Classification and Proposed Nomenclature for Inherited Defects of Thyroid Hormone Action, Cell Transport, and Metabolism

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 3 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 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 3,000 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, 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 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

Commonly used name (references are for first reported cases)	Synonyms	Gene involved and inheritance (OMIM)	Phenotype
			consistent (pathognomonic)	common
Level of the defect 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)a [1,2,3]	thyroid hormone unresponsiveness, generalized RTH, RTH beta; Refetoff syndrome	THRB gene (190160) dominant negative (rarely recessive)	high serum FT4 and non-suppressed TSH	high serum FT3 and rT3, high thyroglobulin, goiter, attention deficit hyperactivity disorder (ADHD), tachycardia
Non TR-RTHb [13]		unknown	same as above	same as above
RTH alphac [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
Idiopathic and other THADs		to be determined	unknown

FT₃ = Free T₃; FT₄ = free T₄; BMI = body mass index.

^aProposed future terminology: RTH beta.

^bRTH without mutations in the THRB gene.

^cA 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.

Disclosure Summary

The authors have nothing to declare.