Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2,3), only three years after the cloning of the THR genes (4,5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed thyrotropin (TSH), often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist.
During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom, in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced cellular access of the biologically active thyroid hormone, triiodothyronine (T3), were identified. These are caused by defects of thyroid hormone cell membrane transport (8,9) and a defect reducing the intracellular metabolism generating T3 from thyroxine (T4) (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.”
Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11,12), we propose using the term “RTH α,” and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20,000 references, only a few related to resistance to thyroid hormone.
Table 1.
Inheritable Forms of Impaired Sensitivity to Thyroid Hormone
| Level of the defect | Phenotype | |||
|---|---|---|---|---|
| Commonly used namea | Synonyms | Gene involved and inheritance (OMIM) | Consistent (pathognomonic) | Common |
| Thyroid hormone cell membrane transport defects (THCMTD) | ||||
| Monocarboxylate transporter 8 (MCT8) defect (8,9) | Allan-Herndon-Dudley syndrome | MCT8 (SLC16A2) gene (300095); X-chromosome linked | High T3, low rT3 and T4, normal or slightly elevated TSH; low BMI; hypotonia, spastic quadriplegia; not walking or rarely ataxic gait; no speech or dysarthria, mental retardation | Hypermetabolism, paroxysmal dyskinesia, reduced muscle mass, seizures, poor head control, difficulty sitting independently |
| Idiopathic and other THCMTDs | To be determined | Unknown | ||
| Thyroid hormone metabolism defects (THMD) | ||||
| Selenocysteine insertion sequence binding protein 2 (SBP2) defect (10) | SBP2 (SECISBP2) gene (607693); recessive | High T4 and rT3, low T3, normal or slightly elevated TSH; growth retardation | Azoospermia, immunodeficiency, photosensitivity, delayed bone maturation, myopathy, hearing impairment, delayed developmental milestones | |
| Idiopathic and other THMDs | To be determined | Unknown | ||
| Thyroid hormone action defects (THAD): nuclear receptor and other | ||||
| Resistance to thyroid hormone (RTH)b (1–3) | Thyroid hormone unresponsiveness, generalized RTH, RTH beta; Refetoff syndrome | THRB gene (190160); dominant negative (rarely recessive) | High serum FT4 and nonsuppressed TSH | High serum FT3 and rT3, high thyroglobulin, goiter, attention deficit hyperactivity disorder (ADHD), tachycardia |
| Non TR-RTHc (13) | Unknown | Same as above | Same as above | |
| RTH alphad (11,12) | Congenital nongoitrous hypothyroidism 6 | THRA gene (190120); dominant negative | Low serum T4/T3 ratio; cognitive impairment, short lower limbs, delayed closure of skull sutures, delayed bone and dental development, skeletal dysplasia, macrocephaly; constipation; anemia | Low rT3, seizures, placid behavior |
| Hypersensitivity to thyroid hormone (HTH) | Unknown | Low FT4 and FT3 with normal TSH and no serum transport defects | Normal thyroid gland | |
| Idopathic and other THADs | To be determined | Unknown | ||
References are for first reported cases.
Proposed future terminology: RTH β.
RTH without mutations in the THRB gene.
A single case with a mutation involving both TRα1 and TRα2 presented a more complex phenotype, including severe bone malformations, hypercalcemia with hyperparathyroidism, and diarrhea rather than constipation. It is unclear whether all observed abnormalities are due to the THRA gene mutation alone.
T3, triiodothyronine; rT3, reverse T3; T4, thyroxine; TSH, thyrotropin; FT3, free T3; FT4, free T4; BMI, body mass index; TR, thyroid hormone receptor.
Acknowledgments
This work was supported in part by Grants R37DK15070 and UL1TR000430 from the National Institutes of Health.
Author Disclosure Statement
The authors have nothing to declare.
References
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