Autoimmune thyroid disease and thyroid function test fluctuations in patients with resistance to thyroid hormone

in European Journal of Endocrinology
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  • 1 Department of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Chuo-ku, Kobe, Japan
  • | 2 Department of Surgery, Center for Excellence in Thyroid Care, Kuma Hospital, Chuo-ku, Kobe, Japan

Correspondence should be addressed to E Nishihara; Email: nishihara@kuma-h.or.jp
Open access

Objective

Resistance to thyroid hormone beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β (THRB) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations.

Design and methods

We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHβ patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital.

Results

Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHβ patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P  = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHβ. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD.

Conclusions

The frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives. More than 20% of RTHβ patients temporarily showed laboratory findings atypical of RTHβ during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Abstract

Objective

Resistance to thyroid hormone beta (RTHβ) is an inherited syndrome caused by mutations in the thyroid hormone receptor β (THRB) gene. Patients with RTHβ typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHβ patients and further to explore their association with THRB gene mutations.

Design and methods

We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHβ patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital.

Results

Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHβ patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P  = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHβ. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD.

Conclusions

The frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives. More than 20% of RTHβ patients temporarily showed laboratory findings atypical of RTHβ during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Introduction

Resistance to thyroid hormone beta (RTHβ) is an inherited condition, which was first described by Refetoff et al. (1). Mutations in the thyroid hormone receptor β (THRB) gene have been identified in the majority of patients with RTHβ, with more than 4000 patients belonging to over 600 families (2). In general, patients with RTHβ are identified using discrepant thyroid function test and elevated serum levels of free T4 (FT4) and free T3 (FT3) with non-suppressed thyroid-stimulating hormone (TSH). Most studies involving a large number of patients with RTHβ originate from North America and Europe (3, 4, 5). However, no studies involving a large series of patients with RTHβ have been conducted in Asian countries including Japan.

Barkoff et al. reported that 23.3% of patients with RTHβ had a comorbid autoimmune thyroid disease (AITD). They described that individuals with RTHβ have an increased likelihood of developing AITD (6). Vela et al. (4) and Rivolta et al. (7) reported that thyroid autoantibodies were found in 25 and 22.2% of patients with RTHβ in Spain and South America, respectively. However, these studies did not investigate the increase in thyroid autoantibodies in patients with RTHβ in comparison to a control. A study of the general Japanese population reported that thyroid autoantibodies were detected in 23.4% of women and 14.8% of men with non-palpable goiters (8). No study has reported the prevalence of AITD among Japanese patients with RTHβ.

The main purpose of this study was to evaluate the clinical, laboratory, and imaging findings of patients with RTHβ in Japan, an iodine-sufficient or even excess area, and further to explore their association with THRB gene mutations.

Patients and methods

Participants

A total of 174 patients with probands suspected of having RTHβ consulted Kuma Hospital and underwent THRB sequencing between July 2003 and May 2020. Among them, 45 patients were confirmed to have THRB mutations. Relatives of these patients underwent gene analysis to determine if any of them also had THRB mutations. THRB gene sequencing confirmed mutations in 23 and normal sequences (WT) in 30 relatives. Overall, the study included 98 individuals divided into three groups: 45 probands, 23 affected relatives, and 30 unaffected relatives. All patients with RTHβ (68 patients) were genetically confirmed as having THRB gene mutations. All participants provided informed consent to participate in this study. The study protocol was approved by the Ethics Committee of Kuma Hospital (No. 20200709-1) and was conducted in accordance with the principles of the Declaration of Helsinki.

Clinical characteristics and symptoms

The clinical characteristics of the patients were obtained from the medical records. Sixty-seven patients with RTHβ were asked to answer a questionnaire and completed to describe their subjective symptoms. To assess concurrent atrial fibrillation, we evaluated the medical history and checked pulse in all 68 patients at the initial examination. Further ECG examination was performed for 32 patients.

Laboratory and ultrasound tests

Laboratory results of 63 patients with RTHβ and 25 unaffected relatives were available, while 5 patients with RTHβ (A317T, Y321C, I431L, I431fs, and P453H) and 5 unaffected relatives were excluded because they were under the age of 15 (Supplementary Fig. 1, see section on supplementary materials given at the end of this article). Between July 2003 and December 2018, TSH, FT4, and FT3 levels were measured using chemiluminescent immunoassays (Abbott); reference ranges, TSH (0.3–4.9 μIU/mL), FT4 (0.7–1.6 ng/dL), and FT3 (1.7–3.7 pg/mL). After January 2019, electrochemiluminescence immunoassays (Roche Diagnostics); reference ranges, TSH (0.5–5.0 μIU/mL), FT4 (0.9–1.7 ng/dL), and FT3 (2.3–4.0 pg/mL) were used.

Basal thyroid function tests were performed at least 1 month after patients who were misdiagnosed with Graves’ disease discontinued anti-thyroid drugs. All participants except one unaffected relative were checked for thyroid autoantibodies ( Supplementary Fig. 1) using methods described as follows. Before March 2008, four patients and one unaffected relative were evaluated by hemagglutination assay kits (microsomal hemagglutinin antibody (MCHA): Microsome test and thyroglobulin hemagglutinin antibody (TGHA): Thyroid test, Fuji Rebio Inc., Tokyo, Japan) and one patient was evaluated using RIA for thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) (Cosmic Co, Hiroshima, Japan). After April 2008, TPOAb and TgAb were measured for 58 patients with RTHβ and 23 unaffected relatives using an electrochemiluminescence immunoassay (Roche Diagnostics). For MCHA and TGHA, titers of 1:100 or more were regarded as positive. TPOAb ≥0.3 IU/mL and TgAb ≥0.3 IU/mL by RIA, and TPOAb ≥16.0 IU/mL and TgAb ≥28.0 IU/mL by electrochemiluminescence immunoassay were determined to be positive.

Data based on ultrasound examination were available in 56 patients with RTHβ and in 21 unaffected relatives who were at least 15 years old (Supplementary Fig. 1). Thyroid volume was measured by ultrasound and was calculated using the equation as described previously (9). For evaluation of the malignant potential, we used the ultrasound classification system based on the shape and echo features of thyroid nodules as reported previously (10, 11) and measured the maximum diameter of nodule sizes.

The patients with AITD have satisfied the diagnostic criteria, that is, positive values for TPOAb and/or TgAb, with either hypoechoic and/or inhomogeneous pattern, in thyroid ultrasonography or lymphocytic infiltration in the thyroid gland with cytological examination.

