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Molecular genetics of congenital Hypothyroidism


1. Congenital hypothyroidism (CH) is a relatively frequent endocrine neonatal disease with a prevalence of 1 to 3,000 newborns. It is usually detected by neonatal screening programs through serum determinations of TSH and total T4. 2. The etiology of CO is, usually, subdivided in permanent and transitory conditions. Permanent conditions that will result in CH are: a) agenesia, ectopy and thyroid hypoplasiab) hereditary defects in thyroid hormone synthesisc) destruction of the fetal thyroid by radioiodined) central hypothyroidisme) peripheral resistance to thyroid hormoneAmong the transitory conditions it could be listed: severe iodine deficiency, iodine excess, placental transfer of PITU, MMI, blocking maternal antibodies. It is agreed that about 60% of all children with CG will have thyroid ectopy (sublingual thyroid), 10-15% - will present complete agenesis of the thyroid, about 10-2011/0dyshormonogenesís and 10% will have congenital hypoplasia. 3. The etiological basis for thyroid dysgenesis is poorly understood. There is more females affected as compared to males, a number of cases have been reported in siblings or in kindreds, and environmental factors early in embryogenesis may also play a role. Genetic mechanisms may be involved either as mutations occurring in genes that are essential for thyroid gland formation or complex multigenic disturbances would result indefective thyroid embryogenesis, affecting its subsequent descent to the cervical region. A few candidate genes (TTF-1, TTF-2, PAX-,8) have been proposed and mutations in these genes have resulted in thyroid dysgenesis. Table 1. Thyroid dysgenesis and mutations in thyroid transcription factorsClinical presentation Molecular geneticsThyroid agenesis Lung disease Deletion of TTF-1 gene Ectopic thyroid Mutation in PAX-8 geneThyroid hypoplasia Mutation in PAX-8 geneMutation in TSHR ene IThyroid hemiagenesisKidney disease Mutations inP.4X-8 GENEThyroid embryogenesis and subsequent migration to the final anterior cervical region are influenced positively by the three transcription factors genes: TTF-1, ITF-2 and P,4X-8,both in experimental animals and humans. It has been demonstrated that PAX-8 actively stimulates the promoters of the genes for transcription of thyroglobulin and thyroperoxidase... (AU)

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Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
NEVES, SOLANGE CAIRES; MEZALIRA, PAOLA ROSSI; DIAS, VERA M. A.; CHAGAS, ANTONIO J.; VIANA, MARIA; TARGOVNIK, HECTOR; KNOBEL, MEYER; MEDEIROS-NETO, GERALDO; RUBIO, ILEANA G. S.. Monoallelic thyroid peroxidase gene mutation in a patient with congenital hypothyroidism with total iodide organification defect. Arquivos Brasileiros de Endocrinologia e Metabologia, v. 54, n. 8, SI, p. 732-737, . (99/03570-3)
NASCIMENTO‚ A.C.; GUEDES‚ D.R.; SANTOS‚ C.S.; KNOBEL‚ M.; RUBIO‚ I.G.S.; MEDEIROS-NETO‚ G.. Thyroperoxidase gene mutations in congenital goitrous hypothyroidism with total and partial iodide organification defect. THYROID, v. 13, n. 12, p. 1145-1151, . (99/03570-3)
VONO-TONIOLO‚ J.; RIVOLTA‚ C.M.; TARGOVNIK‚ H.M.; MEDEIROS-NETO‚ G.; KOPP‚ P.. Naturally occurring mutations in the thyroglobulin gene. THYROID, v. 15, n. 9, p. 1021-1033, . (99/03570-3)
DENISE PERONE; SILVÂNIA S. TEIXEIRA; SUELI A. CLARA; DANIELA C. DOS SANTOS; CÉLIA R. NOGUEIRA. Aspectos genéticos do hipotireoidismo congênito. Arquivos Brasileiros de Endocrinologia e Metabologia, v. 48, n. 1, p. 62-69, . (99/03570-3)
PERONE, DENISE; MEDEIROS-NETO, GERALDO; NOGUEIRA, CELIA REGINA; CHAGAS, ANTONIO JOSE; ALVES DIAS, VERA MARIA; VIANA, MARIA FATIMA; KOPP, PETER. Analysis of the PAX8 gene in 32 children with thyroid dysgenesis and functional characterization of a promoter variant. JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM, v. 29, n. 2, p. 193-201, . (99/03570-3)

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