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Oliveira do Hospital, Portugal

Kaupert L.,University of Sao Paulo | Lemos-Marini S.,University of Medical Sciences of Costa Rica | De Mello M.,University of Campinas | Moreira R.,University of Sao Paulo | And 6 more authors.
Clinical Genetics

The 21-hydroxylase deficiency (21OHD) is caused by CYP21A2 mutations resulting in severe or moderate enzymatic impairments. 21OHD females carrying similar genotypes present different degrees of external genitalia virilization, suggesting the influence of other genetic factors. Single nucleotide variants (SNVs) in the CYP3A7 gene and in its transcription factors, related to fetal 19-carbon steroid metabolism, could modulate the genital phenotype. To evaluate the influence of the 21OHD genotypes and the CYP3A7, PXR and CAR SNVs on the genital phenotype in 21OHD females. Prader scores were evaluated in 183 patients. The CYP3A7, PXR and CAR SNVs were screened and the 21OHD genotypes were classified according to their severity: severe and moderate groups. Patients with severe genotype showed higher degree of genital virilization (Prader median III, IQR III-IV) than those with moderate genotype (III, IQR II-III) (p<0.001). However, a great overlap was observed between genotype groups. Among all the SNVs tested, only the CAR rs2307424 variant correlated with Prader scores (r2=0.253; p=0.023). The CYP21A2 genotypes influence the severity of genital virilization in 21OHD females. We also suggest that the CAR variant, which results in a poor metabolizer phenotype, could account for a higher degree of external genitalia virilization. © 2012 John Wiley & Sons A/S. Source

Dupont J.,Servico de Genetica | Pereira C.,Unidade de Endocrinologia Pediatrica | Medeira A.,Servico de Genetica | Duarte R.,Portuguese Diabetes Association | And 2 more authors.
Journal of Pediatric Endocrinology and Metabolism

Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes diagnosed within the first 6 months of life. Heterozygous activation mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K ATP) channel, which acts as a key role in insulin secretion regulation, account for about half of the cases of PNDM. The majority of the patients represent isolated cases resulting from de novo mutations. Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay, is called developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome and the milder form, with less severe developmental delay and without epilepsy, is designated intermediate DEND syndrome. Individuals with KCNJ11 mutations have been successfully transitioned from insulin to sulfonylurea (SU) therapy. Furthermore, there have been cases reported with variable improvement in neurological function following a successful switching. We describe a 12-year-old Portuguese girl with PNDM due to the previously reported R201C mutation in the KCNJ11 gene. Her medical history includes prematurity and moderate developmental delay. The mutation was inherited from her mother who has isolated PNDM. The patient was successfully transferred from insulin to SU, whereas her mother showed SU resistance. Despite good glycemic control, no improvements in the cognitive performance were verified. We present our experience in switching treatment from insulin to oral SUs in this family, and also discuss whether or not the girl's developmental delay is related with the Kir6.2 mutation. To our knowledge, this is the first Portuguese patient reported with successful transition to SU treatment. © 2012 by Walter de Gruyter Berlin Boston. Source

Mendes C.,Unidade de Endocrinologia Pediatrica | Vaz Matos I.,Unidade de Endocrinologia Pediatrica | Ribeiro L.,Unidade de Endocrinologia Pediatrica | Oliveira M.J.,Unidade de Endocrinologia Pediatrica | And 2 more authors.
Acta Medica Portuguesa

