygous activating mutations of KCNJ11 (Kir6.2) are the most common cause of permanent neonatal diabetes mellitus (PNDM) and several cases have been successfully treated with oral sulfonylureas. We report on the attempted transfer of insulin therapy to glibenclamide in a 4-year old child with PNDM and DEND syndrome, bearing a C166Y mutation in KCNJ11. An inpatient transition from subcutaneous NPH insulin (0.2 units/kg/d) to oral glibenclamide (1 mg/kg/d and 1.5 mg/kg/d) was performed. Glucose and C-peptide responses stimulated by oral glucose tolerance test (OGTT), hemoglobin A1c levels, the 8-point self-measured blood glucose (SMBG) profile and the frequency of hypoglycemia episodes were analyzed, before and during treatment with glibenclamide. Neither diabetes control nor neurological improvements were observed. We concluded that C166Y mutation was associated with a form of PNDM insensitive to glibenclamide.
Arquivos brasileiros de endocrinologia e metabologia 12/2008; 52(8):1350-5. · 0.68 Impact Factor
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ABSTRACT: Cystic fibrosis-related diabetes (CFRD) is a major co-morbidity generally affecting patients over 15 years old and it is associated with increased morbidity and mortality. The pathophysiology includes exocrine tissue destruction, insulin deficiency and insulin resistance; the carbohydrate metabolism dysfunction begins with an altered kinetic in insulin secretion followed by a progressive insulin deficiency. Postprandial hyperglycemia is the first abnormality seen in CF patients and the classical symptoms of diabetes may not be recognized. The screening strategy proposed is annual random plasma glucose or fasting plasma glucose investigation, as well as the performance the oral glucose tolerance test (OGTT). Two categories of diabetes are related to CF: CFRD without fasting hyperglycemia (fasting glucose < 126 mg/dL and 2h OGTT glucose > 200 mg/dL) and CFRD with fasting hyperglycemia (fasting glucose > 126 mg/dL). Nutritional management and hyperglycemia control are the CFRD treatment goals. Insulin control is the standard medical therapy for CFRD with fasting hyperglycemia and the benefits of oral insulin secretagogue and sensitizing agents are still controversial.
Arquivos brasileiros de endocrinologia e metabologia 04/2008; 52(2):188-97. · 0.68 Impact Factor
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Thais Della Manna
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ABSTRACT: Although it is type 1 diabetes mellitus of autoimmune origin that is most prevalent in childhood and adolescence, other forms of diabetes can also affect this population, resulting in different prognosis and treatment.
Information was obtained by means of a bibliographic review, carried out by running searches for scientific articles in the MEDLINE and LILACS databases, in addition to classic publications on the subject, with the most representative being chosen.
This article discusses the pathophysiological mechanisms, clinical presentation and treatment of the various forms of diabetes that affect the pediatric age group, such as type 1 diabetes mellitus , type 2 diabetes mellitus, maturity-onset diabetes of youth, neonatal diabetes, mitochondrial diabetes, diabetes of generalized lipodystrophy, diabetes secondary to other pancreatic diseases, diabetes secondary to other endocrine diseases, diabetes associated with infections and cytotoxic drugs and diabetes related to certain genetic syndromes.
Recognition of the primary pathophysiologic mechanism of the form of diabetes presented can guide specific treatment, optimizing metabolic control and minimizing complications over the long term.
Jornal de Pediatria 12/2007; 83(5 Suppl):S178-83. · 1.01 Impact Factor
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ABSTRACT: To look for technical simplification and economic efficiency in the treatment of pediatric diabetic ketoacidosis (DKA) with subcutaneous use of the fast-acting insulin analog (lispro) and compare its use with regular intravenous insulin treatment.
In this controlled clinical trial from June 2001 to June 2003, we randomized 60 episodes of DKA with a blood glucose level > or = 16.6 mmol/l (300 mg/dl), venous pH <7.3 and/or bicarbonate <15 mmol/l, or ketonuria greater than + +. Of the 60 episodes, 30 were treated with subcutaneous lispro (0.15 units/kg) given every 2 h (lispro group) and the other 30 cases received continuous intravenous regular insulin (0.1 unit x kg(-1) x h(-1); CIRI group). Volume deficit was repaired with 10-ml/kg aliquots of 0.9% sodium chloride. Laboratory monitoring included hourly bedside capillary glucose, venous blood gas, beta-hydroxybutyrate, and electrolytes. Plasma blood glucose levels were measured on admission, 2 h after admission, when capillary blood glucose reached < or = 13.8 mmol/l (250 mg/dl), and 6, 12, and 24 h thereafter.
