This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The objectives of this clinical investigation are to establish and test clinical protocols that will serve to evaluate syndromes of resistance to thyroid hormone as defined in the broadest sense. Resistance to thyroid hormone are syndromes of reduced end-organ responsiveness to thyroid hormone. Conditions under consideration encompass those physioloigcal defects that interfere with the biological activity of a chemically intact thyroid hormone supplied in normal amount. These include: 1) Abnormalities in cell membrane transport of thyroid hormone; 2) Abnormalities in the conversion of the prohormone 3,3 ,5,5 -tetraiodothyronine (thyroxine, T4) into the active thyroid hormone, 3,3 ,5-triiodothyronine (T3) and 3) Abnormalities at the level of nuclear action of T3 due to TH receptor (TR)? defects, known as the classical resistance to thyroid hormone (RTH) or similar syndromes without TR? gene mutations. The latter, termed nonTR-RTH, are associated with abnormalities in cofactors mediating the action of thyroid hormone at the nucleus. These cofactors are common to related nuclear receptors, and it is postulated that they may also produce subtle resistance to glucocorticoid action. These defects may be suspected based on thyroid function tests. However basal thyroid function tests are not sufficient to make an accurate diagnosis and require a careful analysis of the subject s phenotype as proposed in this application. Furthermore characterization of the phenotypes of these syndromes would establish criteria for genetic testing which in turn could allow for prenatal diagnosis and possibly early intervention and treatment. This would be particularly important in defects that are associated with significant neurologic sequelae (e.g. MCT8 mutations) where early intervention may reverse or prevent the associated findings.
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