Abstract
Objective
Resistance to thyroid hormone beta (RTHβ) is a rare disorder characterized by a fairly heterogeneous clinical presentation due to varying degrees of tissue response to thyroid hormone. The present study aimed to evaluate the clinical and laboratory features and genotype-phenotype relationship of Turkish patients with RTHβ.
Methods
Patients who underwent a THRβ gene analysis between September 2019 and September 2023 were retrospectively reviewed.
Results
Fifty patients with the clinical features of RTHβ syndrome or a family history of an index case were included. A total of eight different heterozygous pathogenic/likely pathogenic missense variants, three of which were novel, were detected in THRB in 30 patients from 8 unrelated families. Although most patients with RTHβ were asymptomatic, seven patients exhibited various symptoms. Moreover, seven patients had received various treatments before diagnosis. Thyroid autoantibody was positive in 23% of all cases with a variant, and goitre was detected in 56% of children with a variant. While thyroid nodules were detected in seven adult patients, two adults had been diagnosed with papillary thyroid cancer. One child had attention-deficit disorder, learning disability, and type 1 diabetes mellitus. Of the 20 patients without a variant, TSHoma was detected in one.
Conclusion
The present study provides an overview of clinical and genetic characteristics of patients with genetically confirmed RTHβ and expanded the THRB gene variantdatabase with three novel variants. Although most patients with RTHβ are asymptomatic, molecular genetic analysis of the THRB gene and regular follow-up because of the apparent risk of concurrent autoimmune diseases or thyroid cancer is warranted.
Keywords: Thyroid hormones, resistance to thyroid hormone, THRB gene, autoimmune thyroid disease, goitre
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References
Dumitrescu AM, Korwutthikulrangsri M, Refetof S. Impaired sensitivity to thyroid hormone: defects of transport, metabolism, and action. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc. Copyright©2000-2023, MDText.com, Inc.; 2000. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285557/?report=reader
Rurale G, Di Cicco E, Dentice M, Salvatore D, Persani L, Marelli F, Luongo C. Thyroid hormone hyposensitivity: from genotype to phenotype and back. Front Endocrinol (Lausanne). 2020;10:912.
Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev. 1993;14:348-399.
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;21:277-305.
Zhao J, Xu L, Li C, Wang F, Liao L, Dong J. The clinical characteristics and gene mutations associated with thyroid hormone resistance syndrome coexisting with pituitary tumors. Front Endocrinol (Lausanne). 2023;14:1131044.
Lafranchi SH, Snyder DB, Sesser DE, Skeels MR, Singh N, Brent GA, Nelson JC. Follow-up of newborns with elevated screening T4 concentrations. J Pediatr. 2003;143:296-301.
Vela A, Pérez-Nanclares G, Ríos I, Rica I, Portillo N, Castaño L. Thyroid hormone resistance from newborns to adults: a Spanish experience. J Endocrinol Invest. 2019;42:941-949. Epub 2019 Feb 1.
Pappa T, Refetoff S. Human genetics of thyroid hormone receptor beta: resistance to thyroid hormone beta (RTHβ). Methods Mol Biol. 2018;1801:225-240.
Pappa T, Refetoff S. Resistance to thyroid hormone beta: a focused review. Front Endocrinol (Lausanne). 2021;12:656551.
Singh BK, Yen PM. A clinician’s guide to understanding resistance to thyroid hormone due to receptor mutations in the TRα and TRβ isoforms. Clin Diabetes Endocrinol. 2017;3:8.
Sakurai A, Nakai A, DeGroot LJ. Structural analysis of human thyroid hormone receptor beta gene. Mol Cell Endocrinol. 1990;71:83-91.
Ferrara AM, Onigata K, Ercan O, Woodhead H, Weiss RE, Refetoff S. Homozygous thyroid hormone receptor β-gene mutations in resistance to thyroid hormone: three new cases and review of the literature. J Clin Endocrinol Metab. 2012;97:1328-1336. Epub 2012 Feb 8.
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. Thyroid. 2014;24:407-409.
Poyrazoğlu S, Tütüncüler F, Baş F, Darendeliler F. Resistance to thyroid hormone in a Turkish child with A317T mutation in the thyroid hormone receptor-beta gene. Turk J Pediatr. 2008;50:577-580.
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;22:971-978.
Işık E, Beck Peccoz P, Campi I, Özön A, Alikaşifoğlu A, Gönç N, Kandemir N. Thyroid hormone resistance: a novel mutation in thyroid hormone receptor beta(THRB) gene - case report. Turk J Pediatr. 2013;55:322-327.
Aydıner Ö, Karakoç Aydıner E, Akpınar İ, Turan S, Bereket A. Normative data of thyroid volume-ultrasonographic evaluation of 422 subjects aged 0-55 years. J Clin Res Pediatr Endocrinol. 2015;7:98-101.
Brunn J, Block U, Ruf G, Bos I, Kunze WP, Scriba PC. [Volumetric analysis of thyroid lobes by real-time ultrasound (author’s transl)]. Dtsch Med Wochenschr. 1981;106:1338-1340.
Ghervan C. Thyroid and parathyroid ultrasound. Med Ultrason. 2011;13:80-84.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-424. Epub 2015 Mar 5.
