Resistance to Thyroid Hormone Beta: A Focused Review.

Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH) and its more common form is caused by mutations in the thyroid hormone receptor beta (THRB) gene, termed RTHß. The characteristic biochemical profile is that of elevated serum TH levels in absence of thyrotropin suppression. Although most individuals are considered clinically euthyroid, there is variability in phenotypic manifestation among individuals harboring different THRB mutations and among tissue types in the same individual due in part to differential expression of the mutant TRß protein. As a result, management is tailored to the specific symptoms of TH excess or deprivation encountered in the affected individual as currently there is no available therapy to fully correct the TRß defect. This focused review aims to provide a concise update on RTHß, discuss less well recognized associations with other thyroid disorders, such as thyroid dysgenesis and autoimmune thyroid disease, and summarize existing evidence and controversies regarding the phenotypic variability of the syndrome. Review of management addresses goiter, attention deficit disorder and "foggy brain". Lastly, this work covers emerging areas of interest, such as the relevance of variants of unknown significance and novel data on the epigenetic effect resulting from intrauterine exposure to high TH levels and its transgenerational inheritance.

Persistent COUP-TFII expression underlies the myopathy and impaired muscle regeneration observed in resistance to thyroid hormone-alpha.

Thyroid hormone signaling plays an essential role in muscle development and function, in the maintenance of muscle mass, and in regeneration after injury, via activation of thyroid nuclear receptor alpha (THRA). A mouse model of resistance to thyroid hormone carrying a frame-shift mutation in the THRA gene (THRA-PV) is associated with accelerated skeletal muscle loss with aging and impaired regeneration after injury. The expression of nuclear orphan receptor chicken ovalbumin upstream promoter-factor II (COUP-TFII, or Nr2f2) persists during myogenic differentiation in THRA-PV myoblasts and skeletal muscle of aged THRA-PV mice and it is known to negatively regulate myogenesis. Here, we report that in murine myoblasts COUP-TFII interacts with THRA and modulates THRA binding to thyroid response elements (TREs). Silencing of COUP-TFII expression restores in vitro myogenic potential of THRA-PV myoblasts and shifts the mRNA expression profile closer to WT myoblasts. Moreover, COUP-TFII silencing reverses the transcriptomic profile of THRA-PV myoblasts and results in reactivation of pathways involved in muscle function and extracellular matrix remodeling/deposition. These findings indicate that the persistent COUP-TFII expression in THRA-PV mice is responsible for the abnormal muscle phenotype. In conclusion, COUP-TFII and THRA cooperate during post-natal myogenesis, and COUP-TFII is critical for the accelerated skeletal muscle loss with aging and impaired muscle regeneration after injury in THRA-PV mice.

Update on resistance to thyroid hormone syndromeß.

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.

Thyroid hormone resistance syndrome with P453T mutation in thyroid hormone receptor ß gene: A pedigree report.

RATIONALE: Thyroid hormone resistance syndrome (THRS) is an inherited condition characterized by reduced responsiveness of target tissues to thyroid hormone. Due to their nonspecific symptomatic manifestations, these patients can be misdiagnosed. This study reports a pedigree with THRS caused by a mutation in the thyroid hormone receptor ß (THRß) gene. PATIENT CONCERN: The proband, a 36-year-old woman at 19+4 weeks of gestation, was referred to our hospital because of abnormal thyroid function results. She was diagnosed with hyperthyroidism in October 2015, and had been treated with methimazole until her pregnancy. DIAGNOSIS: The proband and 2 of her children were diagnosed with THRS based on genetic analysis. Sequence analysis of the THRß gene showed a heterozygous mutation C>A located at exon 10. The mutation results in a change in proline for threonine at amino acid position 453, P453T. INTERVENTIONS: No treatment will fully and specifically correct the defect. All 3 patients were in normal metabolic status, and thus treatment was not required. OUTCOMES: During a 2-year follow-up period, none of them had any complaints. The 20-year-old son (167 cm in height) and the 18-year-old daughter (150 cm in height) both had low academic performance. LESSONS: Elevated serum thyroid hormone (TH) levels associated with nonsuppressed thyroid-stimulating hormone (TSH) levels usually leads to the diagnosis of THRS. Genetic analysis provides a short cut to diagnosis and the treatment should be based on the patient's clinical manifestations.

Fetal Exposure to High Maternal Thyroid Hormone Levels Causes Central Resistance to Thyroid Hormone in Adult Humans and Mice.

