Alexandra M. Dumitrescu, MD Department of Medicine, The University of Chicago, 5841 S. Maryland Ave MC3090, Chicago, Illinois 0637-1470; email@example.com
Samuel Refetoff, MD, Departments of Medicine, Pediatrics and the Committees on Genetics, The University of Chicago, 5841 S. Maryland Ave MC3090, Chicago,IL 0637-1470;firstname.lastname@example.org
Revised 20 August 2015
Defects along the pathways leading to TH action can manifest as impaired sensitivity to TH. Six steps are presumed to be required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps four distinct phenotypes have been identified in humans. The clinical, laboratory, genetic and molecular characteristics of these defects are the subject of this chapter.
The first defect, recognized almost 50 years ago, produces reduced sensitivity to TH and was given the acronym RTH, for resistance to thyroid hormone. Its major cause, found in more than 3,000 individuals, is mutations in the TH receptor ß(THRB) gene. More recently mutations in the THRA gene were found to produce a different phenotype owing to the distinct tissue distribution of this TH receptor. Two other gene mutations, affecting TH action, but acting at different sites were identified in the last 10 years. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 320 males. A defect of the intracellular metabolism of TH, identified in 11 members from 9 families, is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases.
Knowledge of the molecular mechanisms involved in mediation of TH action allows the recognition of the phenotypes caused by genetic defects in the involved pathways. While these defects have opened the avenue for novel insights into thyroid physiology, they continue to pose therapeutic challenges. For complete coverage of this and related areas in Endocrinology, visit the free online web-textbook, www.endotext.org.
Resistance to thyroid hormone (RTH), a syndrome of reduced responsiveness of target tissues to thyroid hormone (TH) was identified in 1967 (1). An early report proposed various mechanisms including defects in TH transport, metabolism and action (2). However, with the identification of TH receptor beta (THRB) gene mutations 22 years later (3,4), the term RTH become synonymous with defects of this gene (5). Subsequent discoveries of genetic defects that reduce the effectiveness of TH through altered cell membrane transport (6,7) and metabolism (8) have broadened the definition of TH hyposensitivity to encompass all defects that could interfere with the biological activity of a chemically intact hormone secreted in normal or even excess amounts. In this revised chapter, we cover all syndromes resulting from impaired sensitivity to TH, using the recently proposed nomenclature (9) (see Table 1).
Table 1.Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
LEVEL OF THE DEFECT
Commonly used name (References Are for first Reported Cases)
Gene Involved & Inheritance (OMIM)
THYROID HORMONE CELL MEMBRANE TRANSPORT DEFECTS (THCMTD)
Abbreviations: FT3, free T3; FT4, free T4; BMI, body mass index; nonTR-RTH, RTH without mutations in the THRB or THRA genes.
a Proposed future terminology: RTH beta.
b RTH without mutations in the THRB gene.
c A single case with a mutation involving both TR alpha1 and TR allpha2 presented a more complex phenotype, including severe bone malformations, hyper-calcaemia with hyperparathyroidism, and diarrhea rather than constipation. It is unclear if all observed abnormalities are due to the THRA gene mutation alone
(Reproduced from Refetoff S.et al., Thyroid 24:407, 2015, with permission).