Gene analysis

Genomic DNA was extracted from peripheral leukocytes using the QIAamp DNA Blood Mini Kit (Qiagen). Exons 7–10 of the THRB1 gene were amplified by PCR using a High Fidelity PCR Master (Roche Diagnostics). Conditions were as follows: initial denaturation for 10 min (94°C), followed by 35 cycles of denaturation for 1 min (94°C); annealing for 1 min (55°C); and elongation for 1 min (72°C), with a final elongation step at 72°C for 3 min. The four sets of forward and reverse primers were as follows: exon 7, 5’-CAG TAA GCC ATC TGT GCA TC-3’ and 5’-GGC AAT AAC ACC AGT ATC CC-3’; exon 8, 5’-ACT GTA CAG GAT ATC AGT TC-3’ and 5’-AGT ATT CCT GGA AAC TGA TG-3’; exon 9, 5’- TCA CAG AAG GTT ATT CCT ATT-3’ and 5’-ACT CAA GTG ATT GGA ATT AG-3’; and exon 10 ,5’-CTA AGA GGG AAG ACC CTA GA-3’ and 5’-TTT CCC TCC CAA ATA ATC CC-3’. Direct sequencing of PCR products was performed using the Bigdye Terminator v1.1 Cycle Sequencing Kit (Applied Biosystems) and an automatic ABI 3130 sequencer (Applied Biosystems).

Statistical analysis

All analyses were performed using StatFlex version 6.0 software (Artech Co., Osaka, Japan). Values are presented as medians (interquartile range (IQR)). Categorical values were compared using a χ2 test, and other values were analyzed using the Mann–Whitney U-test. Statistical significance was set at P  < 0.05.

Results

Genetic testing revealed 35 heterozygous THRB gene mutations. All except two (p.R383H and p.R383S) were localized in three hot spot regions of the THRB described previously (2). They included 33 missense, 1 deletion, and 1 insertion mutation. The most prevalent mutations in this study were A317T and R438C, each harbored by three unrelated families (Fig. 1 and Table 1).

Figure 1
Figure 1

Mutations of THRB in our study. The number of different families showing the same mutation is shown in brackets. Genetic variants that include one or more members with AITD are shown in bold.

Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0584

Table 1

Types and characteristics of THRB mutations. Total numbers are indicated in parentheses.

ExonTSHB mutationNumber of familyMale/femaleAITH (positive/total examined members)Data inconsistent with RTHβ
7A234V11/11/2Overt hypothyroidism (1)
7A234D12/22/4
7A234T11/11/2
7Q235R11/00/1NA
7W239R10/11/1
7Q241P11/11/2
7R243W10/20/2
8G251R10/10/1Subclinical thyrotoxicosis (1)
8G261del10/10/1
8A268D10/11/1NA
8I276N10/10/1
9M310V10/10/1
9M313T22/02/2Overt hypothyroidism (1)
9R316H10/11/1Subclinical thyrotoxicosis (1)
9A317T30/30/2NA
9R320C10/10/1NA
9Y321C21/21/2
9E333K10/10/1NA
9R338L21/43/5
9R338Q11/01/1NA
9R338W20/21/2
9K342I12/35/5Overt hypothyroidism (2)

Overt thyrotoxicosis (2)
9G347R11/00/1
9S350P11/01/1
10R383H12/20/4Euthyroidism (2)
10R383S10/10/1
10R429Q20/20/2Subclinical thyrotoxicosis (1)
10I431L21/10/1
10R438C31/21/3
10R438H10/11/1Overt hypothyroidism (1)
10L450P10/10/1
10F451I10/10/1
10P453H11/31/3
10P453A20/21/2NA
10I431fs11/10/1Subclinical thyrotoxicosis (1)
(21/47)(26/63)

NA, not available.

The clinical characteristics of the 45 probands with RTHβ are shown in Table 2. The median age at diagnosis among probands was 36.0 (25.0–49.5) years, and over 40% of the patients were found to have RTHβ for the first time at age, 40 years or older. Of the probands, 57.8% initially consulted our hospital for further investigation of RTHβ due to abnormalities in their thyroid function test results. Collating the data of all patients with RTHβ (Table 3), the questionnaire showed that palpitations and goiter were the main chief complaints and were present in 38.8 and 34.3% of the patients, respectively. Medical history and ECGs showed that 7.4% (5/68) of the patients had concurrent atrial fibrillation. Importantly, 13.2% (9/68) of the patients were misdiagnosed with Graves’ disease at initial evaluation; consequently, nine patients were prescribed anti-thyroid drugs (six with thiamazole and two with propylthiouracil) and one patient who had undergone subtotal thyroidectomy at a hospital elsewhere was also prescribed thiamazole after recurrence of thyroid enlargement to 62 mL.

Table 2

Baseline characteristics of RTHβ patients (45 probands). Data are presented as median (interquartile range, IQR).

Parameter
Male/female9/36
Age at diagnosis among probands (years)36.0 (25.0–49.5)
 0–106.7%
 11–208.9%
 21–3022.2%
 31–4020.0%
 41–5022.2%
 51–608.9%
 >6111.1%
Reasons for visit
 Goiter22.2%
 Palpitation20.0%
 Abnormal thyroid function*57.8%

*Abnormal thyroid function found during the examination of symptoms that are not related to RTH, or during the health checkup.

Table 3

Baseline characteristics of 68 RTHβ patients (total; probands and relatives).

Parameter
Male/female21/47
Probands/relatives45/23
Frequency of subjective symptoms
 Palpitation38.8%
 Goiter34.3%
 Sweating23.9%
 Hand tremor13.4%
 Anxiety14.9%
 Weight loss11.9%
Misdiagnosed as Graves’ disease13.2%

FT4 and FT3 levels were significantly higher in patients with RTHβ compared to unaffected relatives (Table 4). Among RTHβ patients, 42.1% of male patients and 40.9% of female patients had positive TPOAb and/or TgAb. The frequency of thyroid autoantibodies in male RTHβ patients was significantly higher compared to unaffected male relatives (P  = 0.019). We also performed thyroid ultrasound and/or fine-needle aspirations for cytology in all RTHβ patients (n = 26) and all unaffected relatives (n = 7) who had positive thyroid autoantibodies. Hypoechoic and/or inhomogeneous pattern in ultrasonography was detected in all subjects but one. The remaining one had lymphocytic infiltration in cytological specimens in the thyroid. All 33 subjects showing positive thyroid autoantibodies had these typical findings of chronic thyroiditis defined as AITD. There were no significant differences in TSH levels (median (IQR), 2.8 (1.7–3.9) vs 2.0 (1.4–2.7) μIU/mL, P  = 0.052) or ages (40.0 (27.3–59.3) vs 36.0 (28.5–48.5) years old, P  = 0.46) between RTHβ patients with and without AITD. The median thyroid volume among RTHβ patients was significantly larger compared to unaffected relatives (P  = 0.0033 in male and 0.0072 in female, respectively). While 34.3% presented with a subjective symptom of goiter (Table 3), the ultrasound data showed that twice as many patients (73.2%) had goiter with a thyroid volume ≥20 mL. While nodules with solid components were detected in 42.9% of the RTHβ patients, malignancy was not suspected in any of them upon ultrasound evaluation and fine-needle aspiration.

Table 4

Laboratory and ultrasound data (RTHβ vs unaffected relatives, data age >15 years old). Data are presented as median (IQR). AITD pattern: hypoechoic and/or inhomogeneous pattern.

RTHβ (n = 63)unaffected relatives (n = 25)P value
Male/female19/446/190.56
TSH (μIU/mL)2.2 (1.5–3.2)1.9 (1.0–2.6)0.15
FT4 (ng/dL)1.9 (1.8–2.2)1.1 (1.0–1.3)<0.0001
FT3 (pg/mL)4.8 (4.2–5.6)2.9 (2.8–3.1)<0.0001
Antibody positivity
 Male8/19 (42.1%)0/6 (0.0%)0.019
  TPOAb positive6/19 (31.6%)0/6 (0.0%)0.050
  TgAb positive7/19 (36.8%)0/6 (0.0%)0.031
 Female18/44 (40.9%)7/18 (38.9%)0.88
  TPOAb positive14/44 (31.8%)#5/18 (27.8%)0.75
  TgAb positive17/44 (38.6%)##7/18 (38.9%)0.99
Ultrasound findings
Thyroid volume (mL)
 Male31.9 (24.6–43.4)13.3 (11.6–19.4)0.0033
 Female26.4 (18.1–37.2)14.4 (10.2–19.8)0.0072
Presence of nodules24/56 (42.9%)6/21 (28.6%)0.25
 Nodule size (mm)
  <53/56 (5.4%)2/21 (9.5%)
 5–1011/56 (19.6%)3/21 (14.3%)
 10–205/56 (8.9%)1/21 (4.8%)
  >205/56 (8.9%)0/21 (0.0%)
AITD pattern in antibody positive patients25/267/70.49

#Including two patients with positive MCHA (microsomal hemagglutinin antibody); ##Including two patients with positive TGHA (thyroglobulin hemagglutinin antibody).

We evaluated the sequential thyroid function in 44 RTHβ patients who consulted our hospital more than twice (Supplementary Fig. 1). Among them, 13 patients (29.5%), 8 with AITD and 5 without AITD, temporarily showed data inconsistent with RTHβ during the observation period (Table 5). Serial changes of data in each individual had been evaluated under the same assay condition. Although its prevalence between RTHβ patients with and without AITD was not different, overt hypothyroidism (Table 6 and Supplementary Fig. 2) with elevated TSH and low FT4 levels and overt thyrotoxicosis (Table 7 and Supplementary Fig. 3) with low TSH and high FT4 levels were detected only among seven patients with AITD. These patients complained of symptoms associated with fluctuating thyroid function and required treatment. Thyroid function test results consistent with RTHβ were detected at various time points (Tables 6, 7, and Supplementary Figs 2, 3). Two patients having the R383H mutation temporarily showed normal thyroid hormone and TSH levels without AITD (Tables 1 and 5). There were no over-represented mutations in the group with data inconsistent with RTHβ (Table 1).

Table 5

Sequential thyroid function tests available in RTHβ patients with and without AITD. Data are presented as median (IQR).

AITH (+)AITH (−)P value
Number1925
Age (years old)39.0 (25.0–57.0)36.0 (28.8–48.5)0.85
Observation period (months)73.0 (24.0–127.0)39.0 (16.0–108.3)0.34
Thyroid function tests inconsistent with RTHβ (n (%))8 (42.1%)5 (20%)0.11
 Overt hypothyroidism50
 Euthyroidism02
 Subclinical thyrotoxicosis13
 Overt thyrotoxicosis20
Table 6

Cases of RTHβ showing overt hypothyroidism due to chronic thyroiditis. Laboratory data at the start of levothyroxine (LT4) treatment is presented. TPOAB and TgAB was estimated by electrochemiluminescence immunoassay for all cases except Case 4, where hemagluttination assay, MCHA and TGHA was used.

Case detail/ CaseGenderTSH (μIU/mL)FT4 (ng/dL)FT3 (pg/mL)TPOAb (IU/mL)TgAb (IU/mL)THRB mutation
Initially diagnosed with chronic thyroiditis. After LT4 replacement, thyroid function began to show data consistent with RTHβ. Further evaluation revealed a mutation in THRB.
 Case 1F200*0.7NT366.0144.5K342I
 Case 2F97.80.6NT509.4316.9K342I
 Case 3F130.30.72.419.4836.3A234V
 Reference range for cases 1, 2 and 30.3–4.00.8–2.12.2–5.6<16.0< 28.0
Initial thyroid function showed data consistent with RTHβ. Further evaluation revealed a mutation in THRB. During the follow up, TSH level began to be elevated.
 Case 4F72.90.94.21:16001:100R438H
 Reference range0.3–4.00.8–2.12.2–5.6<1:100<1:100
 Case 5M>1000.32.0447.5247.6M313T
 Reference range0.3–4.90.7–1.61.7–3.7<16.0< 28.0

F, female; M, male; NT, not tested.

Table 7

Cases of RTHβ showing overt thyrotoxicosis.

CaseDetailGenderTSH (μIU/mL)FT4 (ng/dL)FT3 (pg/mL)TPOAb (IU/mL)TgAb (IU/mL)TRAb (IU/mL)RAIU (%)THRB mutation
1Initial thyroid function test showed overt thyrotoxicosis. From his family history, survey of RTHβ revealed a mutation in THRB. (RTHβ coexisted with Graves’ disease)M0.0292.17.5>600377.63.79.9*K342I
2Initial thyroid function test showed data compatible to RTHβ and further evaluation revealed a mutation in THRB. During the follow up, the laboratory data began to show overt thyrotoxicosis. (RTHβ coexisted with painless thyroiditis)F0.0067.728.558.0610.9<0.82.8**K342I
Reference Range0.5–5.00.9–1.72.3–4.0<16.0<28.0<2.0

Reference range at *at three hours: 5–15%; ** at 24 hours: 10–40%.

RAIU, radioactive iodine uptake; F, female; M, male

Discussion

This study describes the characteristics of 68 Japanese patients with RTHβ in a single institute specializing in thyroid care. We found that RTHβ patients, especially men, showed a higher frequency of AITD. More than 20% of patients with RTHβ temporarily showed thyroid tests inconsistent with RTHβ during their follow-up, and patients with AITD and specific mutations of THRB were prone to display such findings.

