Case Reports in Endocrinology

Case Reports in Endocrinology / 2018 / Article

Case Report | Open Access

Volume 2018 |Article ID 4081769 |

Tetsuya Kimura, Yoshitaka Hayashi, Yuka Tsukamoto, Yasuyuki Okamoto, "The Mutant Thyroid Hormone Receptor Beta R320P Causes Syndrome of Resistance to Thyroid Hormone", Case Reports in Endocrinology, vol. 2018, Article ID 4081769, 3 pages, 2018.

The Mutant Thyroid Hormone Receptor Beta R320P Causes Syndrome of Resistance to Thyroid Hormone

Academic Editor: Eli Hershkovitz
Received04 Oct 2018
Accepted18 Dec 2018
Published31 Dec 2018


A 31-year-old Japanese male patient with a history of atrial fibrillation showed elevated serum levels of free thyroxine and triiodothyronine and a normal level of thyrotropin. The same abnormal hormone pattern was also found in his son. These data indicated that the index patient and the son have thyroid hormone resistance syndrome. Exon sequencing using DNA from these two patients revealed that both patients harbored a heterozygous mutation in the THRB gene: G1244C in exon 9, which results in R320P substitution. Therefore, thyroid hormone resistance syndrome caused by THRB mutation (RTHβ) was diagnosed. The mutation of the arginine to proline has not been found to date. In conclusion, herein, we have described the first case of RTHβ that is associated with R320P mutation.

1. Introduction

Thyroid hormone is required for metabolism and physiological functions in various organs such as the heart, brain, liver, and bone. Excess of thyroid hormone activity results in increased heart rate, increased nerve irritability, increased energy consumption, and osteoporosis. To exert its functions, thyroid hormone needs to bind to thyroid hormone receptor alpha (TRα) or beta (TRβ). The syndrome of resistance to thyroid hormone (RTH) is a pathologic condition in which patients show decreased sensitivity to thyroid hormone due to gene mutations [1]. In most cases of RTH, mutations occur in TRβ. TRβ that is expressed in the pituitary gland determines the set point of the serum free thyroxine (T4) level. Therefore, the decreased sensitivity of TRβ results in the compensatory increase of serum thyroid hormone level. As a result, in tissues that express TRβ predominately, decreased thyroid hormone sensitivity is balanced by the increased thyroid hormone. However, the increased thyroid hormone exhibits excessive hormonal action in tissues that express TRα, which has normal thyroid hormone sensitivity. Signs and symptoms of RTH include short stature, attention deficit disorder, and resting tachycardia [2]. The incidence of RTH is estimated to be 1 per 40,000–50,000 live births [3]. Most RTH cases show heterozygous THRB mutation and autosomal dominant inheritance. In clinical settings today, RTH is often suspected from abnormal results of thyroid function tests. Elevated serum levels of free thyroxine T4 and/or free triiodothyronine (T3) and unsuppressed thyroid-stimulating hormone (TSH) level are the cardinal features of this entity [4].

In this article, we report a familial case of RTH that is caused by the novel THRB mutation, R320P.

2. Case Presentation

A 31-year-old Japanese male patient visited our clinic to seek an expert opinion from a thyroidologist. His medical history includes atopic dermatitis and atrial fibrillation, for which he had received cardiac catheter ablation when he was 21 and 25 years old. Although his elevated serum levels of thyroid hormones were apparent at the age of 27, the precise cause had not been identified. The patient was 168 cm tall and weighed 64.8 kg (body mass index was 23.0 kg/; the ideal body weight for his height is 62.1 kg). His blood pressure was 137/79 mmHg and pulse rate was 115/min, which were regular. His laboratory data showed elevated serum levels of free T4 and free T3 and a normal level of TSH. Autoantibodies for thyroglobulin and TSH receptor were negative. Ultrasonography revealed diffuse goiter (28 ml in volume), which shows homogeneous isoechogenicity. In routine blood tests, serum levels of lipid, protein, and electrolytes were within normal ranges (Table 1).

