, Volume 13, Issue 1, pp 74–78 | Cite as

Identification of four novel mutations in the thyroid hormone receptor-β gene in 164 Spanish and 2 Greek patients with resistance to thyroid hormone

  • Antonio J. AmorEmail author
  • Irene Halperin
  • Rocío Alfayate
  • Victoria M. Borrás
  • Arancha Escribano
  • Cintia González
  • Antonio Gutiérrez
  • Montserrat Mauri
  • Pilar Pérez
  • Antonio Picó
  • Irene Vourliotaki
  • Josep Oriola
Research paper



The aim of the study was to describe the clinical, biochemical, and genetic features of a sample of Mediterranean patients with RTH (resistance to thyroid hormone) due to mutations in TRβ (thyroid hormone receptor beta) referred to our institution during the last 15 years.


166 blood samples were received for RTH genetic testing between January 1997 and December 2011. Genetic testing was performed by PCR amplification followed by sequencing of exons 7, 8, 9, and 10. Clinical and biochemical features were obtained from available information sent by referring hospitals.


Mutations were identified in 50 patients (29 probands and 21 relatives). 64% were women, and mean±stdev age at diagnosis among probands was 33.2±20.5 years. The following clinical features were recorded: goiter in 50%, hyperkinetic behavior in 32%, and tachycardia in 29%. Up to 19% of the probands had undergone some type of thyroidal ablative therapy before diagnosis. As for biochemical features, mean±stdev TSH was 10.2±21.4 mUI/L, and mean±stdev fT4 was 35.5±10.8 pmol/L. We found four new mutations: p.Phe451Leu, p.Pro452Arg, p.Glu457Gly, and p.Phe459Leu.


The clinical and biochemical characteristics of our samples of Mediterranean populations with RTH were similar to those described in the published literature. Interestingly, in our populations we have identified four novel mutations in the TRβ gene.

Key words

Mediterranean populations Resistance to thyroid hormone Thyroid hormone receptor-β gene mutations 


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  1. 1.
    Refetoff S, DeWind LT, DeGroot LJ, 1967 Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBL possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 27: 279–294.CrossRefPubMedGoogle Scholar
  2. 2.
    Refetoff S, Dumitrescu AM, 2007 Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 21: 277–305.CrossRefPubMedGoogle Scholar
  3. 3.
    Beck-Peccoz P, Persani L, Calebiro D, Bonomi M, Mannavola D, Campi I, 2006 Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis. Best Pract Res Clin Endocrinol Metab 20: 529–546.CrossRefPubMedGoogle Scholar
  4. 4.
    Refetoff S, Weiss RE, Usala SJ, 1993 The syndromes of resistance to thyroid hormone. Endocr Rev 14: 348–399.PubMedGoogle Scholar
  5. 5.
    Beck-Peccoz P, Mannavola D, Persani L, 2005 Syndromes of thyroid hormone resistance. Ann Endocrinol (Paris) 66: 264–269.CrossRefGoogle Scholar
  6. 6.
    Lafranchi SH, Snyder DB, Sesser DE, et al, 2003 Follow-up of newborns with elevated screening T4 concentrations. J Pediatr 143: 296–301.CrossRefPubMedGoogle Scholar
  7. 7.
    Usala SJ, Menke JB, Watson TL, et al, 1991 A homozygous deletion in the c-erbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Mol Endocrinol 5: 327–335.CrossRefPubMedGoogle Scholar
  8. 8.
    Takeda K, Sakurai A, DeGroot LJ, Refetoff S, 1992 Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-beta gene. J Clin Endocrinol Metab 74: 49–55.PubMedGoogle Scholar
  9. 9.
    Ferrara AM, Onigata K, Ercan O, Woodhead H, Weiss RE, Refetoff S, 2012 Homozygous thyroid hormone receptor β-gene mutations in resistance to thyroid hormone: three new cases and review of the literature. J Clin Endocrinol Metab 97: 1328–1336.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Bochukova E, Schoenmakers N, Agostini M, et al, 2012 A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 366: 243–249.CrossRefPubMedGoogle Scholar
  11. 11.
    Van Mullem A, van Heerebeek R, Chrysis D, et al, 2012 Clinical Phenotype Associated with Mutation of Thyroid Hormone Receptor-α1 (TRαl). Endocr Rev 2: 33(03_MeetingAbstracts): OR26-1.Google Scholar
  12. 12.
    Adams M, Matthews C, Collingwood TN, Tone Y, Beck-Peccoz P, Chatterjee KK, 1994 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. J Clin invest 94: 506–515.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Brucker-Davis F, Skarulis MC, Grace MB, et al, 1995 Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National institutes of Health Prospective study. Ann intern Med 123: 572–583.CrossRefPubMedGoogle Scholar
  14. 14.
    Rivolta CM, Olcese MC, Belforte FS, et al, 2009 Genotyping of resistance to thyroid hormone in South American population. Identification of seven novel missense mutations in the human thyroid hormone receptor beta gene. Mol Cel Probes 23: 148–153.CrossRefGoogle Scholar
  15. 15.
    Gómez JJL, Pomar MDB, Casariego AV, Rodríguez IC, 2009 Selective pituitary resistance to thyroid hormone in a patient treated with amiodarone. Endocrinol Nutr 56: 418–421.CrossRefPubMedGoogle Scholar
  16. 16.
    Lado Abeal J, Albero Gamboa R, Araujo Vilar D, et al, 2011 Clinical and molecular study of five families with resistance to thyroid hormones. Med Clin (Barc) 137: 551–554.CrossRefGoogle Scholar
  17. 17.
    Vlaeminck-Guillem V, Margotat A, Torresani J, D’herbomez M, Decoulx M, Wémeau JL, 2000 Resistance to thyroid hormone in a family with no TRbeta gene anomaly: pathogenic hypotheses. Ann Endocrinol (Paris) 61: 194–199.Google Scholar
  18. 18.
    Reutrakul S, Sadow PM, Pannain S, et al, 2000 Search for abnormalities of nuclear corepressors, coactivators, and a coregulator in families with resistance to thyroid hormone without mutations in thyroid hormone receptor beta or alpha genes. J Clin Endocrinol Metab 85: 3609–3617.PubMedGoogle Scholar
  19. 19.
    Mamanasiri S, Yesil S, Dumitrescu AM, et al, 2006 Mosaicism of a thyroid hormone receptor-beta gene mutation in resistance to thyroid hormone. J Clin Endocrinol Metab 91: 3471–3477.CrossRefPubMedGoogle Scholar
  20. 20.
    Weiss RE, Refetoff S, 1999 Treatment of Resistance to Thyroid Hormone—Primum Non Nocere. J Clin Endocrinol Metab 84: 401–404.PubMedGoogle Scholar
  21. 21.
    Anzai R, Adachi M, Sho N, Muroya K, Asakura Y, Onigata K, 2012 Long-term 3,5,3′-triiodothyroacetic acid therapy in a child with hyperthyroidism caused by thyroid hormone resistance: pharmacological study and therapeutic recommendations. Thyroid 22: 1069–1075.CrossRefPubMedGoogle Scholar
  22. 22.
    Mohammed IA, Aldasouqi S, Schnute R, Refetoff S, Weiss RE, Iqbal N, 1998 The syndrome of resistance to thyroid hormone, misdiagnosed and treated as thyrotoxicosis. Endocr Pract 4: 391–395.CrossRefPubMedGoogle Scholar
  23. 23.
    Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S, 2010 Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 95: 3189–3193.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Gavin C, Meggison H, Ooi TC, 2008 Proposing a causal link between thyroid hormone resistance and primary autoimmune hypothyroidism. Med Hypotheses 70: 1024–1028.CrossRefPubMedGoogle Scholar
  25. 25.
    Yagi H, Pohlenz J, Hayashi Y, Sakurai A, Refetoff S, 1997 Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3′-triiodothyroinine binding affinity. J Clin Endocrinol Metab 82: 1608–1014.PubMedGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2014

Authors and Affiliations

  • Antonio J. Amor
    • 1
    Email author
  • Irene Halperin
    • 1
  • Rocío Alfayate
    • 3
  • Victoria M. Borrás
    • 4
  • Arancha Escribano
    • 5
  • Cintia González
    • 6
  • Antonio Gutiérrez
    • 5
  • Montserrat Mauri
    • 3
  • Pilar Pérez
    • 7
  • Antonio Picó
    • 3
  • Irene Vourliotaki
    • 8
  • Josep Oriola
    • 2
  1. 1.Endocrinology and Nutrition DepartmentHospital Clínic i UniversitariBarcelonaSpain
  2. 2.Biochemistry and Molecular Genetics DepartmentHospital Clínic i UniversitariBarcelonaSpain
  3. 3.Endocrinology and Nutrition DepartmentHospital General UniversitarioAlicanteSpain
  4. 4.Pediatrics DepartmentHospital General de GranollersBarcelonaSpain
  5. 5.Pediatrics DepartmentHospital Virgen de la ArrixacaMurciaSpain
  6. 6.Endocrinology and Nutrition DepartmentHospital Sant PauBarcelonaSpain
  7. 7.Pediatrics DepartmentHospital Marina BaixaAlicanteSpain
  8. 8.Endocrinology and Metabolism DepartmentVenizelio General HospitalHeraklio, CreteGreece

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