Capillary glucose levels decreased by 2.9 and 2.6 mmol x l(-1) x h(-1) in the lispro and CIRI groups, respectively, but blood glucose fluctuated at different time intervals. In the CIRI group, metabolic acidosis and ketosis resolved in the first 6-h period after capillary glucose reached 13.8 mmol/l, whereas in the lispro group, they resolved in the next 6-h interval; however, both groups met DKA recovery criteria without complications.
DKA treatment with a subcutaneous fast-acting insulin analog represents a cost-effective and technically simplified procedure that precludes intensive care unit admission.
Diabetes Care 08/2005; 28(8):1856-61. · 8.09 Impact Factor
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ABSTRACT: Adrenocortical carcinoma is a rare condition with an unpredictable prognosis as a rule. The authors retrospectively analyzed the clinical outcome of 46 patients (31 F, 15 M) during 16 years building up a numerical index for the prognosis, based on clinical and immunohistochemical data. Four indices were analyzed: J1= (Y + 2L + 4H)/T; J2 = (J1) square root of W/200; J3 = (O + Y + 2L + 4H)/T; J4 = (J3) square root W/200. Y = 1 when chronological age (CA) >33 mo, Y = 0 when CA < or =33 mo; L = 1 for right sided tumor and L = 0 for left sided tumor; H = 1 in presence of hypertension and H = 0 for normal blood pressure; T = length of disease in months; W = weight of tumor (g); O = 1 in the absence of p53 protein and O = 0 in the presence of p53. The chance of bad prognosis was observed when age is >33 mo, tumor is on the right side, systemic hypertension is present, tumor weight >250 g, in the absence of p53, J1, J2, J3 >0.4 (p <0.001) and J4 >0.5 (p <0.01). Clinical data and the mathematical model enabled us to establish probabilities of good prognosis in 78-96% and bad prognosis in 63-83%.
Journal of pediatric endocrinology & metabolism: JPEM 04/2005; 18(4):347-53. · 0.88 Impact Factor
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ABSTRACT: Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are consequent to inactivating mutations of the calcium-sensing receptor (CaR) gene. FHH is usually associated with heterozygous inactivating mutations of the CaR gene, whereas NSHPT is usually due to homozygous inactivation of the CaR gene. FHH is generally asymptomatic and is characterized by mild to moderate lifelong hypercalcemia, relative hypocalciuria, and normal intact PTH, whereas individuals with NSHPT frequently show life-threatening hypercalcemia. In this study, we report a novel inactivating mutation of the CaR gene, identified in a 9-yr-old Brazilian girl who was found to be severely hypercalcemic during investigation of a 6-month history of headaches and vomits. Direct sequencing of the CaR gene from this patient showed a novel homozygous mutation (L13P) in exon 2. Functional characterization by intracellular calcium measurement by fluorometry showed that the mutant receptor had a dose-response curve shifted to the right relative to that of wild type. The proband's consanguineous parents, who had mild asymptomatic hypercalcemia, showed the same mutation in the heterozygous form. The mutation described in this study is the inactivating missense mutation present at the most N-terminal end among the known CaR missense mutations. This study reinforces the fact that patients with homozygous inactivation of the CaR gene may present with severe hypercalcemia in different phases of life.
Journal of Clinical Endocrinology & Metabolism 01/2005; 89(12):5936-41. · 6.50 Impact Factor
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ABSTRACT: Over the last 20 years, after combining treatment of chemotherapy and radiotherapy, there has been an improvement in the survival rate of acute lymphoblastic leukemia patients, with a current cure rate of around 70%. Children with the disease have been enrolled into international treatment protocols designed to improve survival and minimize the serious irreversible late effects. Our oncology unit uses the international protocol: GBTLI LLA-85 and 90, with the drugs methotrexate, cytosine, arabinoside, dexamethasone, and radiotherapy. However, these treatments can cause gonadal damage and growth impairment.
