thyroid hormone resistance syndrome

Summary

Summary: An inherited autosomal recessive trait, characterized by peripheral resistance to THYROID HORMONES and the resulting elevation in serum levels of THYROXINE and TRIIODOTHYRONINE. This syndrome is caused by mutations of gene THRB encoding the THYROID HORMONE RECEPTORS BETA in target cells. HYPOTHYROIDISM in these patients is partly overcome by the increased thyroid hormone levels.

Top Publications

  1. Kim J, Park T, Baek H, Kim G, Yoo H, Park J. A newly identified insertion mutation in the thyroid hormone receptor-beta gene in a Korean family with generalized thyroid hormone resistance. J Korean Med Sci. 2007;22:560-3 pubmed
    b>Thyroid hormone resistance syndrome (RTH) is a rare disorder and is characterized by elevated levels of circulating free thyroid hormones, inappropriate secretion of thyroid stimulating hormone (TSH), and reduced peripheral tissue ..
  2. Ferrara A, Onigata K, Ercan O, Woodhead H, Weiss R, Refetoff S. Homozygous thyroid hormone receptor ?-gene mutations in resistance to thyroid hormone: three new cases and review of the literature. J Clin Endocrinol Metab. 2012;97:1328-36 pubmed publisher
    ..The most common cause of resistance to thyroid hormone (RTH) is heterozygous thyroid hormone receptor ? (THRB) gene mutations. Homozygous mutations in the THRB gene are a rare event...
  3. Carvalho G, Ramos H. [Thyroid hormone resistance syndrome]. Arq Bras Endocrinol Metabol. 2004;48:83-92 pubmed
  4. Yoh S, Chatterjee V, Privalsky M. Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. Mol Endocrinol. 1997;11:470-80 pubmed
    ..We suggest that an altered corepressor interaction is likely to play a critical role in the dominant negative potency of RTH mutants and may contribute to the variable phenotype in this disorder...
  5. Cheng S. Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance. Trends Endocrinol Metab. 2005;16:176-82 pubmed
    ..Mutations of THRB cause a human genetic disease, thyroid hormone resistance syndrome (RTH)...
  6. Kahaly G, Matthews C, Mohr Kahaly S, Richards C, Chatterjee V. Cardiac involvement in thyroid hormone resistance. J Clin Endocrinol Metab. 2002;87:204-12 pubmed
    ..Differences in term of cardiovascular changes were smaller between the RTH and C groups than the RTH and the H or h groups. Thus, an incomplete cardiac response to thyroid hormone is present in RTH...
  7. Ferreira Azevedo M, Barra G, Medeiros L, Simeoni L, Naves L, Neves F. A novel mutation of thyroid hormone receptor beta (I431V) impairs corepressor release, and induces thyroid hormone resistance syndrome. Arq Bras Endocrinol Metabol. 2008;52:1304-12 pubmed
    ..The presence of this mutation reduces potency, but does not affect efficacy of thyroid hormone action, in accordance with the clinical picture of eumetabolism of the affected individuals...
  8. Chatterjee V. Resistance to thyroid hormone--an uncommon cause of thyroxine excess and inappropriate TSH secretion. Acta Med Austriaca. 1994;21:56-60 pubmed
    ..abstract truncated at 250 words)..
  9. Kim J, Choi E, Lee J, Lee K, Kim Y, Kim S, et al. Resistance to thyroid hormone with missense mutation (V349M) in the thyroid hormone receptor beta gene. Korean J Intern Med. 2008;23:45-8 pubmed
    ..We report the first case of a woman with RTH, which was found to be caused by a missense mutation (V349M) in the TR beta gene...

More Information

Publications62

  1. Machado D, SABET A, Santiago L, Sidhaye A, Chiamolera M, Ortiga Carvalho T, et al. A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo. Proc Natl Acad Sci U S A. 2009;106:9441-6 pubmed publisher
  2. Berker D, Aydin Y, Tutuncu Y, Isik S, Delibasi T, Berker M, et al. Somatotropin adenoma and resistance to thyroid hormone. J Endocrinol Invest. 2009;32:284-6 pubmed
    ..Immunohistochemistry was showed as strong GH staining with low Ki 67 index while TSH and other anterior hypophyseal hormones stainings were negative. Post-operative thyroid hormones were still high...