CBCThyroid function tests
Leukocytes (×102/mm3)112Albumin (g/dL)3.8TSH (μIU/mL) [0.4-4]1.982
Neutrophils (%)59.0AST (IU/L)15Free T3 (pg/mL) [2.1-3.9]4.99
Eosinophils (%)16.1ALT (IU/L)13Free T4 (ng/dL) [0.85-1.85]2.76
Basophils (%)0γ-GTP (IU/L)18TRAb (IU/L) [<0.9]0
Lymphocytes (%)17.8LDL-Cho (mg/dL)97TgAb (IU/mL) [<5]0.51
Monocytes (%)7.1Triglyceride (mg/dL)92
Erythrocytes (×104/mm3)518HDL-Cho (mg/dL)41
Hemoglobin (g/dL)14.7BUN (mg/dL)14.9Thyroid function tests (son)
Hematocrit (%)44.1Creatinine (mg/dL)0.8TSH (μIU/mL)3.013
Platelets (×104/mm3)37.6eGFR (ml/min)95.1Free T3 (pg/mL)6.18
Na (mEq/L)137Free T4 (ng/dL)2.95
BiochemistryK (mEq/L)4.1
Total protein (g/dL)7.3Cl (mEq/L)100

Because his 33-month-old son also showed elevated serum levels of free T4 and free T3 and a normal level of TSH (Table 1), we suspected that they had RTH; therefore, we examined sequences of their THRB genes. Both the index patient and his son presented with the same heterozygous germline mutation in the THRB gene: the guanine was changed to cytosine (Figure 1). This point mutation results in the substitution of the wild-type amino acid residue arginine to proline. We could not further examine other family members, because the parents of the index patient had died and his brother and sister could not be contacted.

3. Materials and Methods

3.1. DNA Extraction and Sanger Sequencing

Informed consent was obtained from the patients. Genomic DNA was extracted from peripheral white blood cells. Exons 4 to 10 of the THRB gene were sequenced using sense and antisense primers that were previously reported [5].

3.2. Alignment Analysis

The wild-type and patients’ genome sequences were compared using GENETYX (GENETYX Corp., Shibuya-ku, Japan). The human TRβ coding sequence that was deposited to NCBI [NM_000461.4] was considered wild-type human THRB. According to the guideline for the nomenclature of THRB gene mutations [6], we determined the position of the mutant nucleotide and amino acid residue.

4. Discussion

Humans have two TR genes, THRA and THRB, which are located in chromosomes 17 and 3, respectively. Processed by alternative splicing, these two genes are expressed as four functional isoforms, namely, TRα1, TRβ1, TRβ2, and TRβ3. TRα1 is constitutively expressed at the embryonic stage and, in adults, at the highest level in the brain and the lower levels in the kidneys, skeletal muscles, lungs, heart, and liver. TRβ1 is predominantly expressed in the brain, liver, kidneys, heart, and thyroid gland, TRβ2 is mainly expressed in the thyrotroph, retina, and cochlea, and TRβ3 is predominantly expressed in the kidneys, liver, and lungs [2, 7, 8].

More than 2,000 individuals belonging to about 500 RTH families have been reported since the first THRB mutation was identified in 1989 [9]. Most of the mutations were observed in three hot spots in the ligand-binding domain (LBD) and activation function 2 (AF2) domain, namely, the 234th–264th, 316th–347th, and 429th–454th amino acid residues of TRβ [8]. These hot spots are distributed in exons 7 to 10 of the THRB gene. In this report, we showed the novel mutation R320P in TRβ. As far as we know, this mutation has not been reported to date. Arginine is a hydrophilic amino acid that has a long side chain; in contrast, proline is a hydrophobic amino acid that has a small side chain containing a 5-carbon ring. The arginine residue is located in the LBD of the TRβ protein. Other mutations at the arginine, namely, R320L [5], R320H [10], and R320C [10], were previously reported.

Since the molecular elucidation, RTH had almost always been used to describe a condition involving a mutation in the THRB gene; however, mutations in other genes have been found recently. In addition to THRB, a small fraction of RTH cases are caused by mutations in the monocarboxylate transporter 8 (MCT8) [11, 12] and SECIS-binding protein 2 (SBP2) genes [13]. Furthermore, resistance to thyroid hormone by heterozygous mutations in THRA (currently termed “RTHα”) was first reported in 2012 [14, 15]. The symptoms of RTHα include bradycardia, neurodevelopmental delay, skeletal dysplasia, dysmorphia, and constipation [14, 15]. Recent discoveries of these new mutations in RTH urged thyroidologists to revise the nomenclature of RTH; according to this revision, RTHα and RTHβ are proposed as the names of RTH caused by mutations in THRA and THRB, respectively [4].

