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Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.

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Thyroid hormones exert their action by binding to their thyroid hormone receptors among other mechanisms. They are involved in different cardiac functions, including contractility and rhythm. The mutation of thyroid hormone receptor ß is the main cause of thyroid hormone resistance. The cardiac phenotype of mutated patients has been studied in several cohorts of patients with different mutations. Tachycardia, palpitation and cardiac arrhythmia frequently appear; atrial flutter/fibrillation is found in up to 20%. Cardiac systolic and diastolic functions are impaired compared to hyperthyroid or euthyroid subjects, but cases of heart failure have not been reported. No correlation between genotype and cardiac phenotype has been found. Patients with a mutation of thyroid hormone receptor α frequently present bradycardia and systolic and diastolic functions that are similar to those of hypothyroid subjects. Levothyroxine treatment partly improves these parameters.

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Resistance to thyroid hormone syndrome (RTH) is an autosomal dominant or recessive genetic disease caused by mutation of either the thyroid hormone receptorß (THR-ß) gene or the thyroid hormone receptorα (THR-α) gene. RTH due to mutations of the THR-ß gene (hereafter, RTH-ß) is characterized by a decreased response of the target tissue to thyroid hormone, increased serum levels of free triiodothyronine (FT3) and/or free thyroxine (FT4), and inappropriate secretion of thyroid-stimulating hormone (TSH, normal or elevated). Clinical manifestations of RTH-ß vary from hyperthyroidism to hypothyroidism or simple goiter, and RTH-ß is often misdiagnosed clinically. The present review was prepared for the purpose of expanding knowledge of RTH-ß in order to reduce the rate of misdiagnosis.

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BACKGROUND: Energy expenditure prediction equations are used to estimate energy intake based on general population measures. However, when using equations to compare with a disease cohort with known metabolic abnormalities, it is important to derive one's own equations based on measurement conditions matching the disease cohort. OBJECTIVE: We aimed to use newly developed prediction equations based on a healthy pediatric population to describe and predict resting energy expenditure (REE) in a cohort of pediatric patients with thyroid disorders. METHODS: Body composition was measured by DXA and REE was assessed by indirect calorimetry in 201 healthy participants. A prediction equation for REE was derived in 100 healthy participants using multiple linear regression and z scores were calculated. The equation was validated in 101 healthy participants. This method was applied to participants with resistance to thyroid hormone (RTH) disorders, due to mutations in either thyroid hormone receptor ß or α (ß: female n = 17, male n = 9; α: female n = 1, male n = 1), with deviation of REE in patients compared with the healthy population presented by the difference in z scores. RESULTS: The prediction equation for REE = 0.061 * Lean soft tissue (kg) - 0.138 * Sex (0 male, 1 female) + 2.41 (R2 = 0.816). The mean ± SD of the residuals is -0.02 ± 0.44 kJ/min. Mean ± SD REE z scores for RTHß patients are -0.02 ± 1.26. z Scores of -1.69 and -2.05 were recorded in male (n = 1) and female ( n = 1) RTHα patients. CONCLUSIONS: We have described methodology whereby differences in REE between patients with a metabolic disorder and healthy participants can be expressed as a z score. This approach also enables change in REE after a clinical intervention (e.g., thyroxine treatment of RTHα) to be monitored.

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OBJECTIVE: Hyperthyroidism with increased serum thyroid hormones and also increased thyroid stimulating hormone (TSH) is described as the resistance thyroid hormone (RTH) syndrome. This syndrome may be due to various factors including tumors. We describe the different types of RTH syndrome and mention that this syndrome may be misdiagnosed and mistreated. To illustrate the RTH syndrome we describe such a case which also had two different carcinomas. This case was treated with anti-thyroid drugs, triiodothyroacetic acid and iodine-131 (¹³¹I). In the following 5.5 years after ¹³¹I treatment, TSH progressively increased and was not suppressed by normal doses of L-thyroxine (L-T4). A thyroid nodule was diagnosed as papillary thyroid carcinoma (PTC) and a small cell neuroendocrine carcinoma was diagnosed in the nasal septum. Under L-T4 replacement treatment and after ablation of both carcinomas, TSH returned to normal. Small cell neuroendocrine carcinomas accompanied with PTC, are extremely rare causes of RTH. CONCLUSION: A description of the resistance to thyroid hormone syndrome is presented and this syndrome is illustrated by a referring case which could be of a selective pituitary type or due to the neuroendocrine tumor.

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BACKGROUND: Resistance to thyroid hormone (RTH) is a dominant inherited syndrome of reduced tissue responsiveness to thyroid hormone. It is usually due to mutations located at the ligand-binding domain and adjacent hinge region of the thyroid hormone receptor ß (TRß). We report the clinical and laboratory characteristics and the genetic analysis of a patient with this rare disorder and his family members. METHODS: The clinical presentations and changes of thyroid function tests (TFTs) including magnetic resonance imaging (MRI) of pituitary and other laboratory tests were analysed. TFTs of his family's members were detected as well. Direct DNA sequencing of the TRß gene was done for those with abnormal TFTs. RESULTS: The RTH child had goiter, irritability, aggressiveness, and sudoresis. His TFTs showed high levels of circulating free thyroid hormones (FT(4) and FT(3)) and normal thyroid-stimulating hormone (TSH) concentrations. He felt worse when treated as hyperthyroidism (Grave disease) with thiamazole and his clinical presentations got improved obviously when treated as RTH with bromocriptine without obvious advert effect. We identified a novel missense mutation, A317D, located in exon 9 of the gene of this boy and his mother. His mother had not any clinical presentation, but having abnormal TFTs results. CONCLUSIONS: This patient reported here was concordant with the criteria of RTH. The feature is dysfunction of hypothalamus-pituitary-thyroid axis. A novel mutation was found in the TRß, A317D, of this family. This research verified the phenomena that there is a clinical heterogeneity within the same mutation of different RTH patients.

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Resistance to thyroid hormone (RTH), a syndrome of reduced end-organ responsiveness to thyroid hormone (TH), is mostly caused by mutations in the TH receptor (TR) beta gene. Diagnosis is based on persistent elevations of serum free T(4) and often T(3) levels in the absence of TSH suppression, and confirmation in most cases is by way of genetic testing. The mainstay in the management of RTH patients who are asymptomatic is to recognize the correct diagnosis and avoid antithyroid treatment. Deciding whether to manage these patients with TH replacement is made even more challenging when an affected individual is pregnant. How one approaches such a patient with pregnancy and RTH would depend on the genotype of the fetus. This requires obtaining prenatal information on the genotype of the fetus and a thorough history of the outcome of previous pregnancies as well as a history of the course and outcome of other family members with RTH. If the TRbeta mutation is known in the mother, the fetus can be rapidly genotyped from DNA from amniocentesis for the same mutation, and then management decisions could be made regarding thyroid or antithyroid hormone treatment.

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Thyroid hormone (TH) is essential for the proper development of numerous tissues, notably the brain. TH acts mostly intracellularly, which requires transport by TH transporters across the plasma membrane. Although several transporter families have been identified, only monocarboxylate transporter (MCT)8, MCT10 and organic anion-transporting polypeptide (OATP)1C1 demonstrate a high degree of specificity towards TH. Recently, the biological importance of MCT8 has been elucidated. Mutations in MCT8 are associated with elevated serum T(3) levels and severe psychomotor retardation, indicating a pivotal role for MCT8 in brain development. MCT8 knockout mice lack neurological damage, but mimic TH abnormalities of MCT8 patients. The exact pathophysiological mechanisms in MCT8 patients remain to be elucidated fully. Future research will probably identify novel TH transporters and disorders based on TH transporter defects.

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Thyroid hormone resistance syndrome (RTH) is a rare disorder and is characterized by elevated levels of circulating free thyroid hormones, inappropriate secretion of thyroid stimulating hormone (TSH), and reduced peripheral tissue response to thyroid hormone. 90% of RTH subjects, when studied at the level of the gene, have been found to harbor mutations in the thyroid hormone receptor-beta(THRB) gene. These affected individuals have been shown to possess a variety of missense mutations, resulting from changes in a single nucleotide in the THRB gene that corresponds to amino acid alternation. However, insertion or deletion mutations in the THRB gene sequence are quite rare, and have been observed in only a very few cases. In this study, we describe two such cases, in which two members of the same family were determined to harbor an insertion mutation in exon 10, and had also been diagnosed with generalized RTH. This insertion mutation, specifically the insertion of a cytosine at nucleotide 1358 of the THRB gene, is, to the best of our knowledge, the first such mutation reported among RTH patients in Korea.

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At least six major steps are required for secreted thyroid hormone (TH) to exert its action on target tissues. Mutations interfering with three of these steps have been so far identified. The first recognized defect, which causes resistance to TH, involves the TH receptor beta gene and has been given the acronym RTH. Occurring in approximately 1 per 40,000 newborns, more than 1000 affected subjects, from 339 families, have been identified. The gene defect remains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced sensitivity to TH were recently identified. One, producing severe psychomotor defects in > 100 males from 26 families, is caused by mutations in the cell-membrane transporter of TH, MCT8; the second, affecting the intracellular metabolism of TH in four individuals from two families, is caused by mutations in the SECISBP2 gene, which is required for the synthesis of selenoproteins, including TH deiodinases.

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Resistance to thyroid hormone is a syndrome involving reduced responsiveness of target tissues to thyroid hormone. Most cases involve mutations of the thyroid hormone receptor beta gene. Since many patients demonstrate tachycardia, goiter and elevated serum thyroid hormone levels, some patients have been misdiagnosed with Graves' disease, and nearly one third of patients are being treated inappropriately. It is important to keep this diagnosis in mind when a patient with elevated thyroid hormone level accompanied by normal or slightly increased TSH levels (SITSH) is encountered. Therapy with TRIAC has been used in several patients.

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Resistance to thyroid hormones (RTH) is an inherited syndrome characterised by reduced target tissue responsiveness to these hormones. In the recent years, it has become clear that RTH is probably much more common than is generally recognised, and is often misdiagnosed and inaccurately treated. Subjects suffering from RTH have raised serum thyroid hormone levels and raised or inappropriately normal thyrotropin levels. Two major forms of a clinical presentation of this disorder are asymptomatic or slightly symptomatic subjects with generalised resistance and patients with thyrotoxic features suggesting predominant pituitary resistance. Surprisingly, these various clinical situations are determined by the same genetic defect. In this paper, aetiology, symptoms, clinical classification, diagnosis and treatment of RTH are reviewed with putting special emphasis on the results of recently published studies.

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