  3. van Mullem A, Chrysis D, Eythimiadou A, Chroni E, Tsatsoulis A, de Rijke Y, et al. Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TR?1 receptor: consequences of LT4 treatment. J Clin Endocrinol Metab. 2013;98:3029-38 pubmed publisher
    ..These patients have low free T?, low T?, high T?, low rT?, and normal TSH serum levels, in combination with growth retardation, delayed bone development, and constipation...
  4. Umezawa R, Yamada M, Horiguchi K, Ishii S, Hashimoto K, Okada S, et al. Aberrant histone modifications at the thyrotropin-releasing hormone gene in resistance to thyroid hormone: analysis of F455S mutant thyroid hormone receptor. Endocrinology. 2009;150:3425-32 pubmed publisher
  5. Millichap J. Etiologic classification of attention-deficit/hyperactivity disorder. Pediatrics. 2008;121:e358-65 pubmed publisher
  6. Taniyama M, Otsuka F, Tozaki T, Ban Y. Thyroid profiles in a patient with resistance to thyroid hormone and episodes of thyrotoxicosis, including repeated painless thyroiditis. Thyroid. 2013;23:898-901 pubmed publisher
    ..We assessed the thyroid profile in a patient with RTH and episodes of thyrotoxicosis who experienced repeated painless thyroiditis...
  7. Nishino M, Murakami M. [Secondary hyperthyroidism]. Nihon Rinsho. 2006;Suppl 1:250-4 pubmed
  8. Ma S, Hu M, Yang H, Lian X, Jiang Y. Periodic Paralysis as a New Phenotype of Resistance to Thyroid Hormone Syndrome in a Chinese Male Adult. J Clin Endocrinol Metab. 2016;101:349-52 pubmed publisher
    ..Thyrotoxic periodic paralysis is the most common form of acquired periodic paralysis. However, it has not been reported in a patient with RTH up to now...
  9. Huber B, Desclozeaux M, West B, Cunha Lima S, Nguyen H, Baxter J, et al. Thyroid hormone receptor-beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain. Mol Endocrinol. 2003;17:107-16 pubmed
    ..Thus, these structural analyses provide mechanistic insight into the etiology of RTH disease in human TRbeta mutants that exhibit hormone binding with decreased ligand-dependent corepressor release...
  10. Hauser P, McMillin J, Bhatara V. Resistance to thyroid hormone: implications for neurodevelopmental research on the effects of thyroid hormone disruptors. Toxicol Ind Health. 1998;14:85-101 pubmed
    ..Such studies may provide new insights into the basic pathogenesis of developmental neurotoxicity following exposure to thyroid-disrupting synthetic compounds...
  11. Sato H. Clinical features of primary hyperthyroidism caused by Graves' disease admixed with resistance to thyroid hormone (P453T). Endocr J. 2010;57:687-92 pubmed
    ..In conclusion, it is difficult to make a differential diagnosis between GD with RTH and GD alone if RTH is not diagnosed before the onset of GD. An antithyroid drug is able to cause the remission of GD with RTH...
  12. Tagami T, Gu W, Peairs P, West B, Jameson J. A novel natural mutation in the thyroid hormone receptor defines a dual functional domain that exchanges nuclear receptor corepressors and coactivators. Mol Endocrinol. 1998;12:1888-902 pubmed
    ..These studies also suggest that helix 12 of the thyroid hormone receptor acts as a dual functional domain. After the binding of T3, its conformation changes, causing the disruption of CoR binding and the recruitment of CoAs...
  13. Borck G, Seewi O, Jung A, Schönau E, Kubisch C. Genetic causes of goiter and deafness: Pendred syndrome in a girl and cooccurrence of Pendred syndrome and resistance to thyroid hormone in her sister. J Clin Endocrinol Metab. 2009;94:2106-9 pubmed publisher
    ..We present their history, clinical presentation, and follow-up and report the results of molecular genetic investigations...
  14. Rodríguez Rodríguez I, de la Fuente Aguado J, Páramo Fernández C, Nodar Germiñas A, Rubianes Gonzalez M, Sierra Vaquero J. [Hypophyseal resistance to thyroid hormones]. Rev Clin Esp. 2002;202:43-4 pubmed
  15. Freson K, Izzi B, Jaeken J, Van Helvoirt M, Thys C, Wittevrongel C, et al. Compound heterozygous mutations in the GNAS gene of a boy with morbid obesity, thyroid-stimulating hormone resistance, pseudohypoparathyroidism, and a prothrombotic state. J Clin Endocrinol Metab. 2008;93:4844-9 pubmed publisher
    ..Homozygous GNAS defects have not been described...