The presence of thyroid autoimmunity is generally more common in women; however, there was no difference in sex regarding the frequency of AITD in RTHβ patients in our study. Moreover, the frequency of AITD in male RTHβ patients was significantly higher compared to unaffected relatives; however, this difference was not found in the female patients (Table 4). This result was consistent with the study of Barkoff et al. (6). In addition, the prevalence of AITD in Japanese patients with RTHβ in this study (more than 40%) was higher compared to previous studies (~25%) (4, 6, 7). Japanese individuals are known to have a higher iodine intake than individuals from other countries (12). Although the relationship between iodine intake and the occurrence of AITD is undetermined, several studies have shown a direct relationship between iodine intake and AITD (13, 14). The mechanism of increased AITD in patients with RTHβ has not been elucidated. Gavin et al. have suggested that chronic TSH stimulation in RTHβ patients activates intrathyroidal lymphocytes to produce pro-inflammatory cytokines such as TNF-α, leading to thyroid cell destruction causing AITD (15); however, this hypothesis remains controversial (6).

To the best of our knowledge, no studies have evaluated the sequential thyroid functions and ultrasound findings of a large number of patients with RTHβ. Although RTHβ patients are known to exhibit discrepant thyroid test results, 29.5% of patients in this study temporarily showed data inconsistent with RTHβ. Among these, 88% (7/8) of RTHβ patients with AITD developed overt hypothyroidism or thyrotoxicosis and required treatment (Tables 1, 5, 6, 7, and Supplementary Figs 2, 3). In this study, four of five members in a family with RTHβ caused by K432I and concurrent AITD presented with overt thyrotoxicosis or overt hypothyroidism (Tables 1, 6 and 7). In the past, several RTHβ cases have been reported showing changes in thyroid function due to chronic thyroiditis (16, 17, 18), Graves’ disease (19, 20, 21, 22, 23, 24, 25, 26), and painless thyroiditis (27, 28), which required treatment.

In contrast, RTHβ patients without AITD showed only mild and temporary changes of thyroid function test results atypical of RTHβ (Tables 1 and 5). Among them, two RTHβ cases with the R383H mutation and without AITD in this study temporarily showed normal thyroid hormone levels with TSH levels in the normal range. Although R383 is located outside of the three hot spot regions, the R383H mutation has been previously reported to cause a mild form of RTHβ with small goiter, tachycardia, slightly elevated FT4, and normal TSH level (29). In vitro analysis showed that the R383H mutation had a T3-binding affinity of 70% that of WT and little dominant negative effect, suggesting the importance of the region for dimerization of the receptor (29, 30). Similarly, several other cases of RTHβ (P247L, E311K, R316C, G385E, and R429W), in addition to R383H, presented occasionally normal thyroid hormone levels (31, 32, 33, 34, 35). Two mutants (P247L and R429W) manifest either mild impairment of T3-binding or a weak dominant-negative effect (30, 31, 32). Structurally, the E311K mutant leads to a loss of hydrogen bonds between R383 (33) and the G385E mutant, which is localized adjacent to R383 within the dimerization region (35). Although genotype–phenotype correlation in patients with RTHβ is still controversial (36), we must be aware of fluctuations in thyroid function among patients with RTHβ due to both concurrent AITD and mutant receptor properties.

Ultrasound examinations revealed a high frequency of thyroid nodules in RTHβ patients, but no thyroid cancer. Indeed, only a few cases have been reported to have thyroid cancer concurrent with RTHβ (37, 38, 39). On the other hand, a mutant knock-in mouse with a targeted potent dominant negative TRβ mutant, which is identical in a patient with RTHβ (40), spontaneously developed thyroid cancer when homozygous, but not when heterozygous (41). Apart from the dominant-negative effect for TRβ regulation, multiple signaling pathways, including non-genomic mechanisms, are induced by the mutation of the two alleles of the THRB gene, consequently leading to thyroid carcinogenesis (42, 43). Both case studies and experimental findings in previous reports indicate that although elevated TSH levels may promote thyroid cell proliferation, patients with a heterozygous THRB mutation have no obvious risk for the development of thyroid cancer.

This study has some limitations. This was a retrospective study with varied follow-up periods and a relatively small number of participants in the unaffected relatives group. The median age at diagnosis among probands was 36.0 years, possibly because our hospital has no department of pediatrics; otherwise, Japanese general practitioners are unaware of RTHβ. In addition, 13.2% were misdiagnosed to have Graves’ disease at initial evaluation; however, all misdiagnoses were corrected to RTHβ before 2011. The American Thyroid Association guidelines (44) and the diagnostic criteria for RTHβ published by the Japan Thyroid Association (available at: www.japanthyroid.jp/en/clinical.html accessed May 23, 2021) have led to an increased awareness of RTHβ resulting in a decrease in the frequency of its misdiagnosis.

In conclusion, a higher frequency of AITD and thyroid test results fluctuations in RTHβ patients may obscure the presence of RTHβ during follow-up. Suspicion of RTHβ should prompt physicians to consider repeat laboratory tests at different time periods and performing genetic testing to avoid misdiagnosis and inappropriate treatment.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EJE-21-0584

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Author contribution statement

M O-H and E N designed the study. M O-H extracted the data and performed the statistical analysis. M O-H and E N wrote the manuscript. M H and T K contributed to the patients care and acquisition of data. M I, S F, M N, T A, and A M critically reviewed the article. All authors discussed the results of the study and approved the final manuscript.

Acknowledgements

The authors are grateful to the staff of Kuma Hospital for their valuable contribution. The authors thank Professor Samuel Refetoff for providing valuable advice after reviewing the manuscript.

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    • Export Citation
  • 6

    Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S. Autoimmunity in patients with resistance to thyroid hormone. Journal of Clinical Endocrinology and Metabolism 2010 95 31893193. (https://doi.org/10.1210/jc.2009-2179)

    • Search Google Scholar
    • Export Citation
  • 7

    Rivolta CM, Olcese MC, Belforte FS, Chiesa A, Gruñeiro-Papendieck L, Iorcansky S, Herzovich V, Cassorla F, Gauna A & Gonzalez-Sarmiento R et al.Genotyping of resistance to thyroid hormone in South American population. Identification of seven novel missense mutations in the human thyroid hormone receptor beta gene. Molecular and Cellular Probes 2009 23 148153. (https://doi.org/10.1016/j.mcp.2009.02.002)

    • Search Google Scholar
    • Export Citation
  • 8

    Kasagi K, Takahashi N, Inoue G, Honda T, Kawachi Y, Izumi Y. Thyroid function in Japanese adults as assessed by a general health checkup system in relation with thyroid-related antibodies and other clinical parameters. Thyroid 2009 19 937944. (https://doi.org/10.1089/thy.2009.0205)

    • Search Google Scholar
    • Export Citation
  • 9

    Nishihara E, Nagayama Y, Amino N, Hishinuma A, Takano T, Yoshida H, Kubota S, Fukata S, Kuma K, Miyauchi A. A novel thyrotropin receptor germline mutation (Asp617Tyr) causing hereditary hyperthyroidism. Endocrine Journal 2007 54 927934. (https://doi.org/10.1507/endocrj.k07-088)

