TRβ and TRα proteins are highly homologous, with 80% aminoacid identity within their hormone- binding domains favouring the existence of individuals with resistance to thyroid hormone due to defective TRα (RTHα). Indeed, transgenic mice harbouring mutant TRα are viable and exhibit recognizable phenotypes but associated with normal TH levels, likely accounting for delayed identification of the first human RTHα case in 2012.

Clinical Features

 Interestingly, some features of congenital hypothyroidism, such as umbilical hernia, macroglossia, poor feeding and hoarse cry, are reported in RTHα patients at birth. The majority of patients exhibit delayed growth, which can be predominantly lower seg mental; many have macrocephaly and facial dysmorphic features including broad facies, hypertelorism, a flattened nasal bridge, enlarged tongue, thick lips. Older children and adults have an excessive number of skin tags and moles.

Neurocognitive

 Developmental milestones (motor, speech) in childhood are almost uniformly delayed. Dyspraxia, slow and dysarthric speech, and ataxic gait are also common. IQ is variably reduced, being markedly subnormal in a few cases, but with other patients achieving third level qualifications. Autism spectrum disorder is associated with one case. In severe RTHα cases, MRI has documented cortical microencephaly, reduced cerebellar volume and white matter tract density.

Gastrointestinal

Constipation is common and variable, but was sufficiently severe in one case to warrant consideration of surgical intervention prior to diagnosis of RTHα.

Cardiovascular

Many patients are bradycardic with some indices of cardiac function being within the hypothyroid range.

Metabolic and Endocrine

Resting energy expenditure is reduced, likely reflecting relative hypothyroidism of skeletal muscle and myocardium. No reproductive abnormalities have been identified to date, with both maternal and paternal transmission of the disorder being documented.

Biochemical Features

 TFTs are marginally deranged, with the most consistent abnormality being low or low- normal free T4 with high or high- normal T3, resulting in a low T4/ T3 ratio. Reverse T3 levels are subnormal in some cases. Mild anaemia and raised muscle CK levels are observed frequently. Dyslipidaemia has been recorded in both children and adults.

Skeletal

 Radiographic features in childhood include delayed fusion of fontanelles and excessively serpiginous (Wormian bone) skull sutures, femoral epiphyseal dysgenesis, delayed dentition, and bone maturation. In adulthood, features include a thickened skull vault, cortical hyperostosis, and increased bone mineral density.

Differential Diagnosis

RTHα should be considered in any child with growth retardation or delayed development; the presence of features such as macrocephaly, constipation, anaemia, skeletal dysplasia, or raised muscle CK levels further raises suspicion, reducing the threshold for genetic testing. Low free T4 and high free T3 levels are also features of MCT8 deficiency or dyshormonogenetic hypothyroidism (due to iodine deficiency and/ or a genetic cause), but these conditions can be distinguished clinically from RTHα (Table1).

Table1. Comparison of biochemical and clinical features in syndromes of resistance to thyroid hormone

Molecular Genetics

Nineteen different heterozygous THRA mutations (frameshift/ pre mature stop, missense) inherited from either parent or occurring de novo have been recorded in 30 cases (Figure1). Frameshift/ premature stop TRα1 mutants exhibit either markedly reduced hormone binding and impaired regulation of target genes and are associated with a severe clinical phenotype. Analogous to TRβ mutants in RTHβ, TRα1 mutants inhibit the function of their wild- type receptor counterparts in a dominant negative manner, via a mechanism involving constitutive mutant TRα1- corepressor interaction, with failure of normal dissociation of CoR from TRs in the presence of thyroid hormone (Figure 1).

Fig1. Schematic alignment of TRα1, TRα2 and TRβ1 showing functional regions (N- terminal, DNA- binding domain (DBD), hormone- binding domains); the divergent carboxyterminus of TRα2 is cross- hatched. The location of published (black) and unpublished (orange) RTHα mutations, involving either TRα1 alone or both TRα1 and α2 proteins, is superimposed. Three regions (aminoacids 234 to 282, 309 to 360 and 426 to 460) of TRβ1 within which RTHβ mutations cluster are depicted. The number of different mutations described hitherto within each cluster (orange) is superimposed. No RTHβ mutations have been recorded in regions of the hormone- binding domain that are important for corepressor binding or dimerization with RXR.

Several RTHα cases involve THRA mutations which affect both TRα1 and TRα2 subtypes (Figure 1). When studied in the TRα2 subtype background, these mutations exert no gain or loss- of- function, which correlates with absence of any discernible additional clinical phenotype attributable to mutant TRα2, in these patients. In a single case, unusual phenotypic features (micrognathia, clavicular agenesis, syndactyly of digits, chronic diarrhoea) may not be related to the THRA defect.

