A three-year-old female with a history of recurrent tonsillitis was investigated for failure to thrive and global developmental delay. Clinically, she had a triangular face with low-set ears and intermittent tachycardia. She had growth failure with her weight under the third centile while her height was within normal limits. Other systemic examinations were unremarkable. The presence of an elevated free T4 (FT4) with an inappropriately high thyroid stimulating hormone (TSH) in this patient raised the clinical suspicion of Thyroid Hormone Resistance Syndrome. DNA sequencing confirmed the diagnosis, which showed R243W gene mutation in Thyroid Hormone Receptor-Beta1 (THRB1).
Receptors, Thyroid Hormone ; Thyroid Hormone Resistance Syndrome ; Goiter

OBJECTIVE: To preliminarily investigate the relationship between stimulatory G protein α subunit (GNAS) and thyroid hormone receptor α (THRA) gene mutations and clinical phenotypes in children with congenital hypothyroidism (CH). METHODS: A total of 70 children with CH diagnosed by neonatal screening were enrolled. Their peripheral blood samples were collected to extract genomic DNA. GNAS and THRA genes were screened for mutations using next-generation sequencing. Bioinformatics software was used to analyze the pathogenicity of gene mutations. RESULTS: Of the 70 children with CH, nine missense mutations (three known mutations and six novel mutations) in the GNAS gene were detected in three patients (4%), and one gene polymorphism, c.508A>G(p.I170V), in the THRA gene was detected in four patients. The analysis results of bioinformatics software and ACMG/AMP guidelines showed that the two GNAS gene mutations [c.301C>T(p.R101C) and c.334G>A(p.E112K)] were more likely to be pathogenic. Three children with GNAS gene mutations showed different degrees of hypothyroidism. CONCLUSIONS GNAS gene mutations are related to the development of CH, and children with CH have different clinical manifestations. THRA gene mutations may not be associated with CH.
Chromogranins ; genetics ; Congenital Hypothyroidism ; GTP-Binding Protein alpha Subunits, Gs ; genetics ; Genes, erbA ; Humans ; Infant, Newborn ; Mutation ; Phenotype ; Thyroid Hormone Receptors alpha ; genetics

In recent decades, attention has been directed toward the effects of bisphenol A (BPA) on human health. BPA has estrogenic activity and is regarded as a representative endocrine disruptor. In addition, mounting evidence indicates that BPA can disrupt thyroid hormone and its action. This review examined human epidemiological studies to investigate the association between BPA exposure and thyroid hormone levels, and analyzed in vivo and in vitro experiments to identify the causal relationship and its mechanism of action. BPA is involved in thyroid hormone action not only as a thyroid hormone receptor antagonist, but also through several other mechanisms. Since the use of bisphenols other than BPA has recently increased, we also reviewed the effects of other bisphenols on thyroid hormone action.
Endocrine Disruptors ; Epidemiologic Studies ; Estrogens ; Humans ; In Vitro Techniques ; Receptors, Thyroid Hormone ; Thyroid Gland ; Thyroid Hormones

Resistance to thyroid hormone (RTH) is a condition caused by a mutation in the thyroid hormone receptor gene. It is rarely reported in individuals with no family history of RTH or in premature infants, and its clinical presentation varies. In our case, a premature infant with no family history of thyroid diseases had a thyroid stimulating hormone level of 85.0 µIU/mL and free thyroxine level of 1.64 ng/dL on a thyroid function test. The patient also presented with clinical signs of hypothyroidism, including difficulties in feeding and weight gain. The patient was treated with levothyroxine; however, only free thyroxine and triiodothyronine levels increased without a decrease in thyroid-stimulating hormone levels. Taken together with thyroid gland hypertrophy observed on a previous ultrasound examination, RTH was suspected and the diagnosis was eventually made based on a genetic test. A de novo mutation in the thyroid hormone receptor β gene in the infant was found that has not been previously reported. Other symptoms included tachycardia and pulmonary hypertension, but gradual improvement in the symptoms was observed after liothyronine administration. This report describes a case involving a premature infant with RTH and a de novo mutation, with no family history of thyroid disease.
Diagnosis ; Goiter ; Humans ; Hypertension, Pulmonary ; Hypertrophy ; Hypothyroidism ; Infant ; Infant, Newborn ; Infant, Premature ; Receptors, Thyroid Hormone ; Tachycardia ; Thyroid Diseases ; Thyroid Function Tests ; Thyroid Gland ; Thyroid Hormone Receptors beta ; Thyroid Hormone Resistance Syndrome ; Thyrotropin ; Thyroxine ; Triiodothyronine ; Ultrasonography ; Weight Gain

Thyroid hormone resistance is a rare syndrome of reduced tissue responsiveness to thyroid hormone. We report the case of a 13-month girl with short height and low weight. She was born at 37+6 weeks gestation and weighed 2,470 g. In the neonatal screening test, patients' thyroid stimulation hormone (TSH) level was increased to 13.1 µIU/mL. In follow-up test after getting levothyroxine medication, patients' free T4 level continued to increase and TSH level was normalized. After stop medication, the patient visited Soonchunhyang University Seoul Hospital every 2 to 3 months and done laboratory test, and the result was not changed. Despite good feeding, she consistently shows 5–10 percentile weight and 5–10 percentile height. Her bone age was delayed by 5 months compared to the expected age. In suspicious thyroid hormone resistance, THRβ gene study and brain magnetic resonance imaging (MRI), and T3 suppression test was done. Brain MRI and T3 suppression test shows the exception of pituitary thyroid adenoma. Gene study result was THRβ gene mutation, c.1012C>T (p.Arg338Trp), and heterozygous. This gene mutation was reported at thyroid hormone resistance family. After diagnosis of thyroid hormone resistance, because of the patient is asymptomatic, she does not have medication. We are checking developmental delay, growth delay, and other clinical hypothyroid symptoms.
Brain ; Diagnosis ; Female ; Follow-Up Studies ; Humans ; Infant, Newborn ; Magnetic Resonance Imaging ; Neonatal Screening ; Pregnancy ; Seoul ; Thyroid Function Tests ; Thyroid Gland* ; Thyroid Hormone Receptors beta ; Thyroid Hormone Resistance Syndrome* ; Thyroid Neoplasms ; Thyroxine

