Resistance to Thyroid Hormone (RTH) and Resistance to TSH (RTSH)

  • Alexandra M. Dumitrescu
  • Ronald N. Cohen


Resistance to thyroid hormone (RTH) is a syndrome characterized by variable tissue hyporesponsiveness to thyroid hormone (TH). Mutations in both TH receptors (THRA and THRB) isoforms have been identified and manifest different phenotypes of RTH, RTH-alpha, and RTH-beta. Patients with the RTH-beta phenotype seek medical attention for goiter, abnormal thyroid function tests (TFTs), or through neonatal screening programs. Biochemically, RTH-beta is characterized by elevated TH values in the setting of non-suppressed thyrotropin (TSH) levels. Resistance at the level of the hypothalamus and pituitary leads to elevated TSH, which stimulates the thyroid gland to increase production of TH; however, reduced action elsewhere results in compensated TH hyporesponsiveness to a lesser or greater degree depending on the predominant TH receptor (TR) isoform in the tissue, alpha (α) or beta (β). THRA gene mutations have remained elusive until recently. The first case of RTH-α was identified through whole genome sequencing. Because TRα is not involved in the feedback regulation of the hypothalamic-pituitary-thyroid axis, the TFTs are different from patients with RTH-β, namely, low or normal T4, high normal T3, and normal or slightly elevated TSH. These mild thyroid abnormalities lead patients to present themselves in non-endocrinological clinical departments.

The phenotype of resistance to TSH is characterized by high serum TSH in the absence of goiter. Patients are often identified at birth through neonatal screening for congenital hypothyroidism. Affected individuals have normal or hypoplastic thyroid glands, high serum TSH, and normal or low serum T4 and T3, and symptoms range from euthyroid hyperthyrotropinemia to overt hypothyroidism.


Thyroid hormone receptor Resistance to thyroid hormone RTH-beta RTH-alpha Non-TR RTH Thyrotropin (TSH) TSH receptor Thyroid function tests Mutation Development MCT8 SBP2 Deiodinases 


  1. 1.
    Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stippled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocr. 1967;27:279–94.PubMedCrossRefGoogle Scholar
  2. 2.
    Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev. 1993;14:348–99.PubMedGoogle Scholar
  3. 3.
    Flamant F, Samarut J. Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab. 2003;14(2):85–90.PubMedCrossRefGoogle Scholar
  4. 4.
    Refetoff S. Resistance to thyroid hormone. Werner and Ingbar’s the thyroid: a fundamental and clinical text. In: Braverman LE, Utiger RD, editors. Philadelphia: Lippincott, Williams, and Wilkins; 2000. p. 1028–43.Google Scholar
  5. 5.
    Vlaeminck-Guillem V, Espiard S, Flamant F, Wemeau JL. TRalpha receptor mutations extend the spectrum of syndromes of reduced sensitivity to thyroid hormone. Presse Med. 2015;44(11):1103–12.PubMedCrossRefGoogle Scholar
  6. 6.
    Fraichard A, Chassande O, Plateroti M, Roux JP, Trouillas J, Dehay C, Legrand C, Gauthier K, Kedinger M, Malaval L, Rousset B, Samarut J. The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production. EMBO J. 1997;16(14):4412–20.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Wikstrom L, Johansson C, Salto C, Barlow C, Campos Barros A, Baas F, Forrest D, Thoren P, Vennstrom B. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J. 1998;17(2):455–61.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Vennstrom B, Mittag J, Wallis K. Severe psychomotor and metabolic damages caused by a mutant thyroid hormone receptor alpha 1 in mice: can patients with a similar mutation be found and treated? Acta Paediatr. 2008;97(12):1605–10.PubMedCrossRefGoogle Scholar
  9. 9.
    Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe JW, Bain M, Lindley K, Muntoni F, Vargha-Khadem F, Dattani M, Farooqi IS, Gurnell M, Chatterjee K. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2012;366(3):243–9.PubMedCrossRefGoogle Scholar
  10. 10.
    van Mullem A, van Heerebeek R, Chrysis D, Visser E, Medici M, Andrikoula M, Tsatsoulis A, Peeters R, Visser TJ. Clinical phenotype and mutant TRalpha1. N Engl J Med. 2012;366(15):1451–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31(2):139–70.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umeseno K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. Overview: the nuclear receptor superfamily: the second decade. Cell. 1995;83:835–40.PubMedCrossRefGoogle Scholar
  13. 13.
    Katz RW, Subauste JS, Koenig RJ. The interplay of half-site sequence and spacing on the activity of direct repeat thyroid hormone response elements. J Biol Chem. 1995;270(10):5238–42.PubMedCrossRefGoogle Scholar
  14. 14.
    Umesono K, Murakami KK, Thompson CC, Evans RM. Direct repeats as selective response elements for the thyroid hormone, retinoic acid and vitamin D3 receptors. Cell. 1991;65:1255–66.PubMedCrossRefGoogle Scholar
  15. 15.
    Bodenner DL, Mrocynski MA, Weintraub BD, Radovick S, Wondisford FE. A detailed functional and structural analysis of a major thyroid inhibitory element in the human thyrotropin ß-subunit gene. J Biol Chem. 1991;266:21666–73.PubMedGoogle Scholar
  16. 16.
    Hollenberg AN, Monden T, Flynn TR, Boers M-E, Cohen O, Wondisford FE. The human thyrotropin-releasing hormone gene is regulated by thyroid hormone through two distinct classes of negative thyroid hormone response elements. Mol Endocrinol. 1995;10:540–50.Google Scholar
  17. 17.
    Tomie-Canie M, Day D, Samuels HH, Freedberg IM, Blumenberg M. Novel regulation of keratin gene expression by thyroid hormone and retinoid receptors. J Biol Chem. 1996;271(3):1416–23.CrossRefGoogle Scholar
  18. 18.
    Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors [see comments]. Nature. 1995;377(6548):454–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor [see comments]. Nature. 1995;377(6548):397–404.PubMedCrossRefGoogle Scholar
  20. 20.
    Ordentlich P, Downes M, Xie W, Genin A, Spinner NB, Evans RM. Unique forms of human and mouse nuclear receptor corepressor SMRT. Proc Natl Acad Sci U S A. 1999;96(6):2639–44.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Park EJ, Schroen DJ, Yang M, Li H, Li L, Chen JD. SMRTe, a silencing mediator for retinoid and thyroid hormone receptors- extended isoform that is more related to the nuclear receptor corepressor. Proc Natl Acad Sci U S A. 1999;96(7):3519–24.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Sande S, Privalsky ML. Identification of TRACs (T3 receptor-associating cofactors), a family of cofactors that associate with and modulate the activity of, nuclear hormone receptors. Mol Endocrinol. 1996;10:813–25.PubMedGoogle Scholar
  23. 23.
    Seol W, Choi HS, Moore DD. Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan nuclear receptors. Mol Endocrinol. 1995;9:72–85.PubMedGoogle Scholar
  24. 24.
    Alland L, Muhle R, Hou HJ, Potes J, Chin L, Schreiber-Agus N, DePinho RA. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature. 1997;387:49–55.PubMedCrossRefGoogle Scholar
  25. 25.
    Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression [see comments]. Nature. 1997;387(6628):43–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Nagy L, Kao H-K, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, Evans RM. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell. 1997;89:373–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Feng W, Ribeiro RCJ, Wagner RL, Nguyen H, Apriletti JW, Fletterick RJ, Baxter JD, Kushner PJ, West BL. Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science. 1998;280:1747–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan X-Y, Sauter G, Kallioniemi O-P, Trent JM, Meltzer PS. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Nature. 1997;277:965–8.Google Scholar
  29. 29.
    Cavailles V, Dauvois S, L’Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 1995;14:3741–51.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Chen H, Lin RJ, Schlitz RL, Chakravarti D, Nash A, Nagy L, Privalsky M, Nakatani Y, Evans RM. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell. 1997;90:569–80.PubMedCrossRefGoogle Scholar
  31. 31.
    Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996;85(3):403–14.PubMedCrossRefGoogle Scholar
  32. 32.
    Monden T, Wondisford FE, Hollenberg AN. Isolation and characterization of a novel ligand-dependent thyroid hormone receptor-coactivating protein. J Biol Chem. 1997;272(47):29834–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Onate SA, Tsai SY, Tsai M-J, O'Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995;270:1354–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Takeshita A, Yen PM, Misiti S, Cardona GR, Liu Y, Chin WW. Molecular cloning and properties of a full-length putative thyroid hormone receptor coactivator. Endocrinology. 1996;137:3594–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG. The transcriptional co-activator p/CIP binds CBP and mediates nuclear receptor function. Nature. 1997;387:677–84.PubMedCrossRefGoogle Scholar
  36. 36.
    Voegel JJ, Heine MJS, Zechel C, Chambon P, Gronemeyer H. TIF2, a 160 KD transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J. 1996;15:3667–75.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Sap J, Munoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, Beug H, Vennstrom B. The c-erb-A gene protein is a high-affinity receptor for thyroid hormone. Nature. 1986;324:635–40.CrossRefPubMedGoogle Scholar
  38. 38.
    Weinberger C, Thompson CC, Ong ES, Lebo R, Gruol DJ, Evans RM. The c-erb-A gene encodes a thyroid hormone receptor. Nature. 1986;324:641–6.CrossRefPubMedGoogle Scholar
  39. 39.
    Plateroti M, Gauthier K, Domon-Dell C, Freund JN, Samarut J, Chassande O. Functional interference between thyroid hormone receptor alpha (TRalpha) and natural truncated TRDeltaalpha isoforms in the control of intestine development. Mol Cell Biol. 2001;21(14):4761–72.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Williams GR. Cloning and characterization of two novel thyroid hormone receptor beta isoforms. Mol Cell Biol. 2000;20:8329–42.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Weiss RE. “They have ears but do not hear” (Psalms 135:17): non-thyroid hormone receptor beta (non-TRbeta) resistance to thyroid hormone. Thyroid. 2008;18(1):3–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Weiss RE, Hayashi Y, Nagaya T, Petty KJ, Maruta Y, Tunca H, Seo H, Refetoff S. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor a or b genes may be due to a defective cofactor. J Clin Endocrinol Metab. 1996;81:4196–203.PubMedGoogle Scholar
  43. 43.
    Reutrakal S, Sadow PM, Pannain S, Pohlenz J, Carvalhos GA, Macchia PE, Weiss RE, Refetoff S. Search for abnormalities of nuclear corepressors, coactivators, and a coregulator in families with resistance to thyroid hormone without mutations in thyroid hormone receptor b or a genes. J Clin Endocrinol Metab. 2000;85:3609–17.Google Scholar
  44. 44.
    Romeo S, Menzaghi C, Bruno R, Sentinelli F, Fallarino M, Fioretti F, Filetti S, Balsamo A, Di Mario U, Baroni MG. Search for genetic variants in the retinoid X receptor-gamma-gene by polymerase chain reaction-single-strand conformation polymorphism in patients with resistance to thyroid hormone without mutations in thyroid hormone receptor beta gene. Thyroid. 2004;14(5):355–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Mamanasiri S, Yesil S, Dumitrescu AM, Liao XH, Demir T, Weiss RE, Refetoff S. Mosaicism of a thyroid hormone receptor-beta gene mutation in resistance to thyroid hormone. J Clin Endocrinol Metab. 2006;91(9):3471–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Collingwood TN, Wagner R, Matthews CH, Clifton-Bligh RJ, Gurnell M, Rajanayagam O, Agostini M, Fletterick RJ, Beck-Peccoz P, Reinhardt W, Binder G, Ranke MB, Hermus A, Hesch RD, Lazarus J, Newrick P, Parfitt V, Raggat P, de Zegher F, Chatterjee VKK. A role for helix 3 of the TRb ligand-binding domain in coactivator recruitment identified by characterization of a third cluster of mutations in resistance to thyroid hormone. EMBO J. 1998;17:4760–70.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Safer JD, Cohen RN, Hollenberg AN, Wondisford FE. Defective release of corepressor by hinge mutants of the thyroid hormone receptor found in patients with resistance to thyroid hormone. J Biol Chem. 1998;273(46):30175–82.PubMedCrossRefGoogle Scholar
  48. 48.
    Collingwood TN, Rajanayagam O, Adams M, Wagner R, Cavailles V, Kalkhoven E, Matthews C, Nystrom E, Stenlof K, Lindstedt G, Tisell L, Fletterick RJ, Parker MG, Chatterjee VK. A natural transactivation mutation in the thyroid hormone beta receptor: impaired interaction with putative transcriptional mediators. Proc Natl Acad Sci U S A. 1997;94(1):248–53.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Yoh SM, Chatterjee VK, Privalsky ML. Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. Mol Endocrinol. 1997;11(4):470–80.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Nagaya T, Jameson JL. Thyroid hormone receptor dimerization is required for dominant negative inhibition by mutations that cause thyroid hormone resistance. J Biol Chem. 1993;268:15766–71.PubMedGoogle Scholar
  51. 51.
    Nagaya T, Madison LD, Jameson JL. Thyroid hormone receptor mutants that cause resistance to thyroid hormone. JBC. 1992;267:13014–9.Google Scholar
  52. 52.
    Forrest D, Hanebuth E, Smeyne RJ, Everds N, Stewart CL, Wehner JM, Curran T. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function. EMBO J. 1996;15(12):3006–15.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Hashimoto K, Curty FH, Borges PB, Lee CE, Abel ED, Elmquist JE, Cohen RN, Wondisford FE. An unliganded thyroid hormone receptor causes severe neurological dysfunction. Proc Natl Acad Sci U S A. 2001;98:3998–4003.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kaneshige M, Kaneshige K, Xhu X, Dace A, Garrett L, Carter TA, Kazlauskaite R, Pankretz DG, Wynshaw-Boris A, Refetoff S, Weintraub B, Willingham MC, Barlow C, Cheng S. Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance to thyroid hormone. Proc Natl Acad Sci U S A. 2000;97:13209–14.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab. 2007;21(2):277–305.PubMedCrossRefGoogle Scholar
  56. 56.
    Weiss RE, Refetoff S. Editorial: treatment of resistance to thyroid hormone – primum non nocere. J Clin Endocrinol Metab. 1999;84:401–3.PubMedGoogle Scholar
  57. 57.
    Safer JD, O'Connor MG, Colan SD, Srinivasan S, Tollin SR, Wondisford FE. The thyroid hormone receptor-b mutation R383H is associated with isolated central resistance to thyroid hormone. J Clin Endocrinol Metab. 1999;84:3099–109.PubMedGoogle Scholar
  58. 58.
    Safer JD, Langlois MF, Cohen R, Monden T, John-Hope D, Madura JP, Hollenberg AN, Wondisford FE. Isoform variable action among thyroid hormone receptor mutants provides insight into pituitary resistance to thyroid hormone. Mol Endocrinol. 1997;11:16–26.PubMedCrossRefGoogle Scholar
  59. 59.
    Wan W, Farboud B, Privalsky ML. Pituitary resistance to thyroid hormone syndrome is associated with T3 receptor mutants that selectively impair beta2 isoform function. Mol Endocrinol. 2005;19(6):1529–42.PubMedCrossRefGoogle Scholar
  60. 60.
    Machado DS, Sabet A, Santiago LA, Sidhaye AR, Chiamolera MI, Ortiga-Carvalho TM, Wondisford FE. A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo. Proc Natl Acad Sci U S A. 2009;106(23):9441–6.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Wu SY, Cohen RN, Simsek E, Senses DA, Yar NE, Grasberger H, Noel J, Refetoff S, Weiss RE. A novel thyroid hormone receptor-beta mutation that fails to bind nuclear receptor corepressor in a patient as an apparent cause of severe, predominantly pituitary resistance to thyroid hormone. J Clin Endocrinol Metab. 2006;91(5):1887–95.PubMedCrossRefGoogle Scholar
  62. 62.
    Moran C, Agostini M, Visser WE, Schoenmakers E, Schoenmakers N, Offiah AC, Poole K, Rajanayagam O, Lyons G, Halsall D, Gurnell M, Chrysis D, Efthymiadou A, Buchanan C, Aylwin S, Chatterjee KK. Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)alpha1 and TRalpha2: clinical, biochemical, and genetic analyses of three related patients. Lancet Diabetes Endocrinol. 2014;2(8):619–26.PubMedCrossRefGoogle Scholar
  63. 63.
    Moran C, Schoenmakers N, Agostini M, Schoenmakers E, Offiah A, Kydd A, Kahaly G, Mohr-Kahaly S, Rajanayagam O, Lyons G, Wareham N, Halsall D, Dattani M, Hughes S, Gurnell M, Park SM, Chatterjee K. An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha. J Clin Endocrinol Metab. 2013;98(11):4254–61.PubMedCrossRefGoogle Scholar
  64. 64.
    Yuen RK, Thiruvahindrapuram B, Merico D, Walker S, Tammimies K, Hoang N, Chrysler C, Nalpathamkalam T, Pellecchia G, Liu Y, Gazzellone MJ, D'Abate L, Deneault E, Howe JL, Liu RS, Thompson A, Zarrei M, Uddin M, Marshall CR, Ring RH, Zwaigenbaum L, Ray PN, Weksberg R, Carter MT, Fernandez BA, Roberts W, Szatmari P, Scherer SW. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med. 2015;21(2):185–91.PubMedCrossRefGoogle Scholar
  65. 65.
