Introduction
Thyroid hormone resistance (THR) is a rare genetic condition where tissues respond poorly to thyroid hormones [1]. Mutations in the thyroid hormone receptor beta (THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β) gene cause about 85% of cases, with over 100 mutations identified. Neomutations account for the remaining 15%, meaning affected individuals may lack a family history of the disorder unless they pass it on to their children [2]. Researchers have classified THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β into subtypes to improve understanding and treatment [3]. Clinicians describe it as "generalized" when patients are euthyroid and as "pituitary resistance" when hyperthyroid symptoms appear, as reported by Guo et al. [4,5]. They use the term "isolated peripheral THR" when TSH decreases after high doses of liothyronine (L-T3) without hyperthyroid symptoms, documented in one patient [6]. Genetic classifications identify THR as either homozygous or heterozygous, with subtypes based on mutation characteristics [3]. Most cases involve heterozygous dominant-negative THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β mutations, resulting in defective receptors. Only four homozygous cases have been reported, showing severe symptoms like growth restriction, vision and hearing impairments, and cardiac anomalies [7]. Although most patients with THR remain euthyroid, some show symptoms of hypothyroidism or hyperthyroidism [3]. Elevated free thyroid hormone levels with a non-suppressed TSH serve as the primary diagnostic indicator of tissue hyporesponsiveness [5]. Studying family members with similar thyroid test results can confirm the genetic basis of the disorder and reveal variability in thyroid hormone sensitivity [4]. Currently, no treatment can fully correct the defect in THR [6]. However, most individuals naturally compensate by increasing thyroid hormone production, often eliminating the need for medical intervention [7]. This article presents a case of THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β with cardiac arrhythmia, confirmed through genetic testing.
Discussion
THR is a rare clinical syndrome marked by reduced sensitivity to thyroid hormone, primarily caused by mutations in the THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β gene. THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β affects approximately one in 40,000 individuals [8,9]. Specific genetic mutations cause wide variations in its pathogenesis, influencing symptoms and signs. Refetoff et al. first described THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β resistance in 1967, and Sakurai et al. identified the initial THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β gene mutation in 1989 [3,10,11]. THR is characterized by elevated thyroid hormone levels with normal or slightly increased TSH levels [12]. Assay interference, such as interfering antibodies (anti-streptavidin, anti-ruthenium, heterophilic, or anti-T4/T3 antibodies), substances like biotin, treatments including heparin or nonsteroidal anti-inflammatory drugs, and changes in thyroid hormone transport proteins (albumin, transthyretin, and thyroxine-binding globulin) can cause these paradoxical biochemical findings. A TSH-secreting pituitary adenoma (TSH-oma) also serves as a significant differential diagnosis for THR [13,3]. Campi et al. reported that 12% of 100 subjects with inappropriate TSH secretion were misdiagnosed, including a patient with THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β resistance initially diagnosed with a TSH-producing tumor [14]. Several cases have highlighted the challenges of accurate diagnosis. Liao et al. documented a 54-year-old woman misdiagnosed with a TSH-oma, who showed no improvement after transsphenoidal surgery; genetic studies later confirmed THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β [15,16,17,18]. In Taiwan, Liu et al. described a 10-year-old boy with goiter misdiagnosed as having hyperthyroidism, but molecular studies eventually revealed THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β [19]. Most patients showed no symptoms because excess thyroid hormone production compensated for tissue resistance [20]. When symptoms did appear, the primary clinical features of THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β included goiter (66%-95%), emotional disturbances (60%), attention deficit hyperactivity disorder (ADHD) (40%-60%), sinus tachycardia (33%-75%), and hearing impairment [21,22,12]. Less common features included variable degrees of mental retardation, short stature with reduced subischial leg length, chronic constipation, and bradycardia [22]. In our case, initial TFTs showed normal TSH but elevated fT4 of 2.76. Imaging revealed a large mass in the left thyroid lobe with calcifications and additional nodules bilaterally. FNA biopsy indicated benign findings (Bethesda category II). Despite persistently elevated fT4 and normal TSH, the patient remained clinically euthyroid for 1.5 years. Repeat labs eventually showed elevated TSH and fT4, but the MRI ruled out a TSH-oma. Genetic screening identified a pathogenic variant in the THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β gene, which explained the thyroid abnormalities. Ferrara et al. reported three THR cases with homozygous THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β mutations causing mental retardation, tachycardia, goiter, hearing loss, and growth retardation [23]. Takeda et al. described a case with a complete absence of both THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β alleles [24,25], while Usala et al. documented an amino acid deletion causing THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β [26]. Heterozygous cases showed variable symptoms based on tissue resistance and mutant TR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β protein expression [12]. THR has also been linked to congenital hypothyroidism, thyroid dysgenesis, and ectopic thyroid tissue, with five cases reported [27,28,29,30,31]. ADHD is present in 48-83% of patients, typically treated with standard methods. L-T3 has been effective in refractory cases, improving insomnia and hyperactivity[32,33]. In 2017, Moran et al. reported a pediatric homozygous THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β resistance case with dilated cardiomyopathy and thyrotoxicosis, treated with Triac and methimazole, leading to reduced thyroid hormone, normal TSH, and improved growth and cardiac function [34]. A large retrospective study revealed three key findings regarding THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β resistance during pregnancy: A) higher miscarriage rates in pregnancies with THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β resistance and unaffected fetuses; B) unaffected infants born to mothers with THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β resistance had lower birth weights, possibly due to excess thyroid hormone crossing the placenta; and C) affected infants had normal birth weights due to impaired thyroid hormone sensitivity [22]. Treatment for pregnant women with THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β resistance should be individualized, considering past pregnancy history and fetal genotype after amniocentesis [22]. Kahaly et al. examined the cardiovascular traits of patients with THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β in comparison to those with hyperthyroidism, hypothyroidism, and euthyroid controls. Their study found that 26% of THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β patients experienced tachycardia, 32% reported palpitations, 4% had dyspnea, 6% developed atrial fibrillation, and 4% exhibited mitral valve prolapse. These symptoms were less common and milder than in hyperthyroid patients. Additionally, the echocardiographic analysis revealed that the cardiac systolic and diastolic functions of THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β patients were between those of hyperthyroid and euthyroid individuals [35]. THR treatment is individualized, as no curative therapy exists for THR\documentclass[12pt]{minimal}
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\begin{document}$\beta$\end{document}β defects [3]. Synthesized TH analogs and Roxadustat show promise in vitro but lack in vivo results [36], [37]. TSH suppression with high-dose T3 effectively reduces goiter size, avoiding surgery due to high recurrence rates [38]. Most THR-related thyroid nodules are benign, though some cases of papillary carcinoma require thyroidectomy and radioactive iodine, often resulting in poor outcomes. 3,3,5-Triiodothyroacetic Acid (Triac), combined with levothyroxine, beta-blockers, and calcium/vitamin D, has shown success in managing symptoms like tachycardia, attention deficits, and goiter [39,40,3].