    • Search Google Scholar
    • Export Citation
  • 10

    Yokozawa T, Fukata S, Kuma K, Matsuzuka F, Kobayashi A, Hirai K, Miyauchi A, Sugawara M. Thyroid cancer detected by ultrasound-guided fine-needle aspiration biopsy. World Journal of Surgery 1996 20 84885 3; discussion 853. (https://doi.org/10.1007/s002689900129)

    • Search Google Scholar
    • Export Citation
  • 11

    Ito Y, Amino N, Yokozawa T, Ota H, Ohshita M, Murata N, Morita S, Kobayashi K, Miyauchi A. Ultrasonographic evaluation of thyroid nodules in 900 patients: comparison among ultrasonographic, cytological, and histological findings. Thyroid 2007 17 12691276. (https://doi.org/10.1089/thy.2007.0014)

    • Search Google Scholar
    • Export Citation
  • 12

    Nagataki S The average of dietary iodine intake due to the ingestion of seaweeds is 1.2 mg/day in Japan. Thyroid 2008 18 667668. (https://doi.org/10.1089/thy.2007.0379)

    • Search Google Scholar
    • Export Citation
  • 13

    Kahaly GJ, Dienes HP, Beyer J, Hommel G. Iodide induces thyroid autoimmunity in patients with endemic goitre: a randomised, double-blind, placebo-controlled trial. European Journal of Endocrinology 1998 139 290297. (https://doi.org/10.1530/eje.0.1390290)

    • Search Google Scholar
    • Export Citation
  • 14

    Papanastasiou L, Alevizaki M, Piperingos G, Mantzos E, Tseleni-Balafouta S, Koutras DA. The effect of iodine administration on the development of thyroid autoimmunity in patients with nontoxic goiter. Thyroid 2000 10 493497. (https://doi.org/10.1089/thy.2000.10.493)

    • Search Google Scholar
    • Export Citation
  • 15

    Gavin C, Meggison H, Ooi TC. Proposing a causal link between thyroid hormone resistance and primary autoimmune hypothyroidism. Medical Hypotheses 2008 70 10241028. (https://doi.org/10.1016/j.mehy.2007.08.015)

    • Search Google Scholar
    • Export Citation
  • 16

    Fukata S, Brent GA, Sugawara M. Resistance to thyroid hormone in Hashimoto’s thyroiditis. New England Journal of Medicine 2005 352 517518. (https://doi.org/10.1056/NEJM200502033520523)

    • Search Google Scholar
    • Export Citation
  • 17

    Sato H, Sakai H. A family showing resistance to thyroid hormone associated with chronic thyroiditis and its clinical features: a case report. Endocrine Journal 2006 53 421425. (https://doi.org/10.1507/endocrj.k05-182)

    • Search Google Scholar
    • Export Citation
  • 18

    Kammoun I, Bouzid C, Kandara H, Ben Salem L, Turki Z, Ben Slama C. A case of resistance to thyroid hormone with chronic thyroiditis: discovery of a novel mutation (I54V) Case Reports in Endocrinology 2011 2011 584930. (https://doi.org/10.1155/2011/584930)

    • Search Google Scholar
    • Export Citation
  • 19

    Abdellaoui Y, Magkou D, Bakopoulou S, Zaharia R, Raffin-Sanson ML, Cazabat L. Coexistence of autoimmune hyper- and hypothyroidism in a kindred with reduced sensitivity to thyroid hormone. European Thyroid Journal 2020 9 263268. (https://doi.org/10.1159/000506424)

    • Search Google Scholar
    • Export Citation
  • 20

    González Cabrera N, Kalic AK, Antón Miguel , Sierra Polo P, Vicente Vicente . Hyperthyroidism due to Graves-Basedow disease in a woman refractory to thyroid hormones. Endocrinologia y Nutricion 2012 59 609611. (https://doi.org/10.1016/j.endonu.2011.11.014)

    • Search Google Scholar
    • Export Citation
  • 21

    Ogawa K, Yoshida M, Hayashi Y, Murata Y, Miyata M, Oiso Y. A rare case of resistance to thyroid hormone coexisting with Graves’ disease. Endocrine 2011 40 318319. (https://doi.org/10.1007/s12020-011-9491-0)

    • Search Google Scholar
    • Export Citation
  • 22

    Ramos-Leví AM, Moreno JC, Álvarez-Escolá C, Lacámara N, Montañez MC. Coexistence of thyroid hormone resistance syndrome, pituitary adenoma and Graves’ disease. Endocrinologia y Nutricion 2016 63 139141. (https://doi.org/10.1016/j.endonu.2015.12.003)

    • Search Google Scholar
    • Export Citation
  • 23

    Sato H Clinical features of primary hyperthyroidism caused by Graves’ disease admixed with resistance to thyroid hormone (P453T). Endocrine Journal 2010 57 687692. (https://doi.org/10.1507/endocrj.k10e-066)

    • Search Google Scholar
    • Export Citation
  • 24

    Shiwa T, Oki K, Awaya T, Nakanishi S, Yamane K. Resistance to thyroid hormone accompanied by Graves’ disease. Internal Medicine 2011 50 19771980. (https://doi.org/10.2169/internalmedicine.50.4904)

    • Search Google Scholar
    • Export Citation
  • 25

    Sivakumar T, Chaidarun S. Resistance to thyroid hormone in a patient with coexisting Graves’ disease. Thyroid 2010 20 213216. (https://doi.org/10.1089/thy.2009.0175)

    • Search Google Scholar
    • Export Citation
  • 26

    Sun H, Xu S, Xie S, Cao W, Chen G, Di H, Zheng R, Li X, Mao X, Liu C. Graves’ disease coexisting with resistance to thyroid hormone: a rare case. Clinical Case Reports 2018 6 337341. (https://doi.org/10.1002/ccr3.1344)

    • Search Google Scholar
    • Export Citation
  • 27

    Taniyama M, Otsuka F, Tozaki T, Ban Y. Thyroid profiles in a patient with resistance to thyroid hormone and episodes of thyrotoxicosis, including repeated painless thyroiditis. Thyroid 2013 23 898901. (https://doi.org/10.1089/thy.2012.0004)

    • Search Google Scholar
    • Export Citation
  • 28

    Nagamine T, Noh JY, Emoto N, Kogai T, Hishinuma A, Okajima F, Sugihara H. Painless destructive thyroiditis in a patient with resistance to thyroid hormone: a case report. Thyroid Research 2019 12 8. (https://doi.org/10.1186/s13044-019-0072-2)