5. Conclusion

In conclusion, we described the R320P mutation in a familial case of RTHβ. As far as we know, the proline substitution for the wild-type arginine has not been reported to date.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.


  1. S. Refetoff, L. T. DeWind, and L. J. DeGroot, “Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone,” The Journal of Clinical Endocrinology & Metabolism, vol. 27, no. 2, pp. 279–294, 1967. View at: Publisher Site | Google Scholar
  2. B. K. Singh and P. M. Yen, “A clinician's guide to understanding resistance to thyroid hormone due to receptor mutations in the TRalpha and TRbeta isoforms,” Clinical Diabetes and Endocrinology, vol. 3, no. 8, 2017. View at: Google Scholar
  3. S. H. LaFranchi, D. B. Snyder, D. E. Sesser et al., “Follow-up of newborns with elevated screening T4 concentrations,” Journal of Pediatrics, vol. 143, no. 3, pp. 296–301, 2003. View at: Publisher Site | Google Scholar
  4. S. Refetoff, J. H. Bassett, P. Beck-Peccoz et al., “Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism,” The Journal of Clinical Endocrinology & Metabolism, vol. 99, pp. 768–770, 2014. View at: Google Scholar
  5. M. Adams, C. Matthews, T. N. Collingwood, Y. Tone, P. Beck-Peccoz, and K. K. Chatterjee, “Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene,” The Journal of Clinical Investigation, vol. 94, no. 2, pp. 506–515, 1994. View at: Publisher Site | Google Scholar
  6. P. Beck-Peccoz, V. K. K. Chatterjee, W. W. Chin et al., “Nomenclature of thyroid hormone receptor beta gene mutations in resistance to thyroid hormone,” Clinical Endocrinology, vol. 40, no. 5, pp. 697–700, 1994. View at: Publisher Site | Google Scholar
  7. S.-Y. Cheng, J. L. Leonard, and P. J. Davis, “Molecular aspects of thyroid hormone actions,” Endocrine Reviews, vol. 31, no. 2, pp. 139–170, 2010. View at: Publisher Site | Google Scholar
  8. P. M. Yen, “Physiological and molecular basis of Thyroid hormone action,” Physiological Reviews, vol. 81, no. 3, pp. 1097–1142, 2001. View at: Publisher Site | Google Scholar
  9. S. Refetoff, “Resistance to thyroid hormone: One of several defects causing reduced sensitivity to thyroid hormone,” Nature Clinical Practice Endocrinology & Metabolism, vol. 4, no. 1, 2008. View at: Publisher Site | Google Scholar
  10. R. E. Weiss, M. Weinberg, and S. Refetoff, “Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene. Analysis of 15 families,” The Journal of Clinical Investigation, vol. 91, no. 6, pp. 2408–2415, 1993. View at: Publisher Site | Google Scholar
  11. A. M. Dumitrescu, X.-H. Liao, T. B. Best, K. Brockmann, and S. Refetoff, “A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene,” American Journal of Human Genetics, vol. 74, no. 1, pp. 168–175, 2004. View at: Publisher Site | Google Scholar
  12. E. C. H. Friesema, P. A. Grueters, H. Biebermann et al., “Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation,” The Lancet, vol. 364, no. 9443, pp. 1435–1437, 2004. View at: Publisher Site | Google Scholar
  13. A. M. Dumitrescu, X.-H. Liao, M. S. Y. Abdullah et al., “Mutations in SECISBP2 result in abnormal thyroid hormone metabolism,” Nature Genetics, vol. 37, no. 11, pp. 1247–1252, 2005. View at: Publisher Site | Google Scholar
  14. E. Bochukova, N. Schoenmakers, M. Agostini et al., “A mutation in the thyroid hormone receptor alpha gene,” The New England Journal of Medicine, vol. 366, no. 3, pp. 243–249, 2012. View at: Publisher Site | Google Scholar
  15. A. Van Mullem, R. Van Heerebeek, D. Chrysis et al., “Clinical phenotype and mutant TRα1,” The New England Journal of Medicine, vol. 366, no. 15, pp. 1451–1453, 2012. View at: Publisher Site | Google Scholar

Copyright © 2018 Tetsuya Kimura et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles