Syndromes of Resistance to Thyroid Hormone: Clinical Aspects

  • Deborah Mannavola
  • Paolo Beck-Peccoz
Part of the Endocrine Updates book series (ENDO, volume 22)


Resistance to thyroid hormone (RTH) is a rare syndrome caused by a molecular defect of the thyroid hormone receptor β (TRβ) leading to a decreased responsiveness of target tissues to the action of thyroid hormones. Despite of the specific biochemical presentation, characterized by elevated thyroid hormone levels in the presence of detectable concentration of TSH, the resulting clinical phenotype is extremely variable. Early recognition of RTH is mandatory, since its diagnostic procedures, as well as its management and follow-up differs from that of other forms of hyperthyroidism, i.e. TSH-secreting pituitary adenoma, Graves’ disease and uni- or multinodular toxic goiter. The increasing awareness of the existence of RTH syndrome along with the introduction of ultrasensitive immunometric TSH assay led to duplicate the number of reported new cases every 5 years (Figure 1). In fact, since the first case described in 1967 (1), more than 700 individuals with RTH belonging to about 250 unrelated families have been identified up to day (2, 3). RTH patients have been described all over the world, without apparent geographical and ethnic predominance or preferential sex distribution. The use of TSH measurement, rarely associated with that of total T4, in the neonatal screening for congenital hypothyroidism does not help to understand the real prevalence of RTH, which is indirectly estimated to be around 1 in 50,000 live births (4).


Thyroid Hormone Congenital Hypothyroidism Thyroid Hormone Receptor Thyroid Hormone Level Thyroid Hormone Action 
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  1. 1.
    Refetoff S, DeWind LT, DeGroot LJ. 1967 Familial syndrome combining deaf- mutism, stippled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocr. 27: 279–294.PubMedCrossRefGoogle Scholar
  2. 2.
    Refetoff S, Weiss RE, Usala S. 1993 The syndromes of resistance to thyroid hormone. Endocr Rev. 14: 384–399.Google Scholar
  3. 3.
    Snyder D, Sesser D, Skeels M, Nelson G, LaFranchi S. 1997 Thyroid disorders in newborn infants with elevated screening T4. Thyroid (abstract) 7, suppl 1: S-29Google Scholar
  4. 4.
    Wong GWK, Shek CC, Lam STS, Tsui MKM, Leung SSF. 1995 Detection of resistance to thyroid hormone by cord blood screening. Acta Pediatr. 84: 335–336.CrossRefGoogle Scholar
  5. 5.
    Gershengom MC, Weintraub BD. 1975 Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone: a new syndrome of “inappropriate secretion of TSH”. J Clin Invest. 56: 633–642.CrossRefGoogle Scholar
  6. 6.
    Faglia G, Beck-Peccoz P, Piscitelli G, Medri G. 1987 Inappropriate secretion of thyrotropin by the pituitary. Horm Res. 26: 79–99.PubMedCrossRefGoogle Scholar
  7. 7.
    Kaplan MM, Swartz SL, Larsen PR. 1981 Partial peripheral resistance to thyroid hormone. Am J Med. 70: 1115–1121.PubMedCrossRefGoogle Scholar
  8. 8.
    Announcement. 1994 A registry for resistance to thyroid hormone resistance. Mol Endocrinol. 8: 1558.Google Scholar
  9. 9.
    Adams M, Matthews C, Collingwood TN, Tone Y, Beck-Peccoz P, Chatterjee VKK. 1994 Genetic analisis of 29 kindreds with generalized and pituitary resistence to thyroid hormone. Identification of thirteen novel mutations in the hormone receptor ß gene. J Clin Invest. 94: 506–515.PubMedCrossRefGoogle Scholar
  10. 10.
    Brucker-Davis F, Scarulis MC, Grace MB, Benichou J, Hauser P, Weintraub BD. 1995 Genetic and clinical features in 42 kindreds with resistance to thyroid hormone. Ann Intern Med. 123: 572–583.PubMedGoogle Scholar
  11. 11.
    Beck-Peccoz P, Mannavola D, Asteria C. 1997 Resistance to thyroid hormone. In Contemporary Endocrinology: diseases of the thyroid. Editor Braverman LE. Humana Press, Totowa, NJ. pp: 199–239.Google Scholar
  12. 12.
    Beck-Peccoz P, Chatterjee VKK. 1994 The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid. 4: 225–231.PubMedCrossRefGoogle Scholar
  13. 13.
    Usala SJ, Bale AE, Gesundheit N, et al. 1988 Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbAß gene. Mol Endocrinol 2: 1217–1220.PubMedCrossRefGoogle Scholar
  14. 14.
    Beck-Peccoz P, Chatterjee VKK, Chin WW, et al. 1994 Nomenclature of thyroid hormone receptor ß-gene mutations in resistance to thyroid hormone: consensusstatement from the First Workshop on Thyroid Hormone Resistance, July 10 – 11,1993, Cambridge, United Kingdom. J Clin Endocrinol Metab. 78: 990–993.PubMedCrossRefGoogle Scholar
  15. 15.
    Hayashi Y, Weiss RE, Same DH, et al. 1995 Do clinical manifestation of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-13 receptors? J Clin Endocrinol Metab. 80: 3246–3256.PubMedCrossRefGoogle Scholar
  16. 16.
    Yoh SM, Chatterjee VKK and Privalsky ML. 1997 Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptor and transcriptional corepressors. Mol Endocrinol 11: 470–480.PubMedCrossRefGoogle Scholar
  17. 17.
    Liu Y, Takeshita A, Misiti S, et al. 1998 Lack of coactivators interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors. Endocrinology 139: 4197–4204.PubMedCrossRefGoogle Scholar
  18. 18.
    Yen PM, Chin WW. 1994 Molecular mechanism of dominant negative activity by nuclear hormone receptors. Mol Endo. 8: 1450–1454.CrossRefGoogle Scholar
  19. 19.
    Chatterjee VKK, Nagaya T, Madison L, Datta S, Rentoumis A, Jameson J. 1991 Thyroid hormone resistance syndrome. Inhibition of normal receptor function by mutant thyroid hormone receptors. J Clin Invest. 87: 1977–1784.PubMedCrossRefGoogle Scholar
  20. 20.
    Jameson JL. 1994 Mechanism by which thyroid hormone receptor mutations cause clinical syndromes of resistance to thyroid hormone. Thyroid 4: 485–492PubMedCrossRefGoogle Scholar
  21. 21.
    Weiss RE, Weinberg M, Refetoff S. 1993 Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene. J Clin Invest. 91: 2408–2415.PubMedCrossRefGoogle Scholar
  22. 22.
    Safer JD, O’Connor MG, Colan SD, Srinivasan S, Tollin SR, Wondisford FE. 1999 The thyroid hormone receptor-beta gene mutation R383H is associated with isolated central resistance to thyroid hormone. J Clin Endocinol Metab 84: 3099–3109.CrossRefGoogle Scholar
  23. 23.
    Kahaly JG, Matthews CH, Mohr-Kahaly S, Richards CA, Chatterjee VKK. 2002 Cardiac involvement in Thyroid hormone resistance. J Clin Endocrinol and Metab 87: 204–212.CrossRefGoogle Scholar
  24. 24.
    Same D, Refetoff S, Rosenfield R, Farriaux J. 1988 Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration. J Clin Endocrinol Metab. 66: 740–746.CrossRefGoogle Scholar
  25. 25.
    Persani L, Asteria C, Tonacchera M, et al. 1994 Evidence for the secretion of thyrotropin with enhanced bioactivity in syndromes of thyroid hormone resistance. J Clin Endocrinol Metab. 78: 1034–1039.PubMedCrossRefGoogle Scholar
  26. 26.
    Calvo R, Obregon MJ, Escobar del Rey F, Morreale de Escobar G. 1992 The rat placenta and the transfer of thyroid hormones from the mother to the fetus: effects of maternal thyroid status. Endocrinology. 131: 357–363.PubMedCrossRefGoogle Scholar
  27. 27.
    De Meirleir K, Golstein J, jonckheer MH, Vanhaelst L. 1980 Hypothyroidism with normal thyroid hormone levels as a consequence of autoimmune thyroiditis and peripheral resistance to thyroid hormone. Acta Clin Belg. 35: 107–109.PubMedGoogle Scholar
  28. 28.
    Mannavola D, Romoli R, Attard M, et al. 1997 Uncommon association of thyroid hormone resistance, papillary carcinoma and pituitary macroadenoma in a 64-yr old woman. The Third Workshop on Resistance to Thyroid Hormone. Aspen, Colorado (USA). October 12–13, (Abstract book).Google Scholar
  29. 29.
    Taniyama M, Ishikawa N, Momotani N, Ito K, Ban Y. 2001 Toxic multinodular goitre in a patient with generalized resistance to thyroid hormone who harbours the R429Q mutation in the thyroid hormone receptor 13 gene. Clin Endocrinol 54: 121–124CrossRefGoogle Scholar
  30. 30.
    Bantle JP, Seeling S, Mariash CN, Ulstrom RA, Oppenheimer JH. 1982 Resistance to thyroid hormones: a disorder frequently confused with Graves’ disease. Arch Intern Med. 142: 1867–1871.PubMedCrossRefGoogle Scholar
  31. 31.
    Refetoff S, Salazar A, Smith TJ, Scherberger NH. 1983 The consequences of inappropriate treatment because of failure to recognize the syndrome of pituitary and peripheral tissue resistance to thyroid hormone. Metabolism. 32: 822–834.PubMedCrossRefGoogle Scholar
  32. 32.
    Hopwood NJ, Sauder SE, Shapiro B, Sisson JC. 1986 Familial partial peripheral and pituitary resistance to thyroid hormone: a frequently missed diagnosis? Pediatrics. 78: 1114–1122.PubMedGoogle Scholar
  33. 33.
    Weiss RE, Refetoff S. 1996 Effect of thyroid hormone on growth: lesson learned from the syndrome of resistance to thyroid hormone. Endocrinol Metab Clin North Am 25: 719–730.PubMedCrossRefGoogle Scholar
  34. 34.
    Chatterjee VKK, Beck-Peccoz P. 2001 Resistance to Thyroid Hormone in Endocrinology (4th Edition, vol 2). Edited by DeGroot LJ and Jameson LJ. W.B. Sauderns Company Philladelphia, Pennsilvania.Google Scholar
  35. 35.
    Mixson AJ, Parilla R, Ransom SC, et al. 1992. Correlation of language abnormalities with localization of mutations in 13 kindreds with generalised resistance to thyroid hormone: Identification of four new mutations. J. Clin. Endocrinol. Metab. 75: 1039–1045.PubMedCrossRefGoogle Scholar
  36. 36.
    Hauser P, Zametkin, AL, Martinez P, et al. 1993. Attention deficit-hyperactivity disorder in people with generalised resistance to thyroid hormone. N. Engl. J. Med. 328: 997–1001.PubMedCrossRefGoogle Scholar
  37. 37.
    Elia J, Gulotta C, Rose SR, Mann G, Rapoport J. 1994 Thyroid function and attention-deficif hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 33: 169–172.PubMedCrossRefGoogle Scholar
  38. 38.
    Weiss RE, Stein M, Duck S, et al. 1994 Low intelligence but not attention deficit hyperactivity disorder is associated with resistence to thyroid hormone caused by mutation R316H in the thyroid hormone receptor beta-gene. J Clin Endocr Metab. 78: 1525–1528.PubMedCrossRefGoogle Scholar
  39. 39.
    Spencer T, Biederman J, Wilens T, Guite J, Harding M. 1995 ADHD and thyroid abnormalities: a research note. J Child Psychol Psychiat. 36: 879–885.PubMedCrossRefGoogle Scholar
  40. 40.
    Leonard CM, Martinez P, Weintraub BD, Hauser P. 1995 Magnetic resonance imaging of cerebral anomalies in subjects with resistance to thyroid hormone. Am J Med Genet 60: 238–243PubMedCrossRefGoogle Scholar
  41. 41.
    Hauser P, Mc Millin JM, Bhatara VS. 1998 Resistance to thyroid hormone: implications for neurodevelopmental research on effects of thyroid hormone disruptors. Toxicology and Industrial Health 14: 85–101PubMedGoogle Scholar
  42. 42.
    Deol MS. 1976 The role of thyroxine in the differentiation of the organ of Corti. Acta Otolaryngol. 81: 429–35.PubMedGoogle Scholar
  43. 43.
    Brucker-Davis F, Skarulis MC, Pikus A, et al. 1996 Prevalence and Mechanism of hearing loss in patients with resistance to thyroid hormone. J Clin Endocrinol and Metab 81: 2768–2772.CrossRefGoogle Scholar
  44. 44.
    Bradley DJ, Twole HC, Young WS. 1994 α and β thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform specific transcripional regulatin in vivo. Proc Natl Acad Sci USA. 91: 439–443.PubMedCrossRefGoogle Scholar
  45. 45.
    Forrest D, Hanebuth E, Smeyne RJ, et al. 1996 Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue- specific modulation of receptor function. EMBO J. 15:3006–3015.PubMedGoogle Scholar
  46. 46.
    Forrest D, Erway LC, Ng L, Altschuler R, Curran T. 1996 Thyroid hormone receptor ß is essential for development of auditory function. Nature Genet. 13: 354–357.PubMedCrossRefGoogle Scholar
  47. 47.
    Watanabe K, Kameya T, Yamauchi A, et al. 1993 Thyrotropin-producing adenoma associated with pituitary resistance to thyroid hormone. J Clin Endocrinol Metab 76:1025–1030PubMedCrossRefGoogle Scholar
  48. 48.
    Gurnell M, Rajanayagam O, Barbar I et al. 1998 Reversible pituitary enlargement in the syndrome of resistance to thyroid hormone. Thyroid 8: 679–682.PubMedCrossRefGoogle Scholar
  49. 49.
    Ando S, Sarlis NJ, Oldfield EH, Yen PM. 2001 Somatic mutation of TRß can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor J Clin Endocrinol Metab 86: 5572–5576PubMedCrossRefGoogle Scholar
  50. 50.
    Ando S, Sarlis NJ, Krishnan I, et al. 2001 Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance Mol Endocrinol 15: 1529–1538.PubMedCrossRefGoogle Scholar
  51. 51.
    Mannavola D, Vannucchi G, Fugazzola L, et al. 2001 Resistance to thyroid hormone (RTH) and pituitary lesions: two related disorders? 5th workshop on thyroid hormone resistance. Villa Caramora-Como Italy 6th-8th June. (Abstract book).Google Scholar
  52. 52.
    Lemarchand-Béraud TH, Holm AC, Scazziga BR. 1977 Triiodothyronine and thyroxine nuclear receptors in lymphocytes from normal, hyper- and hypothyroid subjects. Acta Endocrinol (Copenh) 85: 44–54.Google Scholar
  53. 53.
    Usala SJ, Menke JB, Watson TL, et al. 1991 A homozygous deletion in the c-erbAß thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Mol Endocrinol 5: 327–335PubMedCrossRefGoogle Scholar
  54. 54.
    Ono S, Schwartz I, Mueller 0, Root A, Usala S, Bercu B. 1991 Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized thyroid hormone resistance. J Clin Endocrinol Metab. 73: 990–994.PubMedCrossRefGoogle Scholar
  55. 55.
    Ekins R. 1990 Measurement of free hormones in blood. Endocr Rev. 11: 4–5.CrossRefGoogle Scholar
  56. 56.
    Beck-Peccoz P, Piscitelli G, Cattaneo MG, et al. 1984 Evaluation of free thyroxine methods in the presence of iodiothyronine binding autoantibodies. J Clin Endocrinol Metab. 58: 736–739PubMedCrossRefGoogle Scholar
  57. 57.
    Beck-Peccoz P, Persani L, Faglia G. 1992 Glycoprotein hormone a-subunit in pituitary adenomas. Trends Endocrinol Metab 3: 41–45.PubMedCrossRefGoogle Scholar
  58. 58.
    Weiss RE and Refetoff S. Resistance to thyroid hormone. In Reviews in Endocrine & Metabolic Disorder 2000; 1: 97–108. Kluwer Academic Publisher, Boston.Google Scholar
  59. 59.
    Beck-Peccoz P, Piscitelli G, Cattaneo MG, et al. 1983 Successful treatment of hyperthyroidism due to nonneoplastic pituitary TSH hypersecretion with 3,5,3’- triiodothyroacetic acid (TRIAC). J Endocrinol Invest. 6: 217–223.PubMedGoogle Scholar
  60. 60.
    Takeda T, Suzuki S, Liu RT, DeGroot LJ. 1995 Triiodothyroacetic acid has unique potential for therapy of resistance to thyroid hormone. J Clin Endocrinol Metab. 80: 2033–2040.PubMedCrossRefGoogle Scholar
  61. 61.
    Dorey F, Strauch G, Gayno JP. 1990 Thyrotoxicosis due to pituitary resistance to thyroid hormones. Successful control with D-thyroxine: a study in three patients. Clin Endocrinol (Oxf). 32: 221–227.CrossRefGoogle Scholar
  62. 62.
    Hamon P, Bovier-Lapierre M, Robert M, Peynaud D, Pugeat M, Orgiazzi J. 1988 Hyperthyroidismdue to selective pituitary resistance to thyroid hormones in a 15- month-old boy: efficacy of D-thyroxine therapy. J Clin Endocrinol Metab. 67:1089 – 1093PubMedCrossRefGoogle Scholar
  63. 63.
    Magner JA, Petrick P, Menezes-Ferreira MM, Stelling M, Weintraub BD. 1986 Familial generalized resistance of thyroid hormones: report of three kindreds and correlation of patterns of affected tissues with the binding of [125 Ijtriiodothyronine to fibroblast nuclei. J Endocrinol Invest. 9: 459–469.PubMedGoogle Scholar
  64. 64.
    Asteria C, Rajanayagam O, Collingwood TN et al. 1999 Prenatal diagnosis of thyroid hormone resistance. J Clin Endocrinol Metab 84: 405–410.PubMedCrossRefGoogle Scholar
  65. 65.
    Cortelazzi D, Morpurgo PS, Zamperini P et al. 1999 Maternal compound W serial measurements for the managements of fetal hypothyroidism. Eur J Endocrinol 141: 570–578.PubMedCrossRefGoogle Scholar
  66. 66.
    Chiellini G, Apriletti JW, Yoshihara HA et al. 1998 A high-affinity subtype selective agonist ligand for thyroid hormone receptor. Chem Biol 5: 299–306.PubMedCrossRefGoogle Scholar
  67. 67.
    Ye HF, O’Reilly KE, Koh JT. 2001 A subtype-selective thyromimetic designed to bind a mutant thyroid hormone receptor implicated in resistance to thyroid hormone. J Am Chem Soc 123: 1521–1522.PubMedCrossRefGoogle Scholar
  68. 68.
    Schapira M, Raaka BM, Das S, et al. 2003 Discovery of diverse thyroid hormone receptor antagonist by high-throughput docking. Pnas 100: 7354–7359.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Deborah Mannavola
    • 1
  • Paolo Beck-Peccoz
    • 1
  1. 1.Institute of Endocrine Sciences, Ospedale Maggiore IRCCSUniversity of MilanMilanItaly

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