scholarly journals Thyroid hormone resistance detected by routine neonatal screening

2010 ◽  
Vol 54 (8) ◽  
pp. 723-727 ◽  
Author(s):  
Léa Maria Zanini Maciel ◽  
Patrícia Künzle Ribeiro Magalhães
Keyword(s):  
Thyroid Hormone ◽  
Neonatal Screening ◽  
Thyroid Hormone Receptor ◽  
Direct Sequencing ◽  
Receptor Gene ◽  
Confirmatory Test ◽  
Free T4 ◽  
Laboratory Findings ◽  
Normal Delivery ◽  
Brazilian Patient

We report the clinical and laboratory findings, and molecular analysis of a Brazilian patient with resistance to thyroid hormone syndrome (RTH) detected by neonatal screening. The index case was born at term by normal delivery with 2,920 g and 45 cm. TSH of the neonatal screening test performed on the 5th day of life was of 13.1 µU/mL (cut-off = 10 µU/mL). In a confirmatory test, serum TSH level was 4.3 µU/mL, total T4 was 19 µg/dL (confirmed in another sample, Total T4 = > 24.0 µg/dL), free T4 was 3.7 ηg/dL, and free T3 was 6.7 pg/mL. Direct sequencing of the beta thyroid hormone receptor gene revealed mutation c.1357C>A (P453T), confirming the diagnosis of RHT. Family study demonstrated the presence of RTH in his 1-year-and-3-month-old sister, in his 35-year-old father, and in his 68-year-old paternal grandfather. All of them had goiter and only his father had received an erroneous diagnosis of hyperthyroidism. The present case shows that clinical evaluation and a judicious interpretation of total T4/free T4 concentrations in a newborn recalled due to slightly altered neonatal TSH can contribute to the diagnosis of RTH.

scholarly journals E449X mutation in the thyroid hormone receptor β associated with autoimmune thyroid disease and severe neuropsychomotor involvement

2008 ◽  
Vol 52 (8) ◽  
pp. 1205-1210 ◽  
Author(s):  
Maria Helane Costa Gurgel ◽  
Renan M. Montenegro Junior ◽  
Rejane Araujo Magalhaes ◽  
Grayce Ellen da C. Paiva Lima ◽  
Renan Magalhães Montenegro ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Disease ◽  
Autoimmune Thyroid Disease ◽  
Thyroid Hormone Receptor ◽  
Clinical Laboratory ◽  
Stop Codon ◽  
Molecular Study ◽  
Laboratory Findings ◽  
Autoimmune Thyroid ◽  
Brazilian Patient

OBJECTIVE: To report the clinical and molecular aspects of a patient with a diagnosis of Resistance to Thyroid Hormone (RTH) harboring the E449X mutation associated with autoimmune thyroid disease and severe neuropsychomotor retardation. METHODS: We present a case report including clinical and laboratory findings, and molecular analysis of a Brazilian patient with RTH. RESULTS: A 23-year old male presented hyperactivity disorder, attention deficit, delayed neuropsychomotor development, and goiter. Since the age of 1 year and 8 months, his mother had sought medical care for her son for the investigation of delayed neuropsychomotor development associated with irritability, aggressiveness, recurrent headache, profuse sudoresis, intermittent diarrhea, polyphagia, goiter, and low weight. Laboratory tests revealed normal TSH, increased T3, T4, antithyroglobulin and antimicrosomal antibody titers. Increasing doses of levothyroxine were prescribed, reaching 200 µg/day, without significant changes in his clinical-laboratory picture. Increasing doses of tiratricol were introduced, with a clear clinical improvement of aggressiveness, hyperactivity, tremor of the extremities, and greater weight gain. Molecular study revealed a nonsense mutation in exon 10, in which a substitution of a guanine to tyrosine in nucleotide 1345 (codon 449) generates the stop codon TAA, confirming the diagnosis of RTH. CONCLUSION: This patient has severe neuropsychomotor retardation not observed in a single previous report with the same mutation. This may reflect the lack of a genotype-phenotype correlation in affected cases with this syndrome, suggesting that genetic variability of factors other than β receptor of thyroid hormone (TRβ) might modulate the phenotype of RTH.

scholarly journals Thyroid hormone receptor β mutations in the ‘hot-spot region’ are rare events in thyroid carcinomas