Introduction: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is one of the most frequent inborn conditions. It is caused by distinct mutations in the CYP21A2 gene and in the majority of cases the disease’s severity correlates with CYP21A2 allelic variation Our aim was to describe the mutational spectrum of CYP21A2 and evaluate genotype-phenotype correlation in a cohort of portuguese patients with 21-hydroxylase deficiency. Material and Methods: Retrospective study of 22 patients with clinical diagnosis of 21-hydroxylase deficiency. Molecular analysis of CYP21A2 was performed and genotype-phenotype correlation was then established. Results: Genotyping was performed in 22 unrelated patients: 5 with classic salt-wasting (average age of diagnosis 10,2 days; minimum 1, maximum 20 days), 7 with classic simple virilizing (average age of diagnosis 3,5 years; minimum 0 days, maximum 7 years) and 10 with nonclassical form (average age of diagnosis 5,7 years; minimum 4 years, maximum 8 years). The most frequent geneticdefects in the classic forms were I2 splice (24%) and I172N (24%), followed by Q318X (16%) and gene deletions (16%) and in the nonclassical form, the V281L (80%). The overall concordance between genotype and phenotype was 81,8%. Genotype accurately predicted phenotype in 83,3%, 100% and 90% of patients with classic salt-wasting, classic simple virilizing and nonclassical mutations, respectively. Discussion: The frequency of genetic defects in our patients was comparable to similar studies. In most cases there was a good correlation between genotype and phenotype. Conclusions: Molecular analysis of CYP21A2 provides useful information in terms of prediction of disease severity, genetic and prenatal counseling. © Ordem dos Médicos 2015. Source

Gomes M.B.,State University of Rio de Janeiro | Negrato C.A.,Baurus Diabetics Association | Calliari L.E.P.,Pediatric Endocrine Unit | Cobas R.,State University of Rio de Janeiro | And 43 more authors.
Diabetes Research and Clinical Practice

Aims: Determine the relationship between age at menarche, glycemic control and cardiovascular risk factors in patients with type 1 diabetes living in urban areas. Methods: This was a multicenter cross-sectional study conducted in 20 cities in four Brazilian geographic regions. Data were obtained from 1527 female patients, 59.3% Caucasians, aged 25.1. ±. 10.6 years. Diabetes duration was 11.4. ±. 8.1 years. Age at menarche was stratified in four groups: 8-11 (group 1, early menarche), 12 (group 2), 13 (group 3) and 14-18 years (group 4, late menarche). Results: The mean age at menarche was 12.7. ±. 1.7 years without difference among geographical regions, economic status, level of care and ethnicity. BMI had an inverse correlation with age at menarche (r = -0.14, p<. 0.001). No significant difference was observed among the four groups for blood pressure, lipid profile and diabetes-related chronic complications. Logistic regression analysis showed that early age at menarche, 8-11 years (odds ratio (ORs) 1.77 [1.30-2.41], p<. 0.001) and duration of diabetes [ORs 1.01 (1.00-1.03), p = 0.02], were related to greater risk of patients' overweight or obesity; adherence to diet [ORs 0.78 (0.60-0.93), p = 0.01], physical activity [ORs 0.75 (0.94-0.94), p = 0.01], and lower insulin dose (U/kg) [ORs 0.54 (0.59-0.90), p = 0.001] were related to lower risk for overweight or obesity. Conclusions: Early menarche occurred in 23.4% of women with type 1 diabetes living in Brazilian urban areas and was strongly associated with overweight/obesity in pubertal/adult life. Further studies are warranted to establish the relationship between early menarche, glycemic control and cardiovascular risk factors. © 2014 Elsevier Ireland Ltd. Source

Calliari L.E.P.,Unidade de Endocrinologia Pediatrica | Rocha M.N.,Unidade de Endocrinologia Pediatrica | Monte O.,Unidade de Endocrinologia Pediatrica | Longui C.A.,Unidade de Endocrinologia Pediatrica
Arquivos Brasileiros de Endocrinologia e Metabologia

Mutation on NROB1 (DAX1) gene can cause different phenotypes of adrenal insufficiency in infancy. Long-term evolution of these patients shows that it is possible to have an association with hypogonadotropic hypogonadism. In this article we describe the evolution of a patient with NROB1 gene mutation, diagnosed with a mild form of adrenal insufficiency, and we highlight the presence of hypogonadotropic hypogonadism and short stature, besides the presence of attention deficit disorder. Such associations should make physicians aware during the follow-up of patients with this disease.© ABE&M todos os direitos reservados. Source

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