Karakose M, Caliskan M, Arslan MS, Cakal E, Yesilyurt A, Delibasi T. Thyroid hormone resistance in two patients with papillary thyroid microcarcinoma and their BRAFV600E mutation status. Arch Endocrinol Metab. 2015;59:364-366.
Ramos LS, Kizys MML, Kunii IS, Spinola-Castro AM, Nesi-França S, Guerra RA, Camacho CP, Martins JRM, Maciel RMB, Dias-da-Silva MR, Chiamolera MI. Assessing the clinical and molecular diagnosis of inherited forms of impaired sensitivity to thyroid hormone from a single tertiary center. Endocrine. 2018;62:628-638.
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;123:572-583.
Tagami T. An overview of thyroid function tests in subjects with resistance to thyroid hormone and related disorders. Endocr J. 2021;68:509-517. Epub 2021 May 6.
Ohba K, Sasaki S, Misawa Nakamura H, Matsushita A, Kuroda G, Sakai Y, Nakamura H. Clinical outcomes of 34 patients with resistance to thyroid hormone beta: a twenty-year experience in Japan. Endocr J. 2022;69:179-188. Epub 2021 Sep 22.
Chiesa A, Olcese MC, Papendieck P, Martinez A, Vieites A, Bengolea S, Targovnik H, Rivolta C, Rivolta C, Gruñeiro-Papendieck L. Variable clinical presentation and outcome in pediatric patients with resistance to thyroid hormone (RTH). Endocrine. 2012;41:130-137.
Groeneweg S, Peeters RP, Visser TJ, Visser WE. Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes. Mol Cell Endocrinol. 2017;458:82-90. Epub 2017 Feb 21.
Persani L, Borgato S, Romoli R, Asteria C, Pizzocaro A, Beck-Peccoz P. Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states. J Clin Endocrinol Metab. 1998;83:2486-2492.
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;91:3471-3477. Epub 2006 Jun 27.
Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab. 2010;95:3189-3193. Epub 2010 May 5.
Gavin C, Meggison H, Ooi TC. Proposing a causal link between thyroid hormone resistance and primary autoimmune hypothyroidism. Med Hypotheses. 2008;70:1024-1028. Epub 2007 Oct 4.
Fabris N, Mocchegiani E, Mariotti S, Pacini F, Pinchera A. Thyroid function modulates thymic endocrine activity. J Clin Endocrinol Metab. 1986;62:474-478.
Villa-Verde DM, Defresne MP, Vannier-dos-Santos MA, Dussault JH, Boniver J, Savino W. Identification of nuclear triiodothyronine receptors in the thymic epithelium. Endocrinology. 1992;131:1313-1320.
Wu D, Guo R, Guo H, Li Y, Guan H, Shan Z. Resistance to thyroid hormone β in autoimmune thyroid disease: a case report and review of literature. BMC Pregnancy Childbirth. 2018;18:468.
Stagi S, Manoni C, Cirello V, Covelli D, Giglio S, Chiarelli F, Seminara S, de Martino M. Diabetes mellitus in a girl with thyroid hormone resistance syndrome: a little recognized interaction between the two diseases. Hormones (Athens). 2014;13:561-567. Epub 2014 Nov 5.
Cortizo AM, Chazenbalk GD, de Gagliardino EE, García ME, Pisarev MA, Gagliardino JJ. Thyroid hormone binding and deiodination by pancreatic islets: relationship with the in vitro effect upon insulin secretion. Acta Endocrinol (Copenh). 1987;116:66-72.
Verga Falzacappa C, Petrucci E, Patriarca V, Michienzi S, Stigliano A, Brunetti E, Toscano V, Misiti S. Thyroid hormone receptor TRbeta1 mediates Akt activation by T3 in pancreatic beta cells. J Mol Endocrinol. 2007;38:221-233.
Fukuchi M, Shimabukuro M, Shimajiri Y, Oshiro Y, Higa M, Akamine H, Komiya I, Takasu N. Evidence for a deficient pancreatic beta-cell response in a rat model of hyperthyroidism. Life Sci. 2002;71:1059-1070.
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;120:1345-1354. Epub 2010 Mar 8.
Kim WG, Cheng SY. Thyroid hormone receptors and cancer. Biochim Biophys Acta. 2013;1830:3928-3936. Epub 2012 Apr 6.
Taniyama M, Ishikawa N, Momotani N, Ito K, Ban Y. Toxic multinodular goitre in a patient with generalized resistance to thyroid hormone who harbours the R429Q mutation in the thyroid hormone receptor beta gene. Clin Endocrinol (Oxf). 2001;54:121-124.
Fang Y, Liu T, Hou H, Wang Z, Shan Z, Cao Y, Teng X. Resistance to thyroid hormone beta coexisting with papillary thyroid carcinoma-two case reports of a thyroid hormone receptor beta gene mutation and a literature review. Front Genet. 2022;13:1014323.
Gürkan H, Çelik M, Yaylalı GF, Algün E, Çalışkan M, Omma T, Yıldırım R, Unal E, Bülbül BY, Ulusal S. Analysis of THRβ gene in Turkish patients and definition of three novel pathogenic variants. J Clin Res Pediatr Endocrinol. 2017;9:30.