2007 ◽  
Vol 192 (1) ◽  
pp. 83-86 ◽  
Author(s):  
Ana Sofia Rocha ◽  
Ricardo Marques ◽  
Inês Bento ◽  
Ricardo Soares ◽  
João Magalhães ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Hormone ◽  
Transgenic Mice ◽  
Cell Lines ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Hot Spot ◽  
Direct Sequencing ◽  
Human Thyroid ◽  
Thyroid Hormone Receptor Β

Thyroid cancer constitutes the most frequent endocrine neoplasia. Targeted expression of rearranged during transfection (RET)/papillary thyroid carcinoma (PTC) and V600E V-raf murine sarcoma viral oncogene homolog B1 (BRAF) to the thyroid glands of transgenic mice results in tumours similar to those of human PTC, providing evidence for the involvement of these oncogenes in PTC. Kato et al. developed a mouse model that mimics the full spectrum of the human follicular form of thyroid cancer (FTC). FTC rapidly develops in these mice through introduction of the thyroid hormone receptor β (THRB)PV mutant on the background of the inactivated THRB wt locus. Our aim was to verify if, in the context of human follicular thyroid carcinogenesis, THRB acted as a tumour suppressor gene. We screened for mutations of the THRB gene in the hot-spot region, spanning exons 7–10, in 51 thyroid tumours and six thyroid cancer cell lines by PCR and direct sequencing. We did not find mutations in any of the tumours or cell lines analysed. Our findings suggest that, in contrast to the findings on the THRB-mutant transgenic mice, THRB gene mutations are not a relevant mechanism for human thyroid carcinogenesis.

Effects of thyroid hormone receptor gene disruption on myosin isoform expression in mouse skeletal muscles

2000 ◽  
Vol 278 (6) ◽  
pp. R1545-R1554 ◽  
Author(s):  
Fushun Yu ◽  
Sten Göthe ◽  
Lilian Wikström ◽  
Douglas Forrest ◽  
Björn Vennström ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Receptor Gene ◽  
Type I ◽  
Variable Response ◽  
Slow Type ◽  
Isoform Expression ◽  
Edl Muscle ◽  
Deficient Mice

Skeletal muscle is known to be a target for the active metabolite of thyroid hormone, i.e., 3,5,3′-triiodothyronine (T3). T3 acts by repressing or activating genes coding for different myosin heavy chain (MHC) isoforms via T3 receptors (TRs). The diverse function of T3 is presumed to be mediated by TR-α1 and TR-β, but the function of specific TRs in regulating MHC isoform expression has remained undefined. In this study, TR-deficient mice were used to expand our knowledge of the mechanisms by which T3 regulates the expression of specific MHC isoforms via distinct TRs. In fast-twitch extensor digitorum longus (EDL) muscle, TR-α1-, TR-β-, or TR-α1β-deficient mice showed a small but statistically significant decrease ( P < 0.05) of type IIB MHC content and an increased number of type I fibers. In the slow-twitch soleus, the β/slow MHC (type I) isoform was significantly ( P < 0.001) upregulated in the TR-deficient mice, but this effect was highly dependent on the type of receptor deleted. The lack of TR-β had no significant effect on the expression of MHC isoforms. An increase ( P < 0.05) of type I MHC was observed in the TR-α1-deficient muscle. A dramatic overexpression ( P < 0.001) of the slow type I MHC and a corresponding downregulation of the fast type IIA MHC ( P < 0.001) was observed in TR-α1β-deficient mice. The muscle- and fiber-specific differences in MHC isoform expression in the TR-α1β-deficient mice resembled the MHC isoform transitions reported in hypothyroid animals, i.e., a mild MHC transition in the EDL, a dramatic but not complete upregulation of the β/slow MHC isoform in the soleus, and a variable response to TR deficiency in different soleus muscle fibers. Thus the consequences on muscle are similar in the absence of thyroid hormone or absence of thyroid hormone receptors, indicating that TR-α1 and TR-β together mediate the known actions of T3. However, it remains unknown how thyroid hormone exerts muscle- and muscle fiber-specific effects in its action. Finally, although developmental MHC transitions were not studied specifically in this study, the absence of embryonic and fetal MHC isoforms in the TR-deficient mice indicates that ultimately the transition to the adult MHC isoforms is not solely mediated by TRs.

scholarly journals Thyroid Hormone Resistance Syndrome Presenting as Exercise Induced Asthma

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A707-A708
Author(s):  
Joshua D Umscheid ◽  
Naim Mitre ◽  
Fadi Jamil Odeh Al Muhaisen
Keyword(s):  
Genetic Testing ◽  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Receptor Gene ◽  
Target Tissue ◽  
Hormone Resistance ◽  
Color Flow ◽  
Thyroid Hormone Resistance ◽  
Hormone Levels ◽  
Thyroid Hormone Levels

Abstract Background: Pathogenic variants in the thyroid hormone receptor (THRB) gene are associated with thyroid hormone resistance. Over 85% of the genetic mutations are in the beta TR gene. The disorder is characterized mainly by elevated thyroid hormone levels, unsuppressed levels of TSH, and goiter. Clinical case: An 11-year-old male initially seen at the PCP office for tachycardia and chest discomfort, especially during school exercise. He reported shortness of breath. His symptoms will resolve at rest. He was diagnosed initially with asthma and was put on Singular, Pulmicort, and albuterol as needed. His symptoms did not improve with this treatment, and he reported symptoms worsened with albuterol. He had a normal Echocardiogram and chest X-ray. A mild goiter was noted on his physical exam. Thyroid ultrasound showed an enlarged thyroid gland. An ovoid echogenic focus in the inferior thyroid lobe measuring 4 X 7 X 8mm was identified. The nodule was wider than tall, with a solid appearance with no internal color flow. Evaluation in our clinic showed normal TSH at 1.624mcIU/mL (0.35-5.5). FT4 was high at 1.54ng/dL (0.82-1.40), and FT3 elevated at 6.3pg/mL (3.3-4.8). Thyroid antibodies and thyroid-stimulating immunoglobulin (TSI) were normal. A 24 hour I-123 thyroid uptake was approximately 55% (10-30%) with no focal increased or decreased uptake. Given his elevated thyroid hormone levels with unsuppressed TSH in the context of goiter and tachycardia, genetic testing for the Thyroid receptor gene was done. He was found to be heterozygous for a pathogenic variant in THRB, c.1286G&gt;A (p.Arg429Gln). This genotype is consistent with a diagnosis of autosomal dominant Thyroid hormone resistance. The patient was started on Atenolol, given his elevated heart rate, and he reported improvement in his symptoms during exercise. Conclusion: Thyroid hormone resistance was first described as a clinical entity in 1967. The phenotype can vary among individuals. It is characterized by a reduced responsiveness of target tissue to thyroid hormone and binding affinity. The disease can present with goiter, behavioral issues, abnormal growth, and tachycardia. Affected individuals may have attention deficit-hyperactivity disorders (ADHD) and language difficulties. Thyroid hormone resistance can be misdiagnosed, as in our patient. He was diagnosed with asthma and was put on unnecessary medications that worsened his symptoms. Thyroid hormone resistance can also be misdiagnosed with Graves’ disease, given the elevated thyroid hormone. It is essential to highlight the importance of genetic testing in these cases, as an accurate diagnosis will prevent unnecessary treatments with potentially serious side effects.

scholarly journals Familial Dysalbuminemic Hyperthyroxinemia: An Underdiagnosed Entity

2020 ◽  
Vol 9 (7) ◽  
pp. 2105
Author(s):  
Xavier Dieu ◽  
Nathalie Bouzamondo ◽  
Claire Briet ◽  
Frédéric Illouz ◽  
Valérie Moal ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Clinical Symptoms ◽  
Free T4 ◽  
Biochemical Alterations ◽  
Upper Limit ◽  
Albumin Gene ◽  
Thyroid Hormone Receptor Β ◽  
Index Cases

Resistance to thyroid hormone (RTH) is a syndrome characterized by impaired sensitivity of tissues to thyroid hormone (TH). The alteration of TH-binding proteins, such as in Familial Dysalbuminemic Hyperthyroxinemia (FDH), can mimic the abnormal serum thyroid tests typical of RTH. We aimed to characterize a population referred to our center with suspected RTH and estimate the proportion of patients with FDH. For 303 different families, we collected clinical and hormonal data and sequenced the thyroid hormone receptor β gene (THRB) and exon 7 of the albumin gene (ALB). We found 56 THRB variants (i.e., 38% of the 303 index cases, called RTHβ group). Among the samples screened for FDH variants, 18% had the variant R218H in ALB (FDH group); in addition, 71% of the cases had neither variant (non-FDH/RTHβ group). Patients with FDH had significantly lower free T3 (fT3) and free T4 (fT4) levels and more often an isolated elevation of fT4 than RTHβ patients. Clinically, patients with FDH had fewer symptoms than patients with RTHβ. Our study suggests that FDH should be systematically considered when examining patients suspected of having RTH. In most cases, they present no clinical symptoms, and their biochemical alterations show an elevation of fT4 levels, while fT3 levels are 1.11 times below the upper limit of the assay.