  16. Schweizer U, Weitzel J, Schomburg L. Think globally: act locally. New insights into the local regulation of thyroid hormone availability challenge long accepted dogmas. Mol Cell Endocrinol. 2008;289:1-9 pubmed publisher
    ..Finally, a link between Dio expression and energy metabolism has been delineated in mice that may hold great promise for the management of the adiposity pandemic...
  17. Ramos Prol A, Antonia Pérez Lázaro M, Isabel del Olmo García M, León de Zayas B, Moreno Macián F, Navas de Solis S, et al. Differentiated thyroid carcinoma in a girl with resistance to thyroid hormone management with triiodothyroacetic acid. J Pediatr Endocrinol Metab. 2013;26:133-6 pubmed publisher
    b>Thyroid hormone resistance syndrome is characterized by a reduced target tissue response to the action of thyroid hormone, which leads to high levels of free thyroxine and free triiodothyronine with non-suppressed levels of thyrotropin (..
  18. Williams J. Adverse effects of thyroid hormones. Drugs Aging. 1997;11:460-9 pubmed
    ..Thus, avoidance of dosages that cause thyrotrophin suppression, when not clinically indicated, is the primary approach to the management of these adverse effects...
  19. Sarkar S, Mondal R, Nandi M, Ghosh J. Immune thrombocytopenic purpura in a child with thyroid hormone resistance - a rare presentation. J Pediatr Endocrinol Metab. 2013;26:125-7 pubmed publisher
    ..She was subsequently found to have RTH. High-dose thyroid hormone replacement was required to overcome the resistance that not only ameliorated the features of hypothyroidism but also brought an apparent remission of ITP...
  20. Brown N, Smart A, Sharma V, Brinkmeier M, Greenlee L, Camper S, et al. Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse. J Clin Invest. 2000;106:73-9 pubmed
  21. Margotat A, Sarkissian G, Malezet Desmoulins C, Peyrol N, Vlaeminck Guillem V, Wemeau J, et al. [Identification of eight new mutations in the c-erbAB gene of patients with resistance to thyroid hormone]. Ann Endocrinol (Paris). 2001;62:220-5 pubmed
    ..Eight of these mutations had not been described previously. Two are located in an area not known to harbor naturally occurring mutations. This observation could lead to define a fourth cluster of mutations in the c-erbAB gene...
  22. Hamon B, Hamon P, Bovier Lapierre M, Pugeat M, Savagner F, Rodien P, et al. A child with resistance to thyroid hormone without thyroid hormone receptor gene mutation: a 20-year follow-up. Thyroid. 2008;18:35-44 pubmed publisher
    ..No mutations were found in the coding sequence of TRbeta1, TRbeta2, TRalpha1, RXRgamma, SMRT, NCoR1, and NCoA1. In this patient the putative long-term effects of the persisting high bone resorption are unknown...
  23. Christin Maitre S, Duron F. Fetal loss associated with excess thyroid hormone exposure. JAMA. 2004;292:2085-6; author reply 2086 pubmed
  24. Torre P, Bertoli M, Di Giovanni S, Scommegna S, Conte C, Novelli G, et al. 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 Invest. 2005;28:657-62 pubmed
    ..To determine the endocrine, neuropsychological and genetic features of a child with resistance to thyroid hormone (RTH), and his response to long-term triiodothyroacetic acid (TRIAC) therapy...
  25. Brent G. Mechanisms of thyroid hormone action. J Clin Invest. 2012;122:3035-43 pubmed publisher
  26. Suzuki H, Cheng S. Compensatory role of thyroid hormone receptor (TR) alpha 1 in resistance to thyroid hormone: study in mice with a targeted mutation in the TR beta gene and deficient in TR alpha 1. Mol Endocrinol. 2003;17:1647-55 pubmed
    ..Therefore, TR alpha1 could play a compensatory role in mediating the functions of T3 in heterozygous patients with RTH. This compensatory role may be especially crucial for postnatal growth...
  27. Beck Peccoz P, Persani L, Calebiro D, Bonomi M, Mannavola D, Campi I. Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis. Best Pract Res Clin Endocrinol Metab. 2006;20:529-46 pubmed
    ..Recognition of these rare thyroid disorders is of great importance not only for informed genetic counselling but also for avoiding diagnostic mistakes that may lead to incorrect and potentially dangerous treatments...
  28. Refetoff S. Resistance to thyrotropin. J Endocrinol Invest. 2003;26:770-9 pubmed
    ..A larger proportion of families express the phenotype of resistance to TSH in the absence of a TSHr defect. In many the inheritance is dominant and the genetic cause has not been yet determined...
