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 | ||
a
References are for first reported cases.
b
Proposed future terminology: RTH β.
c
RTH without mutations in the THRB gene.
d
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.