Context: Fetuses exposed to the high thyroid hormone (TH) levels of mothers with resistance to thyroid hormone beta (RTH-ß), due to mutations in the THRB gene, have low birth weight and suppressed TSH. Objective: Determine if such exposure to high TH levels in embryonic life has a long-term effect into adulthood. Design: Observations in humans with a parallel design on animals to obtain a preliminary information regarding mechanism. Setting: University research centers. Patients or other participants: Humans and mice with no RTH-ß exposed during intrauterine life to high TH levels from mothers who were euthyroid due to RTH-ß. Controls were humans and mice of the same genotype but born to fathers with RTH-ß and mothers without RTH-ß and thus, with normal serum TH levels. Interventions: TSH responses to stimulation with thyrotropin-releasing hormone (TRH) during adult life in humans and male mice before and after treatment with triiodothyronine (T3). We also measured gene expression in anterior pituitaries, hypothalami, and cerebral cortices of mice. Results: Adult humans and mice without RTH-ß, exposed to high maternal TH in utero, showed persistent central resistance to TH, as evidenced by reduced responses of serum TSH to TRH when treated with T3. In mice, anterior pituitary TSH-ß and deiodinase 3 (D3) mRNAs, but not hypothalamic and cerebral cortex D3, were increased. Conclusions: Adult humans and mice without RTH-ß exposed in utero to high maternal TH levels have persistent central resistance to TH. This is likely mediated by the increased expression of D3 in the anterior pituitary, enhancing local T3 degradation.

Description of the thyroid hormone resistance syndrome illustrated by such a case, which had two different carcinomas and was mistreated with iodine-131.

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.

Fetal thyroïdology.

Advances in prenatal imaging techniques and in fetal hormonology now allow for identification of disorders of thyroid function in the fetus. These can potentially be treated in utero by giving drugs to the mother. This review shows the feasibility of in utero treatment of fetal thyroid disorders, either indirectly by treating the mother or by giving the necessary drugs directly to the fetus. For goitrous fetal hypothyroidism leading to hydramnios, repeated intra-amniotic injections of thyroxine have been reported to decrease the size of the fetal thyroid. Experience with such procedures is limited but positive. The risk that direct in utero treatment of the fetus may provoke premature labor or cause infection should be carefully evaluated. In women with Graves' disease, autoimmune fetal hyperthyroidism can generally be treated in a noninvasive way by optimizing treatment of the mother, such as by increasing the dose of antithyroid drugs. Follow-up of the efficacy and the possible long-term consequences of medical interventions to normalize thyroid function of the fetus are of great importance. Specialized care of the fetus should be provided by skilled teams with extensive experience in prenatal care.

Thyroid hormone transporters and resistance.

Cellular entry is an important step preceding intracellular metabolism and action of thyroid hormone (TH). Transport of TH across the plasma membrane does not take place by simple diffusion but requires transporter proteins. One of the most effective and specific TH transporters identified to date is monocarboxylate transporter 8 (MCT8), the gene of which is located on the X chromosome. Although MCT8 is expressed in many tissues, its function appears to be most critical in the brain. Hemizygous MCT8 mutations in males cause severe psychomotor retardation, known as the Allan-Herndon-Dudley syndrome (AHDS), and abnormal serum TH levels. AHDS thus represents a type of TH resistance caused by a defect in cellular TH transport.

[Syndromes of resistance to thyroid hormone and inappropriate secretion of TSH (SITSH)].

Resistance to thyroid hormone (RTH) is a syndrome in which the responsiveness of end organs to thyroid hormone (TH) is reduced. Given that the TH-responsive end-organs include pituitary thyrotrophs, almost all patients with RTH manifest unsuppressed thyrotropin (TSH) despite elevated free-T4 and free-T3 levels. This abnormal finding in the thyroid function test is termed "syndrome of inappropriate secretion of TSH" (SITSH) or "central hyperthyroidism". Patients with TSH-secreting pituitary tumors(TSHoma) also manifest SITSH. Thus, the differential diagnosis of RTH vs. TSHoma is sometimes difficult and challenging. In this review article, the etiology of RTH and diagnostic approach for SITSH are explained and an algorithm for differential diagnosis of RTH vs. TSHoma is proposed.

Resistencia a hormonas tiroideas no asociada a mutación de la isoforma beta del receptor de hormonas tiroideas: caso clínico / Thyroid hormone resistance not associated to mutation on the beta isoform of the thyroid hormone receptor: report of one case

Thyroid hormone resistance (RTH) is inherited as an autosomal dominant trait, with variable clinical presentations. The hallmark of the syndrome is a variable degree of resistance to thyroid hormones, with high levels of circulating thyroid hormones, inappropriately normal or elevated TSH values and a clinical pattern of mixed hypothyroidism and hyperthyroidism. RTH is related in more than 85 percent of cases to thyroid hormone beta receptor mutations. We report a 11 years female with a history of treatment with propylthiouracil (PTU) for hyperthyroidism, presenting with a progressive goiter. Thyroidectomy was performed, removing 233 grams of thyroid tissue showing follicular hyperplasia. After surgery, a fast growth of the remnant thyroid gland was observed along with tachycardia. Laboratory showed a TSH of 38 mU/mL a triiodothyronine level of 300 ng/dL a thyroxin level of 14.8 ug/dL and a free thyroxin of 3.19 ng/dL, suggesting the diagnosis of RTH. The molecular study was negative for mutation of the beta isoform of thyroid hormone receptor. The possible theories that can explain these findings are discussed.

[Resistance to thyroid hormone].

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.

