Vera Maria Alves Dias

Thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus: prevalence and risk factors.

UNLABELLED Studies show great variation in prevalence of anti-thyroid antibodies in children with type 1 diabetes mellitus (DM1). There still is no consensus regarding screening of autoimmune thyroiditis in patients with DM1, especially in asymptomatic patients. AIM To investigate the natural history and prevalence of autoimmune thyroiditis in pediatric patients with DM1 and relate it to potential risk factors. PATIENTS AND METHODS This study is a historical cohort, through research of the records of 474 patients with DM1 from 9 months to 25 years of age, between 1980 and 2005 - 222 boys (46.8%) and 252 girls (53.2%), with an average duration of DM1 of 9.3 +/- 5.8 years. The sample was selected by having at least one measurement of TSH and anti-thyroid autoantibodies (antithyroperoxidase or anti-microssomal and/or anti-thyroglobulin) at any time from diagnosis of DM1. A questionnaire was answered in order to study the variables of interest for the study. Thyroid function disorder was defined as altered levels of TSH, with or without altered free T4 levels. RESULTS A total of 383 patients (9 months to 25 years of age) were studied, 199 girls (52%) and 184 boys (48%). Sixty-four (16.7%) had positive anti-thyroid antibodies, predominantly girls (p = 0.064). Average duration of DM1 was 9.3 +/- 5.8 years and those above this age had a higher incidence of thyroiditis (p = 0.01). The prevalence of thyroid function disorder in patients with DM1 was 7.3% (n = 28), mostly with thyroiditis (32.8% vs 2.2% with negative antibodies, p < 0.001). There was a positive association between thyroiditis, as well as thyroid function disorders, and other autoimmune disorders (p < 0.001 and p < 0.02, respectively). CONCLUSIONS Prevalence of thyroiditis in the diabetic population is considerably higher than in the general population. Annual laboratory determinations of anti-TPO antibodies and dosage of TSH should be part of routine tests in the diabetic population, especially in girls, children with DM1 for > 9 years, patients above 12 years of age, and those in whom DM1 is associated with another autoimmune disease. Anti-thyroid antibody positivity may indicate the necessity for thyroid function testing at shorter intervals.

Hipotiroidismo congênito transitório: perfil das crianças identificadas no programa estadual de triagem neonatal de Minas Gerais, Brasil

Early diagnosis and treatment of congenital hypothyroidism are the main goals of the neonatal screening programs. A retrospective analysis was carried out to assess the characteristics and etiologies of congenital transient hypothyroidism (CTH) in the Newborn Screening Program of the State of Minas Gerais, Brazil. To reach a diagnosis of CTH, altered screening and serum confirmatory T4 and TSH tests and normal serum free T4 and TSH at 4 and 8 weeks after the withdrawal of levothyroxine were used. We studied 21 children with CTH who represented 4.23% of the whole group with detected hypothyroidism and followed them up in the Screening Program. These patients received LT4 therapy for a variable period of one month to three years. Serum confirmatory TSH levels varied from 10.4 to 583.4 microUI/mL. Maternal antibodies, TRAB and anti-TPO, were associated to CTH in two children and iodine overload in one of them. We concluded that CTH is an important component in neonatal screening and hormonal treatment during the first months of the life is essential. The TSH initial levels are not relevant to determine whether the thyroid dysfunction is transient or permanent.

