Resistance to thyroid hormone α (RTHα) (OMIM 614450)
The key role of TRα in the human skeleton has been exemplified by discovery of a new syndrome of resistance to thyroid hormone due to dominant-negative mutations in
THRA (RTHα) [
65]. The skeletal manifestations of this condition (OMIM 614450) are consistent with the characteristic consequences of congenital and juvenile hypothyroidism, and reflect impaired T3 action in cartilage and bone. To date, 15
THRA mutations in 11 separate codons affecting 29 individuals from 16 families have been described. Nine result in the expression of a mutant TRα1 protein alone, and six affect both TRα1 and TRα2 [
66‐
76]. Affected individuals have normal serum TSH with low/normal T4, high/normal T3 concentrations and characteristically elevated fT3:fT4 and T3:rT3 ratios [
77,
78].
Children with RTHα due to expression of mutant TRα1 alone have skeletal dysplasia manifest by variable features that include delayed bone age and tooth eruption, patent skull sutures with wormian bones and delayed closure of the fontanelles, macrocephaly, flattened nasal bridge, hypertelorism, disproportionate (sub-ischial) short stature mainly affecting the lower limbs, epiphyseal dysgenesis, acetabular hypoplasia, congenital hip dislocation, vertebral ossification defects and defective bone mineralization [
66,
67,
71,
73]. Adults have been studied less comprehensively, but variable skeletal abnormalities include increased cortical bone mass, disproportionate short stature, macrocephaly with skull vault thickening and hearing loss due to otosclerosis [
67,
70,
73,
74]. As the number of reported cases has increased, a phenotype–genotype correlation has emerged. Missense mutations that impair T3 binding and result in only mild or moderate dominant-negative activity of mutant TRα1 are associated with fewer and less severe abnormalities. By contrast, nonsense mutations resulting in the expression of a truncated TRα1 protein with absent T3 binding and potent dominant-negative activity result in marked skeletal dysplasia and developmental delay. Accordingly, T4 treatment of children harbouring severe mutations has had little effect on growth and skeletal development, whereas treatment of individuals with milder missense mutations has been more promising [
66,
67,
70,
71,
73,
74,
76].
More recently,
THRA mutations affecting both TRα1 and TRα2 have been described [
67,
69,
72,
76]. Affected children and adults had a similar spectrum of abnormalities characteristic of the skeletal dysplasia and variable response to T4 treatment reported in individuals with mutations affecting TRα1 alone. In vitro analysis of the functional defects of mutant TRα1 proteins was also consistent with the phenotype–genotype correlation described above, while all studies showed that wild-type and mutant TRα2 proteins were transcriptionally inactive and had no dominant-negative activity [
67,
69,
72,
76]. Nevertheless, a severe and atypical phenotype was described in a 27-year-old woman with an N359Y substitution affecting both TRα1 and TRα2 [
68]. Her unique combination of skeletal abnormalities includes intrauterine growth retardation and failure to thrive, macrocephaly, hypertelorism, micrognathia, short and broad nose, agenesis of the clavicles and 12th ribs, elongated thorax, ovoid vertebrae, scoliosis, congenital hip dislocation, short limbs and dwarfism, unilateral humero-radial synostosis, elbow dislocation and syndactyly. The TRα1
N359Y mutant protein had impaired T3 binding and transactivation function with moderate dominant-negative activity, while no clear functional abnormality of the TRα2
N359Y mutant was identified [
68,
79].
Together, these reports define a new genetic disorder, RTHα, characterized by profound and consistent developmental abnormalities of the skeleton that recapitulate findings in mice with dominant-negative
Thra mutations [
80‐
85]. Overall, similar phenotypes in patients with mutations affecting either TRα1 alone, or both TRα1 and TRα2, suggest TRα2 has little or no physiological role in the skeleton. However, the unique phenotype in the patient with the N359Y substitution affecting both TRα1 and TRα2, in whom no other de novo mutations could be identified by whole exome sequencing [
68], raises the intriguing possibility that TRα2 may fulfil an unrecognized function during skeletal development.
Resistance to thyroid hormone β (RTHβ) (OMIM 188570)
RTHβ results from dominant-negative mutations of
THRB that cause disruption of the HPT axis leading to a characteristic increase in TSH along with inappropriately normal or increased circulating T4 and T3 levels [
86‐
88]. The clinical syndrome is complex with a mixed phenotype comprising hyperthyroid-like responses in some tissues and hypothyroid effects in others. These variable tissue responses depend on several factors including genetic background, the severity of the
THRB mutation, the relative amounts of expressed mutant and wild-type TRβ proteins and tissue-specific differences in the ratio of TRα and TRβ protein expression. In addition to these confounding issues, patients may have received varying prior management including treatment with anti-thyroid drugs, thyroid hormone analogues or surgery. In this context, it is not surprising that descriptions of skeletal abnormalities in RTHβ are variable and largely restricted to case reports or case series. Long-term prospective studies in large families will be necessary to advance understanding [
1]. Nevertheless, analysis of the skeletal consequences of mutations of
Thrb in mouse models of RTHβ is consistent with a skeletal phenotype of accelerated bone development in juveniles and increased bone turnover with osteoporosis in adults that is due to increased T3 action in cartilage and bone [
1,
83,
89‐
91].