Thyroid Hormone Resistance Syndrome: A Case Report with Literature Review
DOI:
https://doi.org/10.71079/ASIDE.CR.07222523Abstract
Resistance to thyroid hormone receptor beta (THRβ) is a rare condition causing abnormal thyroid function tests (TFTs) characterized by elevated thyroid hormone levels with unsuppressed Thyroid Stimulating Hormone (TSH). Thyroid hormone action involves multiple steps, and mutations affecting these steps are key to understanding and managing thyroid disorders. We present a case of THRβ resistance associated with cardiac arrhythmia. A 40-year-old male with a history of atrial fibrillation (AF) was referred for evaluation of abnormal TFTs and thyroid nodules. TFTs revealed a normal TSH and elevated free thyroxine. Imaging showed a large, peripherally enhancing necrotic mass with calcification in the left thyroid lobe and a 0.8 cm hypodense area in the right lobe. Thyroid ultrasound confirmed bilateral nodules, with the largest in the lower pole of the left lobe. The fine-needle aspiration biopsy was benign (Bethesda category II). Inherited THRβ pathogenic variants cause thyroid hormone resistance, often resulting in an enlarged thyroid gland. Despite this resistance, patients may still show clinical signs of cardiac arrhythmias. Diagnosing thyroid hormone resistance helps avoid unnecessary treatment for asymptomatic patients.
Keywords:
Thyroid hormone receptor beta, Resistance to thyroid hormone, Cardiac arrhythmia, Case report, Thyroid function testsFull Text
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) 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 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 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 with cardiac arrhythmia, confirmed through genetic testing.
Case Presentation
A 40-year-old man with a history of atrial fibrillation (AF) presented to the endocrinology clinic for evaluation of abnormal thyroid function tests (TFTs) and a thyroid nodule. He had recently been hospitalized for AF with a rapid ventricular response. He also had a history of receiving a two-month course of amiodarone treatment three years earlier. Initially, we found discrepant TFTs in which TSH was 1.375 (normal range: 0.55–4.78) and Free Thyroxine (fT4) was elevated at 2.76 (normal range: 0.89 – 1.76). Regarding imaging studies, a neck computed tomography (CT) scan showed a large, peripherally enhancing mass with central necrosis and calcification encompassing nearly the entire left thyroid lobe (2.2 × 3.6 × 4.6 cm). The scan also identified a 0.8 cm hypodense area in the right thyroid lobe. Thyroid Ultrasound: Bilateral thyroid nodules were present, with the largest nodule in the lower pole of the left lobe Figure 1. Regarding Fine Needle Aspiration (FNA) Biopsy, the left thyroid nodule showed Bethesda Category II findings, including benign-appearing follicular cells and abundant colloid. MRI brain ruled out TSH-secreting adenoma. He reported thyroid abnormalities in his son and brother but was unable to provide details. He was referred for genetic screening, which showed THR with a pathogenic variant: c.9628>G (p.Y321C)
Discussion
THR is a rare clinical syndrome marked by reduced sensitivity to thyroid hormone, primarily caused by mutations in the THR gene. THR 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 resistance in 1967, and Sakurai et al. identified the initial THR 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 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 [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 [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 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 gene, which explained the thyroid abnormalities. Ferrara et al. reported three THR cases with homozygous THR 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 alleles [24,25], while Usala et al. documented an amino acid deletion causing THR [26]. Heterozygous cases showed variable symptoms based on tissue resistance and mutant TR 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 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 resistance during pregnancy: A) higher miscarriage rates in pregnancies with THR resistance and unaffected fetuses; B) unaffected infants born to mothers with THR 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 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 in comparison to those with hyperthyroidism, hypothyroidism, and euthyroid controls. Their study found that 26% of THR 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 patients were between those of hyperthyroid and euthyroid individuals [35]. THR treatment is individualized, as no curative therapy exists for THR 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].
Conclusions
THR resistance is an uncommon and often underdiagnosed endocrine disorder. Pathogenic variants in the THR gene cause resistance to thyroid hormone, typically presenting with elevated thyroid hormone levels and thyroid gland enlargement. Despite receptor resistance, patients may develop, likely due to elevated T4 and T3 concentrations affecting the heart, where Thyroid hormone receptor alpha (THR) is predominantly expressed. Recognizing thyroid hormone resistance is essential to avoid unnecessary treatment in asymptomatic cases.
Declaration
This case was previously presented as a poster at the Endocrine Society Meeting 2024. Poster abstract link: here
中文摘要
甲状腺激素受体β抵抗综合征：病例报告与文献综述
甲状腺激素受体β（THRβ）抵抗是一种罕见疾病，导致甲状腺功能检查（TFTs）异常，表现为甲状腺激素水平升高且促甲状腺激素（TSH）未被抑制。甲状腺激素作用涉及多个步骤，影响这些步骤的突变是理解和管理甲状腺疾病的关键。我们报告一例伴心律失常的THRβ抵抗病例。一名40岁男性，既往有房颤（AF）病史，被转诊评估异常TFTs和甲状腺结节。TFTs显示TSH正常，游离甲状腺素升高。影像学显示左叶周边强化、坏死、钙化的大型肿块，右叶有0.8 cm低密度区。甲状腺超声证实双叶结节，最大结节位于左叶下极。细针穿刺活检结果为良性（Bethesda II级）。遗传性THRβ致病变异导致甲状腺激素抵抗，常伴甲状腺肿大。尽管存在抵抗，患者仍可能出现心律失常的临床表现。诊断甲状腺激素抵抗可避免对无症状患者进行不必要的治疗。
本中文摘要为机器辅助翻译，仅供参考；以英文摘要为准。 Machine-assisted Chinese translation of the English abstract; the English abstract is the version of record.
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Article history
- Received
- 12 Jan 2025
- Received in revised form
- 19 Mar 2025
- Accepted
- 6 May 2025
- Published
- 22 Jul 2025