    • Search Google Scholar
    • Export Citation
  • 29

    Clifton-Bligh RJ, de Zegher F, Wagner RL, Collingwood TN, Francois I, Van Helvoirt M, Fletterick RJ, Chatterjee VK. A novel TR beta mutation (R383H) in resistance to thyroid hormone syndrome predominantly impairs corepressor release and negative transcriptional regulation. Molecular Endocrinology 1998 12 609621. (https://doi.org/10.1210/mend.12.5.0113)

    • Search Google Scholar
    • Export Citation
  • 30

    Hayashi Y, Sunthornthepvarakul T, Refetoff S. Mutations of CpG dinucleotides located in the triiodothyronine (T3)-binding domain of the thyroid hormone receptor (TR) beta gene that appears to be devoid of natural mutations may not be detected because they are unlikely to produce the clinical phenotype of resistance to thyroid hormone. Journal of Clinical Investigation 1994 94 607615. (https://doi.org/10.1172/JCI117376)

    • Search Google Scholar
    • Export Citation
  • 31

    Pohlenz J, Manders L, Sadow PM, Kansal PC, Refetoff S, Weiss RE. A novel point mutation in cluster 3 of the thyroid hormone receptor beta gene (P247L) causing mild resistance to thyroid hormone. Thyroid 1999 9 11951203. (https://doi.org/10.1089/thy.1999.9.1195)

    • Search Google Scholar
    • Export Citation
  • 32

    Catargi B, Monsaingeon M, Bex-Bachellerie V, Ronci-Chaix N, Trouette H, Margotat A, Tabarin A, Beck-Peccoz P. A novel thyroid hormone receptor-beta mutation, not anticipated to occur in resistance to thyroid hormone, causes variable phenotypes. Hormone Research 2002 57 137142. (https://doi.org/10.1159/000057965)

    • Search Google Scholar
    • Export Citation
  • 33

    Slezak R, Lukienczuk T, Noczynska A, Karpinski P, Lebioda A, Misiak B, Sasiadek MM. A novel p.E311K mutation of thyroid receptor beta gene in resistance to thyroid hormone syndrome, inherited in autosomal recessive trait. Hormone and Metabolic Research 2012 44 704707. (https://doi.org/10.1055/s-0032-1312666)

    • Search Google Scholar
    • Export Citation
  • 34

    Ueda Y, Tagami T, Tamanaha T, Kakita M, Tanase-Nakao K, Nanba K, Usui T, Naruse M, Shimatsu A. A family of RTHβ with p.R316C mutation presenting occasional syndrome of inappropriate secretion of TSH. Endocrine Journal 2015 62 251260. (https://doi.org/10.1507/endocrj.EJ14-0422)

    • Search Google Scholar
    • Export Citation
  • 35

    Korwutthikulrangsri M, Dosiou C, Dumitrescu AM, Refetoff S. A novel G385E variant in the cold region of the T3-binding domain of thyroid hormone receptor beta gene and investigations to assess its clinical significance. European Thyroid Journal 2019 8 293297. (https://doi.org/10.1159/000503860)

    • Search Google Scholar
    • Export Citation
  • 36

    Hayashi Y, Weiss RE, Sarne DH, Yen PM, Sunthornthepvarakul T, Marcocci C, Chin WW, Refetoff S. Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors? Journal of Clinical Endocrinology and Metabolism 1995 80 32463256. (https://doi.org/10.1210/jcem.80.11.7593433)

    • Search Google Scholar
    • Export Citation
  • 37

    Kim HK, Kim D, Yoo EH, Lee JI, Jang HW, Tan AH, Hur KY, Kim JH, Kim KW & Chung JH et al.A case of resistance to thyroid hormone with thyroid cancer. Journal of Korean Medical Science 2010 25 13681371. (https://doi.org/10.3346/jkms.2010.25.9.1368)

    • Search Google Scholar
    • Export Citation
  • 38

    Paragliola RM, Lovicu RM, Locantore P, Senes P, Concolino P, Capoluongo E, Pontecorvi A, Corsello SM. Differentiated thyroid cancer in two patients with resistance to thyroid hormone. Thyroid 2011 21 793797. (https://doi.org/10.1089/thy.2010.0233)

    • Search Google Scholar
    • Export Citation
  • 39

    Ramos-Prol A, Antonia Pérez-Lázaro M, Isabel del Olmo-García M, León-de Zayas B, Moreno-Macián F, Navas-de Solis S, Merino-Torres JF. Differentiated thyroid carcinoma in a girl with resistance to thyroid hormone management with triiodothyroacetic acid. Journal of Pediatric Endocrinology and Metabolism 2013 26 133136. (https://doi.org/10.1515/jpem-2012-0230)

    • Search Google Scholar
    • Export Citation
  • 40

    Parrilla R, Mixson AJ, McPherson JA, McClaskey JH, Weintraub BD. Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two ‘hot spot’ regions of the ligand binding domain. Journal of Clinical Investigation 1991 88 21232130. (https://doi.org/10.1172/JCI115542)

    • Search Google Scholar
    • Export Citation
  • 41

    Suzuki H, Willingham MC, Cheng SY. Mice with a mutation in the thyroid hormone receptor beta gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. Thyroid 2002 12 963969. (https://doi.org/10.1089/105072502320908295)

    • Search Google Scholar
    • Export Citation
  • 42

    Cheng SY Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance. Trends in Endocrinology and Metabolism 2005 16 176182. (https://doi.org/10.1016/j.tem.2005.03.008)

    • Search Google Scholar
    • Export Citation
  • 43

    Guigon CJ, Cheng SY. Novel non-genomic signaling of thyroid hormone receptors in thyroid carcinogenesis. Molecular and Cellular Endocrinology 2009 308 6369. (https://doi.org/10.1016/j.mce.2009.01.007)

    • Search Google Scholar
    • Export Citation
  • 44

    Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA & Stan MN et al.2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 2016 26 13431421. (https://doi.org/10.1089/thy.2016.0229)

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    • Export Citation

 

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    Mutations of THRB in our study. The number of different families showing the same mutation is shown in brackets. Genetic variants that include one or more members with AITD are shown in bold.

  • 1

    Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. Journal of Clinical Endocrinology and Metabolism 1967 27 279294. (https://doi.org/10.1210/jcem-27-2-279)

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    • Export Citation
  • 2

    Dumitrescu AM, Korwutthikulrangsri M, Refetoff S. Impaired sensitivity to thyroid hormone: defects of transport, metabolism, and action. In Werner and Ingbar’s the Thyroid a Fundamental and Clinical Text, 11 th ed., ch. 66, pp. 868907. Eds Braverman LE, Cooper DS, Kopp P. Philadelphia: Wolters Kluwer, 2021.