  29. Visser W, Friesema E, Jansen J, Visser T. Thyroid hormone transport in and out of cells. Trends Endocrinol Metab. 2008;19:50-6 pubmed publisher
    ..The exact pathophysiological mechanisms in MCT8 patients remain to be elucidated fully. Future research will probably identify novel TH transporters and disorders based on TH transporter defects...
  30. Ando S, Sarlis N, Oldfield E, Yen P. Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor. J Clin Endocrinol Metab. 2001;86:5572-6 pubmed
    ..Our results demonstrate that somatic mutation of TRbeta occurred in a TSHoma and was probably responsible for the defect in negative regulation of TSH by thyroid hormone in the tumor...
  31. Wu S, Cohen R, Simsek E, Senses D, Yar N, Grasberger H, et al. 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;91:1887-95 pubmed
    ..Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of variable tissue hyporesponsiveness to thyroid hormone (TH)...
  32. Chang A, Chamberlain Shea H, Carr B. Fetal loss associated with excess thyroid hormone exposure. JAMA. 2005;293:160-1; author reply 161 pubmed
  33. Isik E, Beck Peccoz P, Campi I, Ozon A, Alikasifoglu A, Gonc N, et al. Thyroid hormone resistance: a novel mutation in thyroid hormone receptor beta (THRB) gene - case report. Turk J Pediatr. 2013;55:322-7 pubmed
    ..It is important to consider thyroid hormone levels in association with TSH levels to prevent inappropriate treatment and the potential complications, such as clinical hypothyroidism or an increase in goiter size. ..
  34. Weiss R, Dumitrescu A, Refetoff S. Approach to the patient with resistance to thyroid hormone and pregnancy. J Clin Endocrinol Metab. 2010;95:3094-102 pubmed publisher
    ..If the TRbeta mutation is known in the mother, the fetus can be rapidly genotyped from DNA from amniocentesis for the same mutation, and then management decisions could be made regarding thyroid or antithyroid hormone treatment...
  35. López J, Jimenez M, Campino C. [Familial generalized thyroid hormone resistance. Report of one case]. Rev Med Chil. 2004;132:1096-9 pubmed
    ..The mother and one of his brothers had the same pattern of abnormal serum thyroid hormones. We discuss the diagnostic considerations and the protocol to study this rare pathology...
  36. Tran H. Difficulties in diagnosing and managing coexisting primary hypothyroidism and resistance to thyroid hormone. Endocr Pract. 2006;12:288-93 pubmed
    ..To report a case of resistance to thyroid hormone compounded by autoimmune primary hypothyroidism and to discuss the unusual pattern of results of thyroid function tests...
  37. Schoenmakers N, Moran C, Peeters R, Visser T, Gurnell M, Chatterjee K. Resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha. Biochim Biophys Acta. 2013;1830:4004-8 pubmed publisher
    ..THRB mutations cause a disorder with central (hypothalamic-pituitary) resistance to thyroid hormone action with markedly elevated thyroid hormone and normal TSH levels...
  38. Yagi H, Pohlenz J, Hayashi Y, Sakurai A, Refetoff S. 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. 1997;82:1608-14 pubmed
    ..These results suggest that the substitution of R243 in TRbeta produces RTH by increasing the propensity for the formation of tightly bound homodimers or by reduction of the receptor affinity for T3 only after it binds to DNA...
  39. Zhu X, Kaneshige M, Parlow A, Chen E, Hunziker R, McDonald M, et al. Expression of the mutant thyroid hormone receptor PV in the pituitary of transgenic mice leads to weight reduction. Thyroid. 1999;9:1137-45 pubmed
    ..The circulating levels of growth hormone and insulin-like growth factor I were not affected in the transgenic mice, suggesting that the growth impairment in RTH is complex and is mediated by pathways that are yet to be elucidated...
  40. Sato H, Sakai H. A family showing resistance to thyroid hormone associated with chronic thyroiditis and its clinical features: A case report. Endocr J. 2006;53:421-5 pubmed
    ..The fact that the father showed an elevated TSH level, whereas the patient did not, was thought to be due to decreased thyroid function caused by chronic thyroiditis...
