ABSTRACT
Estudamos 32 crianças com HC devido à agenesia ou ectopia tireoideana para mutações no PAX8 e 30 crianças com hipoplasia da tireóide para mutações no rTSH. Todos os exons de ambos os genes foram amplificados a partir do DNA genômico, seguido por seqüenciamento direto. Encontramos, em dois pacientes com ectopia, duas alterações no gene PAX8, uma no promotor, e outra no exon um. Os outros indivíduos estudados apresentaram as seqüências codificáveis dos genes PAX8 e rTSH normais. Em relação ao caráter funcional e ensaios de luciferase verificamos que no promotor a resposta transcricional diminuiu significativamente na presença de TSH, por um mecanismo dependente de cAMP / We studied 32 children with hypothyrodism (CH) from thyroid agenesis or ectopia for PAX8 mutations, and 30 children with thyroid hypoplasia for rTSH mutations. All exons of both genes were amplified from the genomic DNA, then sequenced directly. We found two alterations in the PAX8 gene in two patients, one in the promoter and the other in exon one. The other children had normal sequences in both PAX8 and rTSH genes. In relation to functional character and luciferase assays, we verified that transcriptional response was significantly reduced in the presence of TSH by a cAMP dependant mechanism...
Subject(s)
Humans , Male , Female , Child , Exons/genetics , Hypothyroidism/congenital , Intellectual Disability , Receptors, Thyrotropin/analysisABSTRACT
BACKGROUND: It has been widely accepted that the epitope(s) and/or functional characteristics of thyrotropin receptor antibodies (TSHRAb) from Graves' patients are heterogenous among patients. However, the clinical significance of such heterogeneity has not been systematically evaluated yet. We were to elucidate and find the clinical significance of heterogeneity for TSH receptor antibodies in Graves' disease. METHODS: We measured stimulating TSHRAb (TSAb) activities using CHO-hTSHR cells, FRTL-5 cells and chimeric receptor expressing cells (Mc1 + 2 and Mc2), specific blocking TSHRAb (TSBAb) activities using Mc2 cells and TBII activities using porcine thyroid membrane in 136 patients with untreated hyperthyroid Graves' disease. RESULTS: Based on various TSHRAb activities from each patient, the patients could be categorized into 7 subgroups by cluster analysis; 1) Group 1 (n = 41) was characterized by moderate TSAb activities both in CHO-hTSHR cells and in FRTL-5 cells, typical TSAb epitope, rare blocking antibodies and high TBII activities. 2) Group 2 (n = 16) was characterized by the presence of blocking TSHRAb in most patients, albeit the other characteristics were the same as those in Group 1. 3) Group 3 (n = 19) patients had low TSAb activities both in CHO-hTSHR cells and in FRTL-5 cells, seldom had blocking TSHRAb, but they had high TBII activities. 4) Group 4 (n = 30) could be categorized as 'mild disease' group, as they had low activities in all kinds of TSHRAb assay and had low antimicrosomal antibody activities. 5) Group 5 (n = 14) was characterized by moderate TSAb activities with atypical epitope(s), rare blocking TSHRAb and moderate TBII activities. 6) Group 6 (n = 10) patients had very high TSAb activities with typical epitopes, seldom blocking TSHRAb and low TBII activities. 7) Group 7 (n = 6) was characterized by very high TSAb activities with atypical epitopes and high TBII activities. Pretreatment serum thyroid hormone level was low only in group 4 patients compared to the other 6 groups (p < 0.05). The size of goiter was significantly larger in those in group 1 and group 3 (p < 0.05) compared to the other 5 groups. The prevalence of clinically significant ophthalmopathy was higher in group 2 patients than the other 6 groups (50% vs. 27.5%, p = 0.06). Among 6 kinds of TSHRAb activities, only the blocking TSHRAb activity was significantly associated with the presence of ophthalmopathy in multivariate analysis. CONCLUSION: These results suggest that the differences in epitopes for TSAb or the presence of blocking TSHRAb is not a major factor in determining the degree of thyrotoxicosis in Graves' disease. Although the pathogenic mechanism is not clear yet, we suggest that patients with ophthalmopathy have different TSHRAb repertoire from those without ophthalmopathy in Graves' disease.
Subject(s)
Adolescent , Adult , Aged , Female , Humans , Male , Cluster Analysis , Comparative Study , Graves Disease/classification , Immunoglobulins, Thyroid-Stimulating/analysis , Logistic Models , Middle Aged , Multivariate Analysis , Receptors, Thyrotropin/analysis , Sensitivity and Specificity , Severity of Illness IndexABSTRACT
Objetivo: Reportar la incidencia de hipotiroidismo congénito(HC) en un programa de tamizaje neonatal.Reportar valores de referencia de tirotropina y tiroxina en neonatos guatemaltecos urbanos. Diseño:Estudio prospectivo, longitudinal.Programa de tamizaje neonatal. Análisis retrospectivo.Contexto:Unidad de Neonatología,Departamento de Pediatría del Hospital General San Juan Dios de Guatemala. Metodología: A todo recién nacido a su egreso del hospital, se le tomó una muestra de 6 gotas de sangre venosa del dorso de la mano, depositada en papel filtro. Análisis de TSH Y T4 por RIA. Los casos con TSH>40 UI/ml, T4 menor de 4.5 Hg/dl se consideraron sospechosos, se corroboró el dato ena nueva muestra del papel filtro. Si se repitió un nivel anormal, se citó al caso y se confirmó o descartó el hipotiroidismo congénito midiendo TSH y T4 en nueva muestra de suero.Edad gestacional, peso al nacer y sexo del caso estudiado fueron anotados en el mismo papel filtro.Resultados: Se evaluaron 28067 muestras de 80734 recién nacidos. Se detectó 16 casos nuevos de HC por el programa y 14 por la clínica de endocrinología.La incidencia promedio de HC fue de 1:1754. Consideramos que no hubo diferencias en los valores de TSH al agrupar por peso al nacer, si en los valores de T4.La edad gestacional si influyó en los valores de TSH.Conclusión: El hipotiroidismo congénito fue una entidad frecuente en neonatos de nuestro Hospital. La incidencia es alta (3 veces) comparada con la de los países desarrollados. Debe continuarse el tamizaje y mejorar las tasas de cobertura.
Subject(s)
Humans , Infant, Newborn , Guatemala , Hypothyroidism , Hypothyroidism/congenital , Neonatal Screening , Receptors, Thyrotropin/analysis , Thyroxine/analysis , Thyroxine/bloodABSTRACT
Thyroid stimulating hormone receptor antibody (TRA) was estimated as a measure of TSH binding inhibitory immunoglobulin (TBII) in 48 persons. These included (i) 14 controls; (ii) 23 patients with Graves' disease who were tested for TRA within 3 months of commencing treatment with carbimazole of which 13 were studied serially; (iii) 5 patients with toxic nodular goitre; (iv) 4 with euthyroid exophthalmos; and (v) 2 neonates of thyrotoxic mothers. TRA was measured with an RIA system, while total thyroxine (T4), free thyroxine concentration (FTC) and TSH were also estimated along with TRA. All controls showed undetectable TRA levels; 87 per cent of patients with Graves' disease were TRA positive within 3 months of starting carbimazole therapy. In the serial study, 5 patients with Graves' disease who had undetectable TRA initially remained so while on treatment. Seven out of the remaining 8 patients showed a decline of TRA levels to normal over 3 to 18 months. This decline coincided with clinical and biochemical recovery.