The authors analyzed 20 children off therapy in order to determine the role of the various doses of radiotherapy regarding endocrinological alterations. They were divided into 3 groups according to central nervous system prophylaxis: Group A underwent chemotherapy, group B underwent chemotherapy plus radiotherapy (18 Gy), and group C underwent chemotherapy plus radiotherapy (24 Gy). Serum concentrations of LH, FSH, GH, and testosterone were determined. Imaging studies included bone age, pelvic ultrasound and scrotum, and skull magnetic resonance imaging.
Nine of the patients who received radiotherapy had decreased pituitary volume. There was a significant difference in the response to GH and loss of predicted final stature (Bayley-Pinneau) between the 2 irradiated groups and the group that was not irradiated, but there was no difference regarding the radiation doses used (18 or 24 Gy). The final predicted height (Bayley-Pinneau) was significantly less (P = 0.0071) in both groups treated with radiotherapy. Two girls had precocious puberty, and 1 boy with delayed puberty presented calcification of the epididymis.
Radiotherapy was been responsible for late side effects, especially related to growth and puberty.
Revista do Hospital das Clínicas 05/2004; 59(2):67-70.
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ABSTRACT: Congenital adrenal hyperplasia caused by 21-hydroxylase deficiency is a common autosomal recessive disorder resulting from mutations in the 21-hydroxylase (CYP21) gene. To develop a strategy to screen for the most commonly occurring CYP21 mutations in Brazil, we performed molecular genotype analysis on 73 children with CAH representing 71 unrelated families. The techniques used for CYP21 molecular genotype analysis were: restriction fragment length polymorphism, single-strand conformational polymorphism, allele-specific oligonucleotide hybridization, allele-specific polymerase chain reaction amplification, and heteroduplex analyses. Mutations were identified on all but eight affected alleles. The intron 2 splicing mutation was the most frequently identified mutation. Screening for the most common mutations detected at least one mutation on 132/142 (93%) alleles. Multiple CYP21 mutations were detected on 16.2% of alleles. The high frequency of multiple mutations on a single allele emphasizes the importance of thorough and accurate molecular genotype analysis of the complex CYP21 locus.
Human Genetics 03/2000; 106(4):414-419. · 5.07 Impact Factor
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ABSTRACT: 1 Doutora em Ciências, Médica Assistente da Unidade de Endocrinologia Pediátrica ICRHC-FMUSP 2 Professor Livre-docente, Chefe da Unidade de Endocrinologia Pediátrica ICRHC-FMUSP 3 Professora Associada do Departamento de Pediatria da FMUSP Resumo Objetivo: avaliar os critérios diagnósticos e a importância da Síndrome Metabólica em crianças e ado-lescentes. Fontes pesquisadas: revisão da literatura na base de dados Medline com os unitermos Síndrome Metabólica, diabetes mellitus tipo 2, crianças, adolescentes, no período entre 1998 e 2006. Síntese dos dados: foram identificados cinco critérios diagnósticos. O principal, é aquele proposto pela NCEP/ATP III modificado para a idade, sendo necessária a presença de pelo menos 3 de 5 parâmetros: níveis de triglicérides ≥ 110 mg/ dL; HDL ≤ 40 mg/dL; circunferência abdominal ≥ 90º percentil segundo sexo e idade; glicemia ≥ 110 mg/dL e pressão sistólica ou diastólica ≥ 90º percentil segundo sexo, idade e estatura. A prevalência da síndrome situa-se entre 0,4 e 26,3% segundo a amostra avaliada. A importância é a caracterização de um conjunto de fatores de risco para a evolução para diabetes mellitus tipo 2 e doença cardiovascular, causas importantes de morbidade e letalidade precoce. Os parâmetros de caracterização clínica da Síndrome Metabólica não são consensuais no momento entre endocrinologistas e cardiologistas. Conclusões: há necessidade de uniformização dos critérios diagnósticos para a Síndrome Metabólica em crianças e um maior entendimento dos fatores e dos níveis de risco para o desenvolvimento de doença cardiovascular. Ao pediatra cabe a vigilância do conjunto de fatores de risco que compõem a Síndrome Metabólica, e implementar medidas que favoreçam um estilo de vida mais saudável com vigilância do peso e atividade física regular. O tratamento medicamentoso poderá ser necessário para crianças e adolescentes com diabetes mellitus tipo 2, dislipidemia e hipertensão arterial. Descritores: Síndrome Metabólica. Diabetes mellitus. Adolescente. Criança. Pediatria (São Paulo) 2006;28(4):272-7.