    • Search Google Scholar
    • Export Citation
  • 3

    Anselmo J, Cao D, Karriosn T, Weiss RE, Refetoff S. Fetal loss associated with excess thyroid hormone exposure. JAMA 2004 292 691695. (https://doi.org/10.1001/jama.292.6.691)

    • Search Google Scholar
    • Export Citation
  • 4

    Vela A, Pérez-Nanclares G, Ríos I, Rica I, Portillo N, Castaño L & Spanish Group for the Study of RTH. Thyroid hormone resistance from newborns to adults: a Spanish experience. Journal of Endocrinological Investigation 2019 42 941949. (https://doi.org/10.1007/s40618-019-1007-4)

    • Search Google Scholar
    • Export Citation
  • 5

    Amor AJ, Halperin I, Alfayate R, Borrás VM, Escribano A, González C, Gutirrez A, Mauri M, Pérez P & Picό A et al.Identification of four novel mutations in the thyroid hormone receptor-β gene in 164 Spanish and 2 Greek patients with resistance to thyroid hormone. Hormones 2014 13 7478. (https://doi.org/10.1007/BF03401322)

    • Search Google Scholar
    • Export Citation
  • 6

    Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S. Autoimmunity in patients with resistance to thyroid hormone. Journal of Clinical Endocrinology and Metabolism 2010 95 31893193. (https://doi.org/10.1210/jc.2009-2179)

    • Search Google Scholar
    • Export Citation
  • 7

    Rivolta CM, Olcese MC, Belforte FS, Chiesa A, Gruñeiro-Papendieck L, Iorcansky S, Herzovich V, Cassorla F, Gauna A & Gonzalez-Sarmiento R et al.Genotyping of resistance to thyroid hormone in South American population. Identification of seven novel missense mutations in the human thyroid hormone receptor beta gene. Molecular and Cellular Probes 2009 23 148153. (https://doi.org/10.1016/j.mcp.2009.02.002)

    • Search Google Scholar
    • Export Citation
  • 8

    Kasagi K, Takahashi N, Inoue G, Honda T, Kawachi Y, Izumi Y. Thyroid function in Japanese adults as assessed by a general health checkup system in relation with thyroid-related antibodies and other clinical parameters. Thyroid 2009 19 937944. (https://doi.org/10.1089/thy.2009.0205)

    • Search Google Scholar
    • Export Citation
  • 9

    Nishihara E, Nagayama Y, Amino N, Hishinuma A, Takano T, Yoshida H, Kubota S, Fukata S, Kuma K, Miyauchi A. A novel thyrotropin receptor germline mutation (Asp617Tyr) causing hereditary hyperthyroidism. Endocrine Journal 2007 54 927934. (https://doi.org/10.1507/endocrj.k07-088)

    • Search Google Scholar
    • Export Citation
  • 10

    Yokozawa T, Fukata S, Kuma K, Matsuzuka F, Kobayashi A, Hirai K, Miyauchi A, Sugawara M. Thyroid cancer detected by ultrasound-guided fine-needle aspiration biopsy. World Journal of Surgery 1996 20 84885 3; discussion 853. (https://doi.org/10.1007/s002689900129)

    • Search Google Scholar
    • Export Citation
  • 11

    Ito Y, Amino N, Yokozawa T, Ota H, Ohshita M, Murata N, Morita S, Kobayashi K, Miyauchi A. Ultrasonographic evaluation of thyroid nodules in 900 patients: comparison among ultrasonographic, cytological, and histological findings. Thyroid 2007 17 12691276. (https://doi.org/10.1089/thy.2007.0014)

    • Search Google Scholar
    • Export Citation
  • 12

    Nagataki S The average of dietary iodine intake due to the ingestion of seaweeds is 1.2 mg/day in Japan. Thyroid 2008 18 667668. (https://doi.org/10.1089/thy.2007.0379)

    • Search Google Scholar
    • Export Citation
  • 13

    Kahaly GJ, Dienes HP, Beyer J, Hommel G. Iodide induces thyroid autoimmunity in patients with endemic goitre: a randomised, double-blind, placebo-controlled trial. European Journal of Endocrinology 1998 139 290297. (https://doi.org/10.1530/eje.0.1390290)

    • Search Google Scholar
    • Export Citation
  • 14

    Papanastasiou L, Alevizaki M, Piperingos G, Mantzos E, Tseleni-Balafouta S, Koutras DA. The effect of iodine administration on the development of thyroid autoimmunity in patients with nontoxic goiter. Thyroid 2000 10 493497. (https://doi.org/10.1089/thy.2000.10.493)

    • Search Google Scholar
    • Export Citation
  • 15

    Gavin C, Meggison H, Ooi TC. Proposing a causal link between thyroid hormone resistance and primary autoimmune hypothyroidism. Medical Hypotheses 2008 70 10241028. (https://doi.org/10.1016/j.mehy.2007.08.015)

    • Search Google Scholar
    • Export Citation
  • 16

    Fukata S, Brent GA, Sugawara M. Resistance to thyroid hormone in Hashimoto’s thyroiditis. New England Journal of Medicine 2005 352 517518. (https://doi.org/10.1056/NEJM200502033520523)

    • Search Google Scholar
    • Export Citation
  • 17

    Sato H, Sakai H. A family showing resistance to thyroid hormone associated with chronic thyroiditis and its clinical features: a case report. Endocrine Journal 2006 53 421425. (https://doi.org/10.1507/endocrj.k05-182)

    • Search Google Scholar
    • Export Citation
  • 18

    Kammoun I, Bouzid C, Kandara H, Ben Salem L, Turki Z, Ben Slama C. A case of resistance to thyroid hormone with chronic thyroiditis: discovery of a novel mutation (I54V) Case Reports in Endocrinology 2011 2011 584930. (https://doi.org/10.1155/2011/584930)

    • Search Google Scholar
    • Export Citation
  • 19

    Abdellaoui Y, Magkou D, Bakopoulou S, Zaharia R, Raffin-Sanson ML, Cazabat L. Coexistence of autoimmune hyper- and hypothyroidism in a kindred with reduced sensitivity to thyroid hormone. European Thyroid Journal 2020 9 263268. (https://doi.org/10.1159/000506424)

    • Search Google Scholar
    • Export Citation
  • 20

    González Cabrera N, Kalic AK, Antón Miguel , Sierra Polo P, Vicente Vicente . Hyperthyroidism due to Graves-Basedow disease in a woman refractory to thyroid hormones. Endocrinologia y Nutricion 2012 59 609611. (https://doi.org/10.1016/j.endonu.2011.11.014)

    • Search Google Scholar
    • Export Citation
  • 21

    Ogawa K, Yoshida M, Hayashi Y, Murata Y, Miyata M, Oiso Y. A rare case of resistance to thyroid hormone coexisting with Graves’ disease. Endocrine 2011 40 318319. (https://doi.org/10.1007/s12020-011-9491-0)