The clinical phenotype in patients with missense TRα1 mutations is variable and likely correlates with the severity of the underlying receptor defect. Thus, a mild phenotype (mild developmental and pubertal delay, subtle facial abnormalities, normal stature, normal schooling) and favourable response to thyroxine therapy was recorded in a patient with a missense TRα1 mutation (A263V) exhibiting partial, T3- reversible, loss- of- function in vitro; in contrast, a severe phenotype (marked developmental and growth retardation, dysmorphic facial features, special schooling), refractory to thyroxine therapy, was seen in another patient harbouring a missense TRα1 mutation (L274P) with severe, virtually irreversible, dysfunction in vitro with similar correlations of phenotype with genotype- phenotype being reported in other cases.

Given the prevalence (~1 in 40 000) of RTHβ due to over 150 different THRB mutations and marked homology of TRα and TRβ subtypes (with equivalent receptor defects being recorded in RTHα and RTHβ), it is highly likely that RTHα is more common than currently ascertained. Such underdiagnosis may reflect lack of a clear- cut, diagnostic biochemical signature, or a variable phenotype in this disorder.

Pathogenesis

Skeletal abnormalities (delayed fontanelle closure and dentition, femoral epiphyseal dysgenesis, Wormian skull sutures) and dysmorphic features (coarse facies, macroglossia, flattened nasal bridge) in RTHα are recognized features of untreated congenital or childhood hypothyroidism. Likewise, constipation due to reduced colonic motility is a recognized symptom of hypothyroidism and can be complicated by colonic dilatation or ileus.

Thyroid hormone abnormalities in RTHα are attributable to altered TH metabolism, rather than biosynthesis: increased hepatic DIO1 expression (seen in transgenic mice harbouring mutant TRα1), likely mediates enhanced T4 to T3 conversion, resulting in elevated free T3 and low free T4 levels; diminished DIO3 activity (a TRα1- regulated deiodinase) may contribute to reduced conversion of T4 to rT3 and also predispose patients to developing skin tags, as inhibition of this enzyme enhances keratinocyte proliferation in mice. TRα mutations affect the balance between proliferation and differentiation of erythroid progenitor cells in vitro, possibly accounting for the mild anaemia seen in RTHα patients. Idiopathic epilepsy seen in RTHα cases may not be coincidental; increased susceptibility to seizures following photic or audiogenic stimulation and aberrant GABAergic inhibitory inter neuron development have been recorded in TRα mutant mice.

Treatment

Thyroxine therapy of RTHα is beneficial, improving growth, wellbeing, basal metabolic rate, and lowering elevated low- density lipoprotein (LDL) cholesterol and CK levels; in turn, these metabolic changes may limit excessive weight gain in patients. In the childhood patient first described, 7 years of thyroxine therapy have been clearly beneficial, improving lower segment length and total height, alleviating constipation (with improved colonic contractile activity), and enhancing well- being (Moran & Chatterjee, unpublished observations). Addition of growth hormone to thyroxine therapy in childhood does not result in further improvement in growth. Commencement of thyroxine in early childhood may have ameliorated the phenotype in cases harbouring mutant TRα1 whose dysfunction is reversible at higher TH levels. In adult life, these individuals report that thyroxine therapy improves dyspraxia, constipation and enhances social interaction (Moran & Chatterjee, unpublished observations). In virtually all cases thyroxine treatment does not improve anaemia.

Following thyroxine therapy TSH levels fall quickly and remain suppressed, with elevation of fT3 to supraphysiologic levels; serum SHBG rises further from high- normal baseline levels and in one case, biochemical markers of bone turnover became progressively elevated; conversely, cardiac parameters, REE and muscle CK levels are less responsive to thyroxine treatment. These observations suggest preserved sensitivity and possible propensity to TH toxicity of TRβ- containing tissues (e.g. liver) but relative thyroid hormone resistance in TRα1- expressing organs (e.g. heart, skeletal muscle). Accordingly, ideal future therapies would selectively activate mutant or residual normal TRα1 function to overcome resistance in TRα- expressing tissues.

With current circulating abnormal parameters in RTHα being non- specific and insensitive, future identification of RTHα- specific biomarkers would be invaluable: better diagnosis of the disorder with earlier commencement of thyroxine therapy may improve outcome; specific biomarkers may also guide treatment, correlating with overcoming hormone resistance in TRα- expressing tissues and helping avoid TH toxicity in TRβ- containing organs.

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مواضيع ذات صلة

Resistance to Thyroid Hormone Beta

Selenoprotein Deficiency— A Disorder of Thyroid Hormone Metabolism

Allan- Herndon- Dudley Syndrome— A Disorder of Thyroid Hormone Transport

Glucose Phosphate Isomerase Deficiency

Pyruvate Kinase Deficiency

Complications of Thalassemia and Their Management: Endocrinopathies

Complications of Thalassemia and Their Management: Skeletal Changes

Complications of Thalassemia and Their Management : Complications Related to Ineffective Erythropoiesis

Glucose-6-Phosphate Dehydrogenase Deficiency

Pathobiology of Sickle Cell Disease : Disease pathogenesis

Alpha-Thalassemia Syndromes

Acute Intermittent Porphyria