At least six major steps are required for secreted thyroid hormone to exert its action on target tissues: thyroid hormone transport into cells, intracellular activation of the prohormone thyroxine, transfer of the hormone from the cytoplasm to the nucleus, intact thyroid hormone receptors and intact nuclear and cytosolic machinery required for the mediation of thyroid hormone action. Mutations interfering with three of these steps have been so far identified and are the subject of this presentation. The first recognized defect, causing resistance to thyroid hormone (RTH), involves the thyroid hormone receptor β (TRβ) gene and carries the acronym, RTH. Occurring in ~1 of 40 000 newborn, affected subjects belonging to more than 400 families surpass 1500. The gene defect remains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced sensitivity to thyroid hormone were identified in the last 5 years. One, producing severe psychomotor defects in more than 150 males from 57 families, is caused by mutations in the monocarboxylate transporter 8 (MCT8 or SLC16A2), a thyroid hormone cell-membrane transporter of particular importance in early brain development. The second defect, affecting the intracellular metabolism of thyroid hormone is caused by mutations in the selenocysteine insertion sequence binding protein 2 (SECISBP2 or SBP2) gene required for the synthesis of selenoproteins, including the three iodothyronine deiodinases. Eight such individuals, belonging to unrelated families, have been identified. They manifest, in addition to thyroid test abnormalities, defects of variable magnitude in the reproductive, muscular and immune systems. Most challenging is the approach to therapy, when simple hormonal substitution is ineffective.
Partly supported by the Clinical Endocrinology Trust.