    Tylki-Szymanska A, Acuna-Hidalgo R, Krajewska-Walasek M, Lecka-Ambroziak A, Steehouwer M, Gilissen C, Brunner HG, Jurecka A, Rozdzynska-Swiatkowska A, Hoischen A, Chrzanowska KH. Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor alpha gene (THRA). J Med Genet. 2015;52(5):312–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Takeda T, Sakurai A, DeGroot LJ, Refetoff S. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-b gene. J Clin Endocrinol Metab. 1992;74:49–55.PubMedGoogle Scholar
  67. 67.
    Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab. 2010;95(7):3189–93.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Brucker-Davis F, Skarulis MC, Grace MB, Benichou J, Hauser P, Wiggs E, Weintraub BD. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone: the National Institutes of Health prospective study. Ann Intern Med. 1995;123:572–83.PubMedCrossRefGoogle Scholar
  69. 69.
    Weiss RE, Refetoff SE. Effect of thyroid hormone on growth: lessons from the syndrome of resistance to thyroid hormone. Endocrinol Metab Clin N Am. 1996;25:719–30.CrossRefGoogle Scholar
  70. 70.
    Mitchell CS, Savage DB, Dufour S, Schoenmakers N, Murgatroyd P, Befroy D, Halsall D, Northcott S, Raymond-Barker P, Curran S, Henning E, Keogh J, Owen P, Lazarus J, Rothman DL, Farooqi IS, Shulman GI, Chatterjee K, Petersen KF. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest. 2010;120(4):1345–54.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Matochik JA, Zametkin AJ, Cohen RM, Hauser P, Weintraub BD. Abnormalities in sustained attention and anterior cingulate gyrus metabolism in subjects with resistance to thyroid hormone. Brain Res. 1996;723:23–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Weiss RE, Stein MA, Refetoff S. Behavioral effects of liothyronine (L-T3) in children with attention deficit hyperactivity disorder in the presence and absence of resistance to thyroid hormone. Thyroid. 1997;7:389–93.PubMedCrossRefGoogle Scholar
  73. 73.
    Stein MA, Weiss RE, Refetoff S. Neurocognitive characteristics of individuals with resistance to thyroid hormone: comparisons with individuals with attention-deficit hyperactivity disorder. J Dev Behav Pediatr. 1995;16:406–11.PubMedGoogle Scholar
  74. 74.
    Kahn BB, Weintraub BD, Csako G, Zweig MH. Factitious elevation of thyrotropin in a new ultrasensitive assay: implications for the use of monoclonal antibodies in “sandwich” immunoassay. J Clin Endocrinol Metab. 1988;66:526–33.PubMedCrossRefGoogle Scholar
  75. 75.
    Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J Med. 1994;331:1072–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Huang MJ, Liaw YF. Clinical associations between thyroid and liver diseases. J Gastroenterol Hepatol. 1995;10:344–50.PubMedCrossRefGoogle Scholar
  77. 77.
    Pannain S, Feldman M, Eiholzer U, Weiss RE, Scherberg NH, Refetoff S. Familial dysalbuminemic hyperthyroxinemia in a Swiss family caused by a mutant albumin (R218P) shows an apparent discrepancy between serum concentration and affinity for thyroxine. J Clin Endocrinol Metab. 2000;85:2786–92.PubMedGoogle Scholar
  78. 78.
    Petersen CE, Ha CE, Jameson DM, Bhagavan NV. Mutations in a specific human serum albumin thyroxine binding site define the structural basis of familial dysalbuminemic hyperthyroxinemia. J Biol Chem. 1996;271:19110–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of amiodarone on the thyroid. Endocr Rev. 2001;22:240–54.PubMedGoogle Scholar
  80. 80.
    Roca RP, Blackman MR, Ackerley MB, Harman SM, Gregerman RI. Thyroid hormone elevations during acute psychiatric illness: relationship to severity and distinction from hyperthyroidism. Endocr Res. 1990;16:415–47.PubMedCrossRefGoogle Scholar
  81. 81.
