Thyroid Hormone Resistance: Multicentrical Case Series Study

Abstract

Resistance to thyroid hormone syndrome (RTHS) is defined as increased thyroxine and triiodothyronine associated with normal or increased thyrotropin. This is usually due to a pathogenic variant of the gene coding for thyroid hormone receptor B (THRB). THRB is a rare genetic disorder characterized by an altered response of target tissue to the thyroid hormone action. Retrospective cross-sectional observational study with diagnosis of RTHS evaluated in secondary and tertiary hospitals for 6 years, from 2014 to 2020, in order to describe variables including age, sex, anthropometric data, clinical and biochemical characteristics of patients, who were divided according to age, in a pediatric group from 0 to 14 years (index cases), and an adult group composed of adult relatives of index cases. A molecular analysis of the THRB gene was performed. The total retrospective cohort included 7 pediatric patients and 15 adults. We found 22 cases with a clear male predominance (14/22). Mean age is 24.8 years old (22 days-70 years). Patients were referred because of symptoms 18.2% (4/22), analysis results 22.7% (5/22), or familial study 59.1% (13/22). About 31.8% (7/22) cases show goiter, 31.8% (7/22) sympathetic symptoms and 13.6% (3/22) abnormalities in behavior. In most cases, 77.3%, (17/22) show familial background of thyroid abnormalities. It is important to remark that 18.2% (4/22) relatives received previous incorrect treatments such as thyroidectomy, because of wrong diagnosis. In conclusion, a better understanding of RTHS, its prompt molecular diagnosis and genetic counseling, could avoid unnecessary tests and inappropriate treatments.

Key words

resistance to thyroid hormone - thyroid receptor - symptoms - diagnosis - treatment

Publikationsverlauf

Eingereicht: 25. August 2021

Angenommen nach Revision: 14. Dezember 2021

Artikel online veröffentlicht:
07. Februar 2022

• References

• 1 Refetoff S, Bassett JHD, Beck-peccoz P. et al. Classification and proposed nomenclature for transport, and metabolism. J Clin Endocrinol Metab 2014; 99: 768-770
• 2 LaFranchi SH, Snyder DB, Sesser DE. et al. Follow-up of newborns with elevated screening T4 concentrations. J Pediatr 2003; 143: 296-301
• 3 Williams GR, Boelen A, Refetoff S. 13th International workshop on resistance to thyroid hormone and thyroid hormone action. Thyroid 2018; 28: 690-691
• 4 Bernal J. Sindromes de resistencia a las hormonas tiroideas. Endocrinol y Nutr 2011; 58: 185-196 Available from: http://www.elsevier.es/es/linksolver/ft/pii/S1575092211000702
• 5 Lazar MA. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 1993; 14: 184-193
• 6 Agrawal NK, Goyal R, Rastogi A. et al. Thyroid hormone resistance. Postgrad Med J 2008; 84: 473-477
• 7 Pappa T, Refetoff S. Human genetics of thyroid hormone receptor beta:resistance to thyroid hormone beta (RTHβ). Methods Mol Biol 2018; 1801: 225-240
• 8 Moran C, Agostini M, Visser WE. et al. Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients. Lancet Diabetes Endocrinol 2014; 2: 619-626
• 9 Ferrara AM, Onigata K, Ercan O. et al. 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
• 10 Dieu X, Sueur G, Moal V. et al. Apparent resistance to thyroid hormones: From biological interference to genetics. Ann Endocrinol (Paris) 2019; 80: 280-285
• 11 Weiss RE, Hayashi Y, Nagaya T. et al. Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective cofactor. J Clin Endocrinol Metab 1996; 81: 4196-4203
• 12 Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stippled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone12. J Clin Endocrinol Metab 1967; 27: 279-294
• 13 Uter J, Heldmann M, Rogge B. et al. Patients with mutations of the thyroid hormone beta-receptor show an ADHD-like phenotype for performance monitoring: an electrophysiological study. NeuroImage Clin 2020; 26: 102250
• 14 Barkoff MS, Kocherginsky M, Anselmo J. et al. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 2010; 95: 3189-3193
• 15 Guerra-argüero LM, Gutiérrez-saucedo JA, Gómez-coello A. et al. Resistencia a hormonas tiroideas y tiroiditis de Hashimoto. Cir Cir 2011; 453-457
• 16 Choi J-H, Cho JH, Kim JH. et al. Variable clinical characteristics and molecular spectrum of patients with syndromes of reduced sensitivity to thyroid hormone: genetic defects in the THRB and SLC16A2 genes. Horm Res Paediatr 2018; 90: 283-290
• 17 Vela A, Pérez-Nanclares G, Ríos I. et al. Thyroid hormone resistance from newborns to adults: a Spanish experience. J Endocrinol Invest 2019; 42: 941-949
• 18 Xiao X, Lv C, Zhu T. et al. Thyroid hormone resistance and the value of genetics: Three case reports. Medicine (Baltimore) 2019; 98: e14675
• 19 Jackowski T, Petriczko E, Horodnicka-Józwa A. et al. Thyroid hormone resistance syndrome - own experiences. Pediatr Endocrinol Diabetes Metab 2017; 23: 209-214
• 20 Rivas AM, Lado-Abeal J. Thyroid hormone resistance and its management. Vol. 29, Proceedings (Baylor University. Medical Center) 2016; 209-211
• 21 Zaig E, Cohen-Ouaknine O, Tsur A. et al. Clinical and molecular characteristics of eight Israeli families with thyroid hormone receptor beta mutations. Isr Med Assoc J 2018; 20: 679-686
• 22 Toumba M, Neocleous V, Fanis P. et al. Phenotype variability and different genotype of four patients with thyroid hormone resistance syndrome due to variants in the THRB gene. Hippokratia 2019; 23: 135-139
• 23 Pappa T, Anselmo J, Mamanasiri S. et al. Prenatal diagnosis of resistance to thyroid hormone and its clinical implications. J Clin Endocrinol Metab 2017; 102: 3775-3782
• 24 Srichomkwun P, Anselmo J, Liao X-H. et al. Fetal exposure to high maternal thyroid hormone levels causes central resistance to thyroid hormone in adult humans and mice. J Clin Endocrinol Metab 2017; 102: 3234-3240
• 25 Concolino P, Costella A, Paragliola RM. Mutational landscape of resistance to thyroid hormone beta (RTHβ). Mol Diagn Ther 2019; 23: 353-368
• 26 Ramos LS, Kizys MML, Kunii IS. et al. 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
• 27 Sun H, Cao L, Zheng R. et al. Update on resistance to thyroid hormone syndromeβ. Ital J Pediatr 2020; 46: 168
• 28 Groeneweg S, Peeters RP, Visser TJ. et al. Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes. Mol Cell Endocrinol 2017; 458: 82-90