  41. Frank Raue K, Lorenz A, Haag C, Höppner W, Boll H, Knorr D, et al. Severe form of thyroid hormone resistance in a patient with homozygous/hemizygous mutation of T3 receptor gene. Eur J Endocrinol. 2004;150:819-23 pubmed
  42. Schneider M, Fiering S, Pallud S, Parlow A, St Germain D, Galton V. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol. 2001;15:2137-48 pubmed
    ..The increased serum levels of T4 and TSH observed in D2KO animals demonstrate that the D2 is of critical importance in the feedback regulation of TSH secretion...
  43. Parikh S, Ando S, Schneider A, Skarulis M, Sarlis N, Yen P. Resistance to thyroid hormone in a patient without thyroid hormone receptor mutations. Thyroid. 2002;12:81-6 pubmed
    ..It is likely that defects in the regulation of TR genes or mutations in transcriptional cofactors involved in TR signaling account for this patient's phenotype...
  44. Kino T, Pavlatou M, Moraitis A, Nemery R, Raygada M, Stratakis C. ZNF764 haploinsufficiency may explain partial glucocorticoid, androgen, and thyroid hormone resistance associated with 16p11.2 microdeletion. J Clin Endocrinol Metab. 2012;97:E1557-66 pubmed publisher
    ..Microdeletion of small chromosomal segments results in hereditary or sporadic diseases by affecting expression of residing genes...
  45. Jepsen K, Rosenfeld M. Biological roles and mechanistic actions of co-repressor complexes. J Cell Sci. 2002;115:689-98 pubmed
    ..Recently, the biological importance of these proteins has been revealed by studies of genetically engineered mice and human diseases such as acute promyelocytic leukemia (APL) and resistance to thyroid hormone (RTH)...
  46. Usala S. Resistance to thyroid hormone in children. Curr Opin Pediatr. 1994;6:468-75 pubmed
    ..Finally, an ARG-316-HIS mutation (kindred G-H) was associated with relatively weak dominant negative activity and perturbed DNA-binding properties.(ABSTRACT TRUNCATED AT 250 WORDS)..
  47. SABET A, Pallotta J. Dichotomous responses to thyroid hormone treatment in a patient with primary hypothyroidism and thyroid hormone resistance. Thyroid. 2011;21:559-61 pubmed publisher
    ..Patients with RTH may develop hypothyroidism as a result of surgery, mistreatment with radioiodine, or autoimmune thyroid disease...
  48. Tonacchera M, Di Cosmo C, De Marco G, Agretti P, Banco M, Perri A, et al. Identification of TSH receptor mutations in three families with resistance to TSH. Clin Endocrinol (Oxf). 2007;67:712-8 pubmed
    ..Genetic analysis of the TSH receptor gene in seven subjects with subclinical hypothyroidism (SH), in whom the diagnosis of autoimmune thyroid disease had been excluded by laboratory and instrumental techniques currently available...
  49. Yamada M. [Resistance to thyroid hormone]. Nihon Rinsho. 2006;64:2237-42 pubmed
    ..It is important to keep this diagnosis in mind when a patient with elevated thyroid hormone level accompanied by normal or slightly increased TSH levels (SITSH) is encountered. Therapy with TRIAC has been used in several patients...
  50. Rohrer T, Gassmann K, Pohlenz J, Dorr H. [Resistance to thyroid hormone - goiter and attention deficit-hyperactivity disorder as main manifestation]. Dtsch Med Wochenschr. 2002;127:1250-2 pubmed
    ..Careful medical history, clinical examination of the patients and careful interpretation of the laboratory results finally led to the diagnosis resistance to thyroid hormone (RTH)...
  51. Yen P. Molecular basis of resistance to thyroid hormone. Trends Endocrinol Metab. 2003;14:327-33 pubmed
    ..This dominant-negative activity has important implications for other hormone-resistant conditions and in hormone-sensitive tumors. This article examines the molecular basis of RTH...
  52. Kannan S, Safer J. Finding the right balance between resistance and sensitivity: a review of the cardiac manifestations of the syndrome of resistance to thyroid hormone and the implications for treatment. Endocr Pract. 2012;18:252-5 pubmed publisher
    ..To review cardiac manifestations in the syndrome of resistance to thyroid hormone (RTH) and to question the general recommendation that the thyroid-stimulating hormone (TSH) value be the guide to thyroid hormone replacement...
  53. Huber B, Sandler B, West B, Cunha Lima S, Nguyen H, Apriletti J, et al. Two resistance to thyroid hormone mutants with impaired hormone binding. Mol Endocrinol. 2003;17:643-52 pubmed
    ..The observation that the Arg 316 His mutation affects these functions implies a role for helix 1 in linking hormone binding to the DNA-binding domain-LBD configuration...