    • Search Google Scholar
    • Export Citation
  • 22

    Ramos-Leví AM, Moreno JC, Álvarez-Escolá C, Lacámara N, Montañez MC. Coexistence of thyroid hormone resistance syndrome, pituitary adenoma and Graves’ disease. Endocrinologia y Nutricion 2016 63 139141. (https://doi.org/10.1016/j.endonu.2015.12.003)

    • Search Google Scholar
    • Export Citation
  • 23

    Sato H Clinical features of primary hyperthyroidism caused by Graves’ disease admixed with resistance to thyroid hormone (P453T). Endocrine Journal 2010 57 687692. (https://doi.org/10.1507/endocrj.k10e-066)

    • Search Google Scholar
    • Export Citation
  • 24

    Shiwa T, Oki K, Awaya T, Nakanishi S, Yamane K. Resistance to thyroid hormone accompanied by Graves’ disease. Internal Medicine 2011 50 19771980. (https://doi.org/10.2169/internalmedicine.50.4904)

    • Search Google Scholar
    • Export Citation
  • 25

    Sivakumar T, Chaidarun S. Resistance to thyroid hormone in a patient with coexisting Graves’ disease. Thyroid 2010 20 213216. (https://doi.org/10.1089/thy.2009.0175)

    • Search Google Scholar
    • Export Citation
  • 26

    Sun H, Xu S, Xie S, Cao W, Chen G, Di H, Zheng R, Li X, Mao X, Liu C. Graves’ disease coexisting with resistance to thyroid hormone: a rare case. Clinical Case Reports 2018 6 337341. (https://doi.org/10.1002/ccr3.1344)

    • Search Google Scholar
    • Export Citation
  • 27

    Taniyama M, Otsuka F, Tozaki T, Ban Y. Thyroid profiles in a patient with resistance to thyroid hormone and episodes of thyrotoxicosis, including repeated painless thyroiditis. Thyroid 2013 23 898901. (https://doi.org/10.1089/thy.2012.0004)

    • Search Google Scholar
    • Export Citation
  • 28

    Nagamine T, Noh JY, Emoto N, Kogai T, Hishinuma A, Okajima F, Sugihara H. Painless destructive thyroiditis in a patient with resistance to thyroid hormone: a case report. Thyroid Research 2019 12 8. (https://doi.org/10.1186/s13044-019-0072-2)

    • Search Google Scholar
    • Export Citation
  • 29

    Clifton-Bligh RJ, de Zegher F, Wagner RL, Collingwood TN, Francois I, Van Helvoirt M, Fletterick RJ, Chatterjee VK. A novel TR beta mutation (R383H) in resistance to thyroid hormone syndrome predominantly impairs corepressor release and negative transcriptional regulation. Molecular Endocrinology 1998 12 609621. (https://doi.org/10.1210/mend.12.5.0113)

    • Search Google Scholar
    • Export Citation
  • 30

    Hayashi Y, Sunthornthepvarakul T, Refetoff S. Mutations of CpG dinucleotides located in the triiodothyronine (T3)-binding domain of the thyroid hormone receptor (TR) beta gene that appears to be devoid of natural mutations may not be detected because they are unlikely to produce the clinical phenotype of resistance to thyroid hormone. Journal of Clinical Investigation 1994 94 607615. (https://doi.org/10.1172/JCI117376)

    • Search Google Scholar
    • Export Citation
  • 31

    Pohlenz J, Manders L, Sadow PM, Kansal PC, Refetoff S, Weiss RE. A novel point mutation in cluster 3 of the thyroid hormone receptor beta gene (P247L) causing mild resistance to thyroid hormone. Thyroid 1999 9 11951203. (https://doi.org/10.1089/thy.1999.9.1195)

    • Search Google Scholar
    • Export Citation
  • 32

    Catargi B, Monsaingeon M, Bex-Bachellerie V, Ronci-Chaix N, Trouette H, Margotat A, Tabarin A, Beck-Peccoz P. A novel thyroid hormone receptor-beta mutation, not anticipated to occur in resistance to thyroid hormone, causes variable phenotypes. Hormone Research 2002 57 137142. (https://doi.org/10.1159/000057965)

    • Search Google Scholar
    • Export Citation
  • 33

    Slezak R, Lukienczuk T, Noczynska A, Karpinski P, Lebioda A, Misiak B, Sasiadek MM. A novel p.E311K mutation of thyroid receptor beta gene in resistance to thyroid hormone syndrome, inherited in autosomal recessive trait. Hormone and Metabolic Research 2012 44 704707. (https://doi.org/10.1055/s-0032-1312666)

    • Search Google Scholar
    • Export Citation
  • 34

    Ueda Y, Tagami T, Tamanaha T, Kakita M, Tanase-Nakao K, Nanba K, Usui T, Naruse M, Shimatsu A. A family of RTHβ with p.R316C mutation presenting occasional syndrome of inappropriate secretion of TSH. Endocrine Journal 2015 62 251260. (https://doi.org/10.1507/endocrj.EJ14-0422)

    • Search Google Scholar
    • Export Citation
  • 35

    Korwutthikulrangsri M, Dosiou C, Dumitrescu AM, Refetoff S. A novel G385E variant in the cold region of the T3-binding domain of thyroid hormone receptor beta gene and investigations to assess its clinical significance. European Thyroid Journal 2019 8 293297. (https://doi.org/10.1159/000503860)

    • Search Google Scholar
    • Export Citation
  • 36

    Hayashi Y, Weiss RE, Sarne DH, Yen PM, Sunthornthepvarakul T, Marcocci C, Chin WW, Refetoff S. Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors? Journal of Clinical Endocrinology and Metabolism 1995 80 32463256. (https://doi.org/10.1210/jcem.80.11.7593433)

    • Search Google Scholar
    • Export Citation
  • 37

    Kim HK, Kim D, Yoo EH, Lee JI, Jang HW, Tan AH, Hur KY, Kim JH, Kim KW & Chung JH et al.A case of resistance to thyroid hormone with thyroid cancer. Journal of Korean Medical Science 2010 25 13681371. (https://doi.org/10.3346/jkms.2010.25.9.1368)

    • Search Google Scholar
    • Export Citation
  • 38

    Paragliola RM, Lovicu RM, Locantore P, Senes P, Concolino P, Capoluongo E, Pontecorvi A, Corsello SM. Differentiated thyroid cancer in two patients with resistance to thyroid hormone. Thyroid 2011 21 793797. (https://doi.org/10.1089/thy.2010.0233)

    • Search Google Scholar
    • Export Citation
  • 39

    Ramos-Prol A, Antonia Pérez-Lázaro M, Isabel del Olmo-García M, León-de Zayas B, Moreno-Macián F, Navas-de Solis S, Merino-Torres JF. Differentiated thyroid carcinoma in a girl with resistance to thyroid hormone management with triiodothyroacetic acid. Journal of Pediatric Endocrinology and Metabolism 2013 26 133136. (https://doi.org/10.1515/jpem-2012-0230)

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