Genética molecular do hipotireoidismo congênito
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Data
2001-02-01
Autores
Knobel, Meyer
Nogueira, Célia Regina [UNESP]
Medeiros-Neto, Geraldo
Título da Revista
ISSN da Revista
Título de Volume
Editor
Sociedade Brasileira de Endocrinologia e Metabologia
Resumo
O hipotireoidismo congênito (HC) ocorre, mundialmente, em 1/3000-4000 neonatos e pode ser classificado em permanente ou transitório. O HC primário é responsável pela maioria dos afetados, enquanto o secundário e terciário são raros. Nos países iodo-suficientes, a disgenesia tireóidea (DT) é a causa mais freqüente de HC. Os defeitos hereditários da síntese hormonal ocorrem em minoria de crianças portadoras de HC. Fatores ambientais, genéticos e auto-imunes concorrem na etiologia do HC, mas na maioria dos casos de DT a causa é obscura. Atribui-se aos genes envolvidos na ontogenia da glândula tireóidea, como os fatores de transcrição TITF1, TITF2, PAX-8 e receptor de TSH (TSHR), função patogenética na DT. Até o momento não foi descrita anormalidade no gene TITF1 como causa de HC, enquanto foram identificadas mutações no PAX-8 em cinco recém-nascidos com DT. Embora não envolvidas na DT, mutações inativadoras do TSHR podem produzir espectro de defeitos congênitos oscilando entre hipertirotropinemia com eutireoidismo e hipotireoidismo com hipoplasia glandular. A clonagem dos genes envolvidos na biossíntese dos hormônios tireóideos, como o da tireoperoxidase (TPO) e tireoglobulina (Tg), permitiu a identificação de mutações responsáveis por alguns casos de bócio e hipotireoidismo decorrente de defeito de incorporação de iodeto ou anormalidades na síntese de Tg. Recentemente, foi demonstrada a base molecular do defeito de transporte ativo de iodeto e da síndrome de Pendred, respectivamente, devidas a mutações no gene NIS (simportador de sódio e iodeto) e no gene PDS (pendrina). em conclusão, grande parte dos pacientes com HC e DT não tem esclarecida, ainda, a causa molecular desta síndrome.
Congenital hypothyroidism (CH) occurs in 1/3000-4000 neonates worldwide and may be classified as permanent or transient. Primary CH accounts for the majority of affected children, while secondary and tertiary CH are rare. In iodine-sufficient countries, thyroid dysgenesis (TD) is the most frequent cause of CH. Hereditary inborn errors of thyroid hormonogenesis account for about 10-20% CH children. Environmental, genetic and autoimmune factors have been implicated in the etiology of CH, but in the majority of cases the cause of TD remains to be clarified. Candidates for playing a pathogenetic role in TD are genes involved in thyroid gland ontogeny, such as those of thyroid transcription factors TITF1, TITF2, PAX-8 and the TSH-receptor (TSHR). No abnormality in the TITF1 gene has yet been found in CH, while mutations in the PAX-8 gene were identified in at least 5 neonates with TD. Loss of function mutations of the TSHR gene, although not involved in TD, may produce a spectrum of congenital defects ranging from euthyroid hyperthyrotropinemia to overt hypothyroidism with a hypoplastic gland. The cloning of genes implicated in the biosynthesis of thyroid hormones, such as those of thyroperoxidase (TPO) and thyroglobulin (Tg), has led to the identification of mutations responsible for some cases of goitrous hypothyroidism due to iodide organification defect or abnormalities in Tg synthesis. Recently, the molecular basis of the iodide transport defect and Pendred s syndrome were reported, due to mutations, respectively, on the NIS and PDS genes. In conclusion, we still do not have elucidated the molecular basis of TD, the most common of the defects affecting neonates with CH.
Congenital hypothyroidism (CH) occurs in 1/3000-4000 neonates worldwide and may be classified as permanent or transient. Primary CH accounts for the majority of affected children, while secondary and tertiary CH are rare. In iodine-sufficient countries, thyroid dysgenesis (TD) is the most frequent cause of CH. Hereditary inborn errors of thyroid hormonogenesis account for about 10-20% CH children. Environmental, genetic and autoimmune factors have been implicated in the etiology of CH, but in the majority of cases the cause of TD remains to be clarified. Candidates for playing a pathogenetic role in TD are genes involved in thyroid gland ontogeny, such as those of thyroid transcription factors TITF1, TITF2, PAX-8 and the TSH-receptor (TSHR). No abnormality in the TITF1 gene has yet been found in CH, while mutations in the PAX-8 gene were identified in at least 5 neonates with TD. Loss of function mutations of the TSHR gene, although not involved in TD, may produce a spectrum of congenital defects ranging from euthyroid hyperthyrotropinemia to overt hypothyroidism with a hypoplastic gland. The cloning of genes implicated in the biosynthesis of thyroid hormones, such as those of thyroperoxidase (TPO) and thyroglobulin (Tg), has led to the identification of mutations responsible for some cases of goitrous hypothyroidism due to iodide organification defect or abnormalities in Tg synthesis. Recently, the molecular basis of the iodide transport defect and Pendred s syndrome were reported, due to mutations, respectively, on the NIS and PDS genes. In conclusion, we still do not have elucidated the molecular basis of TD, the most common of the defects affecting neonates with CH.
Descrição
Palavras-chave
Tireóide, Hipotireoidismo congênito, Disgenesia tireóidea, Receptor de TSH, Biologia molecular, Thyroid, Congenital hypothyroidism, Thyroid dysgenesis, TSH receptor, Molecular biology
Como citar
Arquivos Brasileiros de Endocrinologia & Metabologia. Sociedade Brasileira de Endocrinologia e Metabologia, v. 45, n. 1, p. 24-31, 2001.