Resistencia a hormonas tiroideas / Thyroid hormone resistance

La resistencia a las hormonas tiroideas es un síndrome genético poco frecuente (uno por 50.000 nacidos vivos), causado por mutaciones en el gen del receptor de hormonas tiroideas y de herencia generalmente autosómica dominante. El receptor mutado, mediante un mecanismo de inhibición dominante, impide la unión de la triyodotironina a su receptor y da lugar a una menor respuesta tisular a la acción de las hormonas tiroideas. Aunque clásicamente se ha dividido a los pacientes en resistencia generalizada y resistencia hipofisaria, hoy se sabe que esta clasificación es más académica que real. La clínica es muy variable y, en muchas ocasiones, los pacientes están asintomáticos, pero es frecuente encontrar bocio, taquicardia, síndrome de hiperactividad-falta de atención, retraso de la edad ósea, etc. Analíticamente, se caracteriza por concentraciones elevadas de tiroxina y triyodotironina libres, junto con concentraciones de tirotropina no suprimidas, y se mantiene la respuesta de esta hormona al estímulo con hormona liberadora de tirotropina. Es preciso realizar el diagnóstico diferencial con otros procesos, pero fundamentalmente con el tumor hipofisario productor de tirotropina. El diagnóstico definitivo se basa en el estudio genético, que fundamentalmente demuestra mutaciones en los exones 7 a 10 del gen del receptor de hormonas tiroideas. El tratamiento depende de la clínica predominante y, por ello, la actitud terapéutica puede ir desde la no intervención (pacientes asintomáticos) hasta la necesidad de utilizar hormonas tiroideas a dosis altas (pacientes hipotiroideos) o de fármacos que disminuyen la acción de las hormonas tiroideas (pacientes hipertiroideos) (AU)

Compensatory role of thyroid hormone receptor (TR) alpha 1 in resistance to thyroid hormone: study in mice with a targeted mutation in the TR beta gene and deficient in TR alpha 1.

Resistance to thyroid hormone (RTH) is caused by mutations of the thyroid hormone receptor beta (TR beta) gene. Almost all RTH patients are heterozygous with an autosomal dominant pattern of inheritance. That most are clinically euthyroid suggests a compensatory role of the TR alpha1 isoform in maintaining the normal functions of thyroid hormone (T3) in these patients. To understand the role of TR alpha1 in the manifestation of RTH, we compared the phenotypes of mice with a targeted dominantly negative mutant TR beta (TR betaPV) with or without TR alpha1. TR betaPV mice faithfully recapitulate RTH in humans in that these mice demonstrate abnormalities in the pituitary-thyroid axis and impairment in growth. Here we show that the dysregulation of the pituitary-thyroid axis was worsened by the lack of TR alpha1 in TR betaPV mice, and severe impairment of postnatal growth was manifested in TR betaPV mice deficient in TR alpha1. Furthermore, abnormal expression patterns of T3-target genes in TR betaPV mice were altered by the lack of TR alpha1. These results demonstrate that the lack of TR alpha1 exacerbates the manifestation of RTH in TR betaPV mice. Therefore, TR alpha1 could play a compensatory role in mediating the functions of T3 in heterozygous patients with RTH. This compensatory role may be especially crucial for postnatal growth.

[Thyroid hormone receptors and the disorders].

Thyroid hormone is essential for normal development and several metabolic pathways. Its action is mediated through its nuclear receptors (thyroid hormone receptors: TRs), which regulate gene transcriptions in a ligand-dependent manner. The abnormality of TR functions is linked with several disorders including resistance to thyroid hormone (RTH), malignancy and euthyroid sick syndrome. For example, mutant TRs were identified to cause RTH and a certain malignancy. The functionally impaired TRs might be related with euthyroid sick syndrome. The analyses of these TRs will elucidate the molecular mechanism or basis for the disorders, and may provide a new insight to find the way of diagnosis and treatment.

Resistance to thyroid hormone: implications for neurodevelopmental research on the effects of thyroid hormone disruptors.

Thyroid hormones are essential for normal behavioral, intellectual, and neurological development. Congenital hypothyroidism, if not treated, can result in irreversible mental retardation, whereas thyroid diseases with more moderate impairment of thyroid function, such as resistance to thyroid hormone, cause less severe intellectual and behavioral abnormalities, including attention deficit hyperactivity disorder. There is increasing evidence that exposure to certain synthetic compounds, including dioxins and polychlorinated biphenyls (PCBs), during the perinatal period can also impair learning, memory, and attentional processes in offspring. Animal and human studies suggest that exposure to these environmental toxicants impair normal thyroid function. Although the precise mechanisms of action of the adverse effects these toxicants have on neurodevelopment have not yet been elucidated, it is possible that they are partially or predominantly mediated by alterations in hormone binding to the thyroid hormone receptor. The convergence of studies that examine the neurodevelopmental consequences of moderate impairment of thyroid function, such as is found in resistance to thyroid hormone, with those studies that demonstrate the adverse behavioral and cognitive effects of perinatal exposure to dioxins and PCBs serves to generate new hypotheses to test in a research setting. Such studies may provide new insights into the basic pathogenesis of developmental neurotoxicity following exposure to thyroid-disrupting synthetic compounds.