BACKGROUND: Expression of hepatic cholesterol 7alpha-hydroxylase (CYP7A1) is negatively regulated by orphan nuclear receptor small heterodimer partner (SHP). In this study, we aimed to find whether thyroid hormone regulates SHP expression by modulating the transcriptional activities of liver receptor homolog-1 (LRH-1). METHODS: We injected thyroid hormone (triiodothyronine, T3) to C57BL/6J wild type. RNA was isolated from mouse liver and used for microarray analysis and quantitative real-time polymerase chain reaction (PCR). Human hepatoma cell and primary hepatocytes from mouse liver were used to confirm the effect of T3 in vitro. Promoter assay and electrophoretic mobility-shift assay (EMSA) were also performed using human hepatoma cell line RESULTS: Initial microarray results indicated that SHP expression is markedly decreased in livers of T3 treated mice. We confirmed that T3 repressed SHP expression in the liver of mice as well as in mouse primary hepatocytes and human hepatoma cells by real-time PCR analysis. LRH-1 increased the promoter activity of SHP; however, this increased activity was markedly decreased after thyroid hormone receptor beta/retinoid X receptor alpha/T3 administration. EMSA revealed that T3 inhibits specific LRH-1 DNA binding. CONCLUSION: We found that thyroid hormone regulates the expression of SHP mRNA through interference with the transcription factor, LRH-1.
Animals ; Bile Acids and Salts ; Carcinoma, Hepatocellular ; Cell Line ; Child ; Child, Orphaned ; Cholesterol ; Cholesterol 7-alpha-Hydroxylase ; DNA ; Hepatocytes ; Humans ; Liver* ; Mice ; Microarray Analysis ; Real-Time Polymerase Chain Reaction ; Receptors, Thyroid Hormone ; RNA ; RNA, Messenger* ; Thyroid Gland* ; Thyroid Hormones ; Transcription Factors

Humans ; Infant ; Infant, Newborn ; Male ; Mutation ; Thyroid Hormone Receptors beta ; genetics ; Thyroid Hormone Resistance Syndrome ; genetics

Resistance to thyroid hormone (RTH) is a rare inherited syndrome characterized by diminished response of the target tissue to thyroid hormone caused, in the majority of cases, by mutation of the thyroid hormone receptor beta (THRbeta) gene. Despite elevated serum levels of free thyroid hormones and thyroid stimulating hormone (TSH), the paucity of symptoms and signs of thyroid dysfunction suggest RTH. We report the case of a 9-year-old girl with goiter. Her thyroid function tests showed increased serum levels of free thyroxine, triiodothyronine, and TSH. The genetic analysis of THRbeta confirmed a novel mutation in exon 9; this was a heterozygous C-to-T change in the 327th codon, substituting threonine for isoleucine (T327I).
Child ; Codon ; Exons ; Female ; Goiter ; Humans ; Isoleucine ; Threonine ; Thyroid Function Tests ; Thyroid Gland* ; Thyroid Hormone Receptors beta* ; Thyroid Hormone Resistance Syndrome ; Thyroid Hormones ; Thyrotropin ; Thyroxine ; Triiodothyronine

The pyruvate dehydrogenase complex (PDC) activity is crucial to maintains blood glucose and ATP levels, which largely depends on the phosphorylation status by pyruvate dehydrogenase kinase (PDK) isoenzymes. Although it has been reported that PDC is phosphorylated and inactivated by PDK2 and PDK4 in metabolically active tissues including liver, skeletal muscle, heart, and kidney during starvation and diabetes, the precise mechanisms by which expression of PDK2 and PDK4 are transcriptionally regulated still remains unclear. Insulin represses the expression of PDK2 and PDK4 via phosphorylation of FOXO through PI3K/Akt signaling pathway. Several nuclear hormone receptors activated due to fasting or increased fat supply, including peroxisome proliferator-activated receptors, glucocorticoid receptors, estrogen-related receptors, and thyroid hormone receptors, also participate in the up-regulation of PDK2 and PDK4; however, the endogenous ligands that bind those nuclear receptors have not been identified. It has been recently suggested that growth hormone, adiponectin, epinephrine, and rosiglitazone also control the expression of PDK4 in tissue-specific manners. In this review, we discuss several factors involved in the expressional regulation of PDK2 and PDK4, and introduce current studies aimed at providing a better understanding of the molecular mechanisms that underlie the development of metabolic diseases such as diabetes.
Adenosine Triphosphate ; Adiponectin ; Blood Glucose ; Epinephrine ; Fasting ; Growth Hormone ; Heart ; Insulin ; Insulin Resistance ; Isoenzymes ; Kidney ; Ligands ; Liver ; Metabolic Diseases ; Muscle, Skeletal ; Oxidoreductases ; Peroxisome Proliferator-Activated Receptors ; Phosphorylation ; Phosphotransferases ; Protein-Serine-Threonine Kinases ; Pyruvate Dehydrogenase Complex ; Pyruvic Acid ; Receptors, Cytoplasmic and Nuclear ; Receptors, Glucocorticoid ; Receptors, Thyroid Hormone ; Starvation ; Thiazolidinediones ; Up-Regulation

BACKGROUNDResistance to thyroid hormone (RTH) is a dominant inherited syndrome of reduced