Avaliação etiológica da hipertirotropinemia em crianças com síndrome de Down

OBJETIVO: Analisar a prevalencia de hipertirotropinemia e estudar sua possivel etiologia em criancas com sindrome de Down atendidas na Policlinica Municipal Antonio Cândido, em Belo Horizonte. METODOS: Foram utilizados os dados dos prontuarios de todas as criancas com sindrome de Down atendidas na policlinica para o calculo da prevalencia da alteracao do hormonio estimulante da tireoide (TSH). As criancas que tiveram TSH elevado (maior que 5 µUI/ml) em pelo menos um exame foram convocadas para novas dosagens de TSH, T4livre, T4total e auto-anticorpo antiperoxidase (ATPO), realizacao de ultra-som da tireoide, tireograma com iodo-131 e teste de descarga do perclorato. As alteracoes encontradas nos exames das criancas que permaneceram com TSH elevado foram comparadas com as das que normalizaram os valores de TSH. RESULTADOS: Foram encontradas, em 169 criancas com sindrome de Down, 86 (50,8%) masculinas, idade entre 1-6 anos (mediana de 4 anos), 67 (39,6%) com TSH aumentado, as quais foram convocadas para novas avaliacoes, comparecendo 46. Nesses pacientes, o TSH se normalizou em 31 (67,4%); em 11 (23,9%) permaneceu entre 5-10µUI/ml; em tres (6,5%) ficou acima de 10 µUI/mL; e em uma (2,2%) constatou-se hipertireoidismo. Os diagnosticos realizados nos pacientes com propedeutica completa (n = 34) foram: bocio (14,7%), hipoplasia (8,8%), tireoidite de Hashimoto (5,9%), defeito na organogenese de iodo (2,9%). Nao se evidenciou relacao entre as amplitudes dos valores de TSH e a persistencia da hipertirotropinemia. Criancas com ATPO positivo estavam associadas a TSH elevado (p = 0,02). CONCLUSOES: Na sindrome de Down, sao frequentes valores de TSH discretamente elevados e instaveis, sendo suas etiologias variaveis. A presenca de ATPO mostrou-se importante no seguimento dessas criancas pelo risco potencial de evolucao para doenca tireoidiana manifesta.

Hipotireoidismo congênito: perfil clínico dos recém-nascidos identificados pelo Programa de Triagem Neonatal de Minas Gerais

OBJECTIVE: To evaluate the clinical profile of newborns with congenital hypothyroidism identified by the Newborn Screening Program of the State of Minas Gerais, Brazil, between 2000 and 2006. METHODS: Analysis of factors involved in this profile, including: TSH and FT4 levels (determined by chemiluminescence, with limits of normality set at 0.3-5.0 µUI/mL and 0.8-1.8 ng/dL, respectively), age at diagnosis and age at treatment. The study sample consisted of 443 children, 55.8% were female and 95% were seen before completing 60 days of life. RESULTS: The most prevalent clinical signals were: umbilical hernia (51%), enlarged anterior fontanel (50.3%), and open posterior fontanel (47.2%). Hypotonia, macroglossia and feeding difficulties were the clinical signs most frequently associated with the biochemical severity of the disease. A delay in bone age was present in 32.1% of the children at diagnosis. The median of serum TSH and FT4 was 120 µUI/mL and 0.62 ng/dL, respectively. The median age at start of treatment was 28 days. CONCLUSION: There are some early clinical signs that suggest a diagnosis of congenital hypothyroidism. Therefore, when presented with a child exhibiting these signs, serum TSH and FT4 should be assayed in order to confirm or rule out the disease, irrespective of the result of screening. Age at start of treatment remains high, but strategies are being implemented to reduce it.

Congenital hypothyroidism: the clinical profile of affected newborns identified by the Newborn Screening Program of the State of Minas Gerais, Brazil

OBJECTIVE To evaluate the clinical profile of newborns with congenital hypothyroidism identified by the Newborn Screening Program of the State of Minas Gerais, Brazil, between 2000 and 2006. METHODS Analysis of factors involved in this profile, including: TSH and FT4 levels (determined by chemiluminescence, with limits of normality set at 0.3-5.0 microUI/mL and 0.8-1.8 ng/dL, respectively), age at diagnosis and age at treatment. The study sample consisted of 443 children, 55.8% were female and 95% were seen before completing 60 days of life. RESULTS The most prevalent clinical signals were: umbilical hernia (51%), enlarged anterior fontanel (50.3%), and open posterior fontanel (47.2%). Hypotonia, macroglossia and feeding difficulties were the clinical signs most frequently associated with the biochemical severity of the disease. A delay in bone age was present in 32.1% of the children at diagnosis. The median of serum TSH and FT4 was 120 microUI/mL and 0.62 ng/dL, respectively. The median age at start of treatment was 28 days. CONCLUSION There are some early clinical signs that suggest a diagnosis of congenital hypothyroidism. Therefore, when presented with a child exhibiting these signs, serum TSH and FT4 should be assayed in order to confirm or rule out the disease, irrespective of the result of screening. Age at start of treatment remains high, but strategies are being implemented to reduce it.