scholarly journals Hypercholesterolemia in Two Siblings with Resistance to Thyroid Hormones Due to Disease-Causing Variant in Thyroid Hormone Receptor (THRB) Gene

Medicina ◽  
2020 ◽  
Vol 56 (12) ◽  
pp. 699
Author(s):  
Maja Pajek ◽  
Magdalena Avbelj Stefanija ◽  
Katarina Trebusak Podkrajsek ◽  
Jasna Suput Omladic ◽  
Mojca Zerjav Tansek ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Pathogenic Mutation ◽  
Laboratory Findings ◽  
Cholesterol Levels ◽  
Resistance To Thyroid Hormones ◽  
Hormonal Resistance ◽  
Disease Variant

Resistance to thyroid hormone beta (RTHβ) is a syndrome characterized by a reduced response of target tissues to thyroid hormones. In 85% of cases, a pathogenic mutation in the thyroid hormone receptor beta (THRB) gene is found. The clinical picture of RTHβ is very diverse; the most common findings are goiter and tachycardia, but the patients might be clinically euthyroid. The laboratory findings are almost pathognomonic with elevated free thyroxin (fT4) levels and high or normal thyrotropin (TSH) levels; free triiodothyronin (fT3) levels may also be elevated. We present three siblings with THRB mutation (heterozygous disease-variant c.727C>T, p.Arg243Trp); two of them also had hypercholesterolemia, while all three had several other clinical characteristics of RTHβ. This is the first description of the known Slovenian cases with RTHβ due to the pathogenic mutation in the THRB gene. Hypercholesterolemia might be etiologically related with RTHβ, since the severity of hormonal resistance varies among different tissues and hypercholesterolemia in patients with THRB variants might indicate the relatively hypothyroid state of the liver. We suggest that cholesterol levels are measured in all RTHβ patients.

scholarly journals Regulation of the mdm2 Oncogene by Thyroid Hormone Receptor

1999 ◽  
Vol 19 (1) ◽  
pp. 864-872 ◽  
Author(s):  
Jian-Shen Qi ◽  
Yaping Yuan ◽  
Vandana Desai-Yajnik ◽  
Herbert H. Samuels
Keyword(s):  
Cell Cycle ◽  
Thyroid Hormone ◽  
Gene Family ◽  
Thyroid Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Receptor Gene ◽  
Gene Promoter ◽  
Orphan Nuclear Receptor ◽  
Retinoid Receptor ◽  
Dna Elements

ABSTRACT The mdm2 gene is positively regulated by p53 through a p53-responsive DNA element in the first intron of the mdm2gene. mdm2 binds p53, thereby abrogating the ability of p53 to activate the mdm2 gene, and thus forming an autoregulatory loop ofmdm2 gene regulation. Although the mdm2 gene is thought to act as an oncogene by blocking the activity of p53, recent studies indicate that mdm2 can act independently of p53 and block the G1 cell cycle arrest mediated by members of the retinoblastoma gene family and can activate E2F1/DP1 and the cyclin A gene promoter. In addition, factors other than p53 have recently been shown to regulate the mdm2 gene. In this article, we report that thyroid hormone (T3) receptors (T3Rs), but not the closely related members of the nuclear thyroid hormone/retinoid receptor gene family (retinoic acid receptor, vitamin D receptor, peroxisome proliferation activation receptor, or retinoid X receptor), regulate mdm2 through the same intron sequences that are modulated by p53. Chicken ovalbumin upstream promoter transcription factor I, an orphan nuclear receptor which normally acts as a transcriptional repressor, also activatesmdm2 through the same intron region of the mdm2gene. Two T3R-responsive DNA elements were identified and further mapped to sequences within each of the p53 binding sites of themdm2 intron. A 10-amino-acid sequence in the N-terminal region of T3Rα that is important for transactivation and interaction with TFIIB was also found to be important for activation of themdm2 gene response element. T3 was found to stimulate the endogenous mdm2 gene in GH4C1 cells. These cells are known to express T3Rs, and T3 is known to stimulate replication of these cells via an effect in the G1 phase of the cell cycle. Our findings, which indicate that T3Rs can regulate the mdm2gene independently of p53, provide an explanation for certain known effects of T3 and T3Rs on cell proliferation. In addition, these findings provide further evidence for p53-independent regulation of mdm2 which could lead to the development of tumors from cells that express low levels of p53 or that express p53 mutants defective in binding to and activating the mdm2 gene.

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