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ABSTRACT: We reviewed retrospectively seven children with congenital toxoplasmosis and precocious puberty. All seven showed very high levels of LH (25.2-155.0 IU/ml) and FSH (7.1-38.2) upon stimulation with GnRH. Three of them showed low GH response to an insulin tolerance test. All the children had severe mental retardation. We emphasize that children with congenital toxoplasmosis should have their hypothalamopituitary function evaluated even in subclinical situations that could be responsible for endocrinological disturbances such as precocious puberty.
Journal of pediatric endocrinology & metabolism: JPEM 15(9):1487-90. · 0.88 Impact Factor
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ABSTRACT: Two groups of girls with premature breast development were studied retrospectively. We tried to identify clinical, radiological, and hormonal parameters that could distinguish between a benign, nonprogressive premature thelarche and a true precocious puberty.
The clinical outcome of 88 girls with breast enlargement before 6.1 years of age was analyzed. Taking into account the progression of their sexual maturation, we allocated the children into 2 groups: "Isolated Premature Thelarche" (n = 63) and "Precocious Puberty" (n = 25) groups. Chronological and bone ages, height and growth velocity centiles, computerized tomography of hypothalamus-pituitary area, pelvic ultrasonography, gonadotropin response to luteinizing hormone-releasing hormone stimulation as well as basal levels of luteinizing hormone, follicle-stimulating hormone, estradiol, and prolactin were studied in both groups. Statistical analysis were performed using the Student t test to compare the sample means. Fisher's exact test and chi2 test were used to analyze the nonparametric variables.
Isolated premature thelarche most frequently affected girls younger than 2 years who presented exaggerated follicle-stimulating hormone response to luteinizing hormone-releasing hormone stimulation test. The precocious puberty group had higher initial stature, accelerated growth rate and bone age, increased uterine and ovarian volumes, high spontaneous luteinizing hormone levels by immunofluorimetric assay, as well as a high luteinizing hormone response and peak luteinizing hormone/follicle-stimulating hormone ratio after luteinizing hormone-releasing hormone stimulation.
At initial presentation, girls who undergo true precocious puberty present advanced bone age, increased uterine and ovarian volumes in addition to breast enlargement, as well as an luteinizing hormone-predominant response after a luteinizing hormone-releasing hormone stimulation test.
Revista do Hospital das Clínicas 57(2):49-54.
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ABSTRACT: Congenital hyperinsulinism (CHI) is a rare pancreatic β-cell disease of neonates, characterized by inappropriate insulin secretion with severe persistent hypoglycemia, with regard to which many questions remain to be answered, despite the important acquisition of its molecular mechanisms in the last decade. The aim of this study was to examine pancreatic histology, β-cell proliferation (immunohistochemistry with double staining for Ki-67/insulin), and β-cell adenosine triphosphate-sensitive potassium channels genes from 11 Brazilian patients with severe medically unresponsive CHI who underwent pancreatectomy. Pancreatic histology and β-cell proliferation in CHI patients were compared to pancreatic samples from 19 age-matched controls. Ten cases were classified as diffuse form (D-CHI) and 1 as focal form (F-CHI). β-cell nucleomegaly and abundant cytoplasm were absent in controls and were observed only in D-CHI patients. The Ki-67 labeling index (Ki-67-LI) was used to differentiate the adenomatous areas of the F-CHI case (10.15%) from the "loose cluster of islets" found in 2 D-CHI samples (2.29% and 2.43%) and 1 control (1.54%) sample. The Ki-67-LI was higher in the F-CHI adenomatous areas, but D-CHI patients also had significantly greater Ki-67-LI (mean value = 2.41%) than age-matched controls (mean value = 1.87%) (P = 0.009). In this 1st genetic study of CHI patients in Brazil, no mutations or new polymorphisms were found in the 33-37 exons of the ABCC8 gene (SUR1) or in the entire exon of the KCNJ11 gene (Kir 6.2) in 4 of 4 patients evaluated. On the other hand, enhanced β-cell proliferation seems to be a constant feature in CHI patients, both in diffuse and focal forms.
Pediatric and Developmental Pathology 13(5):375-84. · 0.99 Impact Factor
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