    Beck-Peccoz P, Bruckner-Davis F, Persani L, Smallridge RC, Weintraub BD. Thyrotropin-secreting pituitary tumors. Endocr Rev. 1996;17:610–38.PubMedGoogle Scholar
  82. 82.
    Safer JD, Colan SD, Fraser LM, Wondisford FE. A pituitary tumor in a patient with thyroid hormone resistance: a diagnostic dilemma. Thyroid. 2001;11:281–91.PubMedCrossRefGoogle Scholar
  83. 83.
    Bogazzi F, Manetti L, Tomisti L, Rossi G, Cosci C, Sardella C, Bartalena L, Gasperi M, Macchia E, Vitti P, Martino E. Thyroid color flow Doppler sonography: an adjunctive tool for differentiating patients with inappropriate thyrotropin (TSH) secretion due to TSH-secreting pituitary adenoma or resistance to thyroid hormone. Thyroid. 2006;16(10):989–95.PubMedCrossRefGoogle Scholar
  84. 84.
    Wu SY, Sadow PM, Refetoff S, Weiss RE. Tissue responses to thyroid hormone in a kindred with resistance to thyroid hormone harboring a commonly occurring mutation in the thyroid hormone receptor beta gene (P453T). J Lab Clin Med. 2005;146(2):85–94.PubMedCrossRefGoogle Scholar
  85. 85.
    Asteria C, Rajanayagam O, Collingwood TN, Persani L, Romoli R, Mannavola D, Zamperini P, Bizu F, Ciralli F, Chatterjee VKK, Beck-Peccoz P. Prenatal diagnosis of thyroid hormone resistance. J Clin Endocrinol Metab. 1999;84:405–10.PubMedCrossRefGoogle Scholar
  86. 86.
    Takeda T, Suzuki S, Liu RT, Degroot LJ. Triiodothyroacetic acid has unique potential for therapy of resistance to thyroid hormone. J Clin Endocrinol Metab. 1995;80:2033–40.PubMedGoogle Scholar
  87. 87.
    Torre P, Bertoli M, Di Giovanni S, Scommegna S, Conte C, Novelli G, Cianfarani S. Endocrine and neuropsychological assessment in a child with a novel mutation of thyroid hormone receptor: response to 12-month triiodothyroacetic acid (TRIAC) therapy. J Endocrinol Investig. 2005;28(7):657–62.CrossRefGoogle Scholar
  88. 88.
    Hamon B, Hamon P, Bovier-Lapierre M, Pugeat M, Savagner F, Rodien P, Orgiazzi J. A child with resistance to thyroid hormone without thyroid hormone receptor gene mutation: a 20-year follow-up. Thyroid. 2008;18(1):35–44.PubMedCrossRefGoogle Scholar
  89. 89.
    Guran T, Turan S, Bircan R, Bereket A. 9 years follow-up of a patient with pituitary form of resistance to thyroid hormones (PRTH): comparison of two treatment periods of D-thyroxine and triiodothyroacetic acid (TRIAC). J Pediatr Endocrinol Metab. 2009;22(10):971–8.PubMedCrossRefGoogle Scholar
  90. 90.
    Hashimoto A, Shi Y, Drake K, Koh JT. Design and synthesis of complementing ligands for mutant thyroid hormone receptor TRbeta(R320H): a tailor-made approach toward the treatment of resistance to thyroid hormone. Bioorg Med Chem. 2005;13(11):3627–39.PubMedCrossRefGoogle Scholar
  91. 91.
    Weiss RE, Dumitrescu A, Refetoff S. Approach to the patient with resistance to thyroid hormone and pregnancy. J Clin Endocrinol Metab. 2010;95(7):3094–102.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Anselmo J, Cao D, Karrison T, Weiss RE, Refetoff S. Fetal loss associated with excess thyroid hormone exposure. JAMA. 2004;292(6):691–5.PubMedCrossRefGoogle Scholar
  93. 93.
    Jansen J, Friesema EC, Milici C, Visser TJ. Thyroid hormone transporters in health and disease. Thyroid. 2005;15(8):757–68.PubMedCrossRefGoogle Scholar
  94. 94.
    Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet. 2004;74(1):168–75.PubMedCrossRefGoogle Scholar
  95. 95.
    Friesema EC, Grueters A, Biebermann H, Krude H, von Moers A, Reeser M, Barrett TG, Mancilla EE, Svensson J, Kester MH, Kuiper GG, Balkassmi S, Uitterlinden AG, Koehrle J, Rodien P, Halestrap AP, Visser TJ. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet. 2004;364(9443):1435–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Dumitrescu AM, Liao XH, Weiss RE, Millen K, Refetoff S. Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice. Endocrinology. 2006;147(9):4036–43.PubMedCrossRefGoogle Scholar
  97. 97.
    Di Cosmo C, Liao XH, Dumitrescu AM, Weiss RE, Refetoff S. A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport. Endocrinology. 2009;150(9):4450–8.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Dumitrescu AM, Liao XH, Abdullah MS, Lado-Abeal J, Majed FA, Moeller LC, Boran G, Schomburg L, Weiss RE, Refetoff S. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet. 2005;37(11):1247–52.PubMedCrossRefGoogle Scholar
  99. 99.
    Di Cosmo C, McLellan N, Liao XH, Khanna KK, Weiss RE, Papp L, Refetoff S. Clinical and molecular characterization of a novel selenocysteine insertion sequence-binding protein 2 (SBP2) gene mutation (R128X). J Clin Endocrinol Metab. 2009;94(10):4003–9.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Schoenmakers E, Agostini M, Mitchell C, Schoenmakers N, Papp L, Rajanayagam O, Padidela R, Ceron-Gutierrez L, Doffinger R, Prevosto C, Luan J, Montano S, Lu J, Castanet M, Clemons N, Groeneveld M, Castets P, Karbaschi M, Aitken S, Dixon A, Williams J, Campi I, Blount M, Burton H, Muntoni F, O'Donovan D, Dean A, Warren A, Brierley C, Baguley D, Guicheney P, Fitzgerald R, Coles A, Gaston H, Todd P, Holmgren A, Khanna KK, Cooke M, Semple R, Halsall D, Wareham N, Schwabe J, Grasso L, Beck-Peccoz P, Ogunko A, Dattani M, Gurnell M, Chatterjee K. Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J Clin Invest. 2010;120(12):4220–35.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Cohen RN, Weintraub BD, Wondisford FE. Chemistry and biosynthesis of thyrotropin. In: Braverman LE, Uller RD, editors. Werner and Ingbar’s the thyroid. Philadelphia: Lippincott, Williams, and Wilkins; 2005. p. 159–75.Google Scholar
  102. 102.
    Stanbury JB, Rocmans P, Buhler UK, Ochi Y. Congenital hypothyroidism with impaired thyroid response to thyrotropin. N Engl J Med. 1968;279:1132–6.PubMedCrossRefGoogle Scholar
  103. 103.
    Sunthornthepvarakul T, Gottschalk ME, Hayashi Y, Refetoff S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med. 1995;332:155–60.CrossRefGoogle Scholar
  104. 104.
    Rapoport B, Chazenbalk GD, Jaume JC, McLachlan SM. The thyrotropin (TSH) receptor: interaction with TSH and autoantibdies. Endocr Rev. 1998;19:673–716.PubMedGoogle Scholar
  105. 105.
    Zhang M, Tong KPT, Fremont V, Chen J, Narayan N, Puett D, Weintraub BD, Szudlinski MW. The extracellular domain suppresses constitutive activity of the transmembrane domain of the human TSH receptor: implications for hormone-receptor interaction and antagonist design. Endocrinology. 2000;141:3514–7.PubMedCrossRefGoogle Scholar
  106. 106.
    Libert F, Passage E, Lefort A, Vassart G, Mattei MG. Localization of human thyrotropin receptor gene to chromosome region 14q31 by in situ hybridization. Cytogenet Cell Genet. 1990;54:82–3.PubMedCrossRefGoogle Scholar
  107. 107.
    Rousseau-Merck MF, Misrahi M, Loosfelt H, Atger M, Milgrom E, Berger R. Assignment of the human thyroid stimulating hormone receptor (TSHR) gene to chromosome 14q31. Genomics. 1990;8:233–6.PubMedCrossRefGoogle Scholar
  108. 108.
    de Roux N, Misrahi M, Brauner R, Houang M, Carel JC, Granier M, Le Bouc Y, Ghinea N, Boumedienne A, Toublanc JE, Milgrom E. Four families with loss of function mutations of the thyrotropin receptor. J Clin Endocrinol Metab. 1996;81:4229–35.PubMedGoogle Scholar
  109. 109.
    Clifton-Bligh RJ, Gregory JW, Ludgate M, John R, Persni L, Asteria C, Beck-Peccoz P, Chatterjee VKK. Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH. J Clin Endocrinol Metab. 1997;82:1094–100.PubMedGoogle Scholar
  110. 110.
    Russo D, Betterle B, Arturi F, Chiefari E, Girelli ME, Filetti S. A novel mutation in the thyrotropin (TSH) receptor gene causing loss of TSH binding but constitutive receptor activation in a family with resistance to TSH. J Clin Endocrinol Metab. 2000;85:4238–42.PubMedGoogle Scholar
  111. 111.
    Abramowicz MJ, Duprez L, Parma J, Vassart G, Heinrichs C. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest. 1997;99:3018–24.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Biberman H, Schoneberg T, Krude H, Schultz G, Guderman T, Gruters A. Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. J Clin Endocrinol. 1997;82:3471–80.Google Scholar
  113. 113.
    Gagne N, Parma J, Deal C, Vassart G, Van Vliet G. Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid distinct entities? J Clin Endocrinol Metab. 1998;83:1771–5.PubMedGoogle Scholar
  114. 114.
    Tonacchera M, Agretti P, Pinchera A, Rosellini V, Perri A, Collecchi P, Vitti P, Chiocato L. Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene. J Clin Endocrinol Metab. 2000;85:1001–8.PubMedGoogle Scholar
  115. 115.
    Xie J, Pannain S, Pohlenz J, Weiss RE, Moltz K, Morlot M, Asteria C, Persani L, Beck-Peccoz P, Parma J, Vassart G, Refetoff S. Resistance to thyrotropin (TSH) in three families is not associated with mutations in the TSH receptor or TSH. J Clin Endocrinol. 1997;82:3933–40.Google Scholar
  116. 116.
    Weinstein LS, Liu J, Sakamoto A, Xie T, Chen M. Minireview: GNAS: normal and abnormal functions. Endocrinology. 2004;145(12):5459–64.PubMedCrossRefGoogle Scholar
  117. 117.
    Grasberger H, Ringkananont U, Lefrancois P, Abramowicz M, Vassart G, Refetoff S. Thyroid transcription factor 1 rescues PAX8/p300 synergism impaired by a natural PAX8 paired domain mutation with dominant negative activity. Mol Endocrinol. 2005;19(7):1779–91.PubMedCrossRefGoogle Scholar
  118. 118.
    Nagasaki K, Narumi S, Asami T, Kikuchi T, Hasegawa T, Uchiyama M. Mutation of a gene for thyroid transcription factor-1 (TITF1) in a patient with clinical features of resistance to thyrotropin. Endocr J. 2008;55(5):875–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Grasberger H, Mimouni-Bloch A, Vantyghem MC, van Vliet G, Abramowicz M, Metzger DL, Abdullatif H, Rydlewski C, Macchia PE, Scherberg NH, van Sande J, Mimouni M, Weiss RE, Vassart G, Refetoff S. Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci. J Clin Endocrinol Metab. 2005;90(7):4025–34.PubMedCrossRefGoogle Scholar
  120. 120.
    Grasberger H, Vaxillaire M, Pannain S, Beck JC, Mimouni-Bloch A, Vatin V, Vassart G, Froguel P, Refetoff S. Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1. Hum Genet. 2005;118(3–4):348–55.PubMedCrossRefGoogle Scholar
  121. 121.
    Park KJ, Park HK, Kim YJ, Lee KR, Park JH, Park JH, Park HD, Lee SY, Kim JW. DUOX2 mutations are frequently associated with congenital hypothyroidism in the Korean population. Ann Lab Med. 2016;36(2):145–53.PubMedCrossRefGoogle Scholar
  122. 122.
    Fu CY, Luo SY, Zhang SJ, Wang J, Zheng HY, Yang Q, Xie BB, Hu XY, Fan X, Luo JS, Chen RY, Su JS, Shen YP, Gu XF, Chen SK. Next-generation sequencing analysis of DUOX2 in 192 Chinese subclinical congenital hypothyroidism (SCH) and CH patients. Clin Chim Acta. 2016;458:30–4.PubMedCrossRefGoogle Scholar
  123. 123.
    Narumi S, Muroya K, Abe Y, Yasui M, Asakura Y, Adachi M, Hasegawa T. TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study. J Clin Endocrinol Metab. 2009;94(4):1317–23.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medicine, Section of Adult and Pediatric Endocrinology, Diabetes, and MetabolismUniversity of ChicagoChicagoUSA

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