Monoallelic thyroid peroxidase gene mutation in a patient with congenital hypothyroidism with total iodide organification defect

The aim of this study was to identify the genetic defect of a patient with dyshormonogenetic congenital hypothyroidisms (CH) with total iodide organification defect (TIOD). A male child diagnosed with CH during neonatal screening. Laboratory tests confirmed the permanent and severe CH with TIOD (99% perchlorate release). The coding sequence of TPO, DUOX2, and DUOXA2 genes and 2957 base pairs (bp) of the TPO promoter were sequenced. Molecular analysis of patients DNA identified the heterozygous duplication GGCC (c.1186_1187insGGCC) in exon 8 of the TPO gene. No additional mutation was detected either in the TPO gene, TPO promoter, DUOX2 or DUOXA2 genes. We have described a patient with a clear TIOD causing severe goitrous CH due to a monoallelic TPO mutation. A plausible explanation for the association between an autosomal recessive disorder with a single TPO-mutated allele is the presence of monoallelic TPO expression.

Identification of a novel mutation in DAX1/NR0B1A gene in two siblings with severe clinical presentation of adrenal hypoplasia congenita

OBJECTIVE To search for mutations in DAX1/NR0B1A gene in siblings to establish the molecular etiology of the adrenal hypoplasia congenita (AHC), a rare potentially life-threatening disorder. CASE REPORT We describe two siblings who presented with salt-wasting syndrome in the newborn period and received hormonal replacement for primary adrenal insufficiency. A diagnostic hypothesis of AHC was suspected because the children maintained, during hormonal treatment, low plasma 17-OH progesterone (17-OHP) and androgens, despite high ACTH levels. RESULTS DAX1 gene was studied by molecular analysis, which showed a mutation, confirming the diagnosis in the siblings and a heterozygous state in the mother. Direct sequencing of DAX1 revealed an insertion of an adenine base (c1382-1383 A ins), which lead to a pMet461Asp substitution. CONCLUSION A novel frameshift mutation of DAX1 gene, which established the molecular etiology of the AHC in the siblings, was identified. Obtaining a precise genetic diagnosis of this adrenal disorder, which, sometimes, cannot be confirmed only by clinical aspects, may have important implications for the long-term management of the disease.

Analysis of the PAX8 gene in 32 children with thyroid dysgenesis and functional characterization of a promoter variant.

Abstract Background: The molecular basis underlying the development of thyroid dysgenesis remains largely unknown. The objective of this study was to analyze the PAX8 gene in 32 children with congenital hypothyroidism due to thyroid dysgenesis for mutations, and to characterize the functional consequences of the mutations. Methods: The 5′-untranslated region and the entire coding region of the PAX8 gene were analyzed in 32 children. Functional analyses with a reporter gene assay were performed in transfected PCCL3 and TSA cells. Results: Thirty children did not have any sequence alterations. Two individuals had a previously identified monoallelic cytosine to thymine transition at position -983 in the promoter (-983C>T; mutant P. A of the ATG of the initiator codon is designated as +1), and a novel guanine to cytosine transversion in the non-coding exon 1 (-465G>C; mutant E). Functional analysis revealed that the basal transcriptional activity of the mutants is decreased compared to the wild type. Gel mobility shift assays indicated that mutant P does not interact with a transacting factor whose nature remains to be elucidated. The DNA binding property of mutant E were similar compared to the wild type. Conclusions: These results suggest that mutations in PAX8 are most likely a very rare cause of thyroid dysgenesis. The observed sequence alterations result in diminished transcriptional activity and, in conjunction with other genetic and non-genetic modifiers, they may contribute to the pathogenesis of thyroid hypoplasia and hypothyroidism.