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Thyroid Hormone Resistance Syndromes

  • Roy E. WeissEmail author
  • Samuel Refetoff
Chapter

Abstract

Syndromes with impaired sensitivity to thyroid hormone (TH) include three types of resistance to thyroid hormone (RTH) syndromes (RTHβ, RTHα, and nonTR-RTH) and also include patients with defects in TH transport into cells (thyroid hormone cell membrane transport defect, THCMTD) and defects in TH metabolism (thyroid hormone metabolism defect, THMD). The overall goal of this chapter is to discuss the treatment options for patients with various syndromes of impaired sensitivity to TH. These are rare conditions with little or no evidence-based information for the “best” treatment of patients. The first step toward treatment of all of these syndromes is making an accurate diagnosis based on a combination of the clinical presentation and laboratory tests that ultimately requires genetic confirmation. Recognizing the etiology leads to a more logical approach to treatment.

Keywords

Resistance to thyroid hormone Thyroid hormone cell membrane transport defect Thyroid hormone metabolism defect Monocarboxylase transporter 8 Deiodinase defect Thyroid hormone receptor beta Thyroid hormone receptor alpha 

References

  1. 1.
    Refetoff S, Bassett JH, Beck-Peccoz P, Bernal J, Brent G, Chatterjee K, De Groot LJ, Dumitrescu AM, Jameson JL, Kopp PA, Murata Y, Persani L, Samarut J, Weiss RE, Williams GR, Yen PM. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. Eur Thyroid J. 2014;3:7–9; J Clin Endocrinol Metab 99:768–70; Thyroid 24:407–9 (Published simultaneously )CrossRefGoogle Scholar
  2. 2.
    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;74:168–75.CrossRefGoogle Scholar
  3. 3.
    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;364:1435–7.CrossRefGoogle Scholar
  4. 4.
    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;150:4450–8.CrossRefGoogle Scholar
  5. 5.
    Verge CF, Konrad D, Cohen M, Di Cosmo C, Dumitrescu AM, Marcinkowski T, Hameed S, Hamilton J, Weiss RE, Refetoff S. Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. J Clin Endocrinol Metab. 2012;97:4515–23.CrossRefGoogle Scholar
  6. 6.
    Kersseboom S, Horn S, Visser WE, Chen J, Friesema EC, Vaurs-Barriere C, Peeters RP, Heuer H, Visser TJ. In vitro and mouse studies supporting therapeutic utility of triiodothyroacetic acid in MCT8 deficiency. Mol Endocrinol. 2014;28:1961–70.CrossRefGoogle Scholar
  7. 7.
    Barez-Lopez S, Obregon MJ, Martinez-de-Mena R, Bernal J, Guadano-Ferraz A, Morte B. Effect of Triiodothyroacetic acid treatment in Mct8 deficiency: a word of caution. Thyroid. 2016;26:618–26.CrossRefGoogle Scholar
  8. 8.
  9. 9.
    Horn S, Kersseboom S, Mayerl S, Muller J, Groba C, Trajkovic-Arsic M, Ackermann T, Visser TJ, Heuer H. Tetrac can replace thyroid hormone during brain development in mouse mutants deficient in the thyroid hormone transporter mct8. Endocrinology. 2013;154:968–79.CrossRefGoogle Scholar
  10. 10.
    Ferrara AM, Liao XH, Ye H, Weiss RE, Dumitrescu AM, Refetoff S. The thyroid hormone analog DITPA ameliorates metabolic parameters of male mice with Mct8 deficiency. Endocrinology. 2015;156:3889–94.CrossRefGoogle Scholar
  11. 11.
    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;37:1247–52.CrossRefGoogle Scholar
  12. 12.
    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;94:4003–9.CrossRefGoogle Scholar
  13. 13.
    Schomburg L, Dumitrescu AM, Liao XH, Bin-Abbas B, Hoeflich J, Kohrle J, Refetoff S. Selenium supplementation fails to correct the selenoprotein synthesis defect in subjects with SBP2 gene mutations. Thyroid. 2009;19:277–81.CrossRefGoogle Scholar
  14. 14.
    Refetoff S. Resistance to thyroid hormone. Clin Lab Med. 1993;13:563–81.CrossRefGoogle Scholar
  15. 15.
    Anselmo J, Refetoff S. Regression of a large goiter in a patient with resistance to thyroid hormone by every other day treatment with triiodothyronine. Thyroid. 2004;14:71–4.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    Anselmo J, Cao D, Karrison T, Weiss RE, Refetoff S. Fetal loss associated with excess thyroid hormone exposure. JAMA. 2004;292:691–5.CrossRefGoogle Scholar
  18. 18.
    Vaidya B, Campbell V, Tripp JH, Spyer G, Hattersley AT, Ellard S. Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation. Clin Endocrinol. 2004;60:711–8.CrossRefGoogle Scholar
  19. 19.
    Weiss RE, Dumitrescu A, Refetoff S. Approach to the patient with resistance to thyroid hormone and pregnancy. J Clin Endocrinol Metab. 2010;95:3094–102.CrossRefGoogle Scholar
  20. 20.
    Asteria C, Rajanayagam O, Collingwood TN, Persani L, Romoli R, Mannavola D, Zamperini P, Buzi F, Ciralli F, Chatterjee VK, Beck-Peccoz P. Prenatal diagnosis of thyroid hormone resistance. J Clin Endocrinol Metab. 1999;84:405–10.CrossRefGoogle Scholar
  21. 21.
    Espiard S, Savagner F, Flamant F, Vlaeminck-Guillem V, Guyot R, Munier M, d'Herbomez M, Bourguet W, Pinto G, Rose C, Rodien P, Wemeau JL. A novel mutation in THRA gene associated with an atypical phenotype of resistance to thyroid hormone. J Clin Endocrinol Metab. 2015;100(8):2841–8.  https://doi.org/10.1210/jc20151120.CrossRefPubMedGoogle Scholar
  22. 22.
    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;2:619–26.CrossRefGoogle Scholar
  23. 23.
    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;98:4254–61.CrossRefGoogle Scholar
  24. 24.
    Tinnikov A, Nordstrom K, Thoren P, Kindblom JM, Malin S, Rozell B, Adams M, Rajanayagam O, Pettersson S, Ohlsson C, Chatterjee K, Vennstrom B. Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1. EMBO J. 2002;21:5079–87.CrossRefGoogle Scholar
  25. 25.
    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;52:312–6.CrossRefGoogle Scholar
  26. 26.
    Woodbury-Smith M, Paterson AD, Thiruvahindrapduram B, Lionel AC, Marshall CR, Merico D, Fernandez BA, Duku E, Sutcliffe JS, O'Conner I, Chrysler C, Thompson A, Kellam B, Tammimies K, Walker S, Yuen RK, Uddin M, Howe JL, Parlier M, Whitten K, Szatmari P, Vieland VJ, Piven J, Scherer SW. Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes. Hum Genet. 2015;134:191–201.CrossRefGoogle Scholar
  27. 27.
    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;21:185–91.CrossRefGoogle Scholar
  28. 28.
    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;366:243–9.CrossRefGoogle Scholar
  29. 29.
    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;366:1451–3.CrossRefGoogle Scholar
  30. 30.
    Refetoff S, Dumitrescu A, Weiss RE. Impaired sensitivity to thyroid hormone. In: Cooper DS, Ross DS, editors. Uptodate. Alphen aan den Rijn: Wolters Kulwer; 2015.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of MedicineThe University of Miami Miller School of MedicineMiamiUSA
  2. 2.Departments of Medicine, Pediatrics and GeneticsThe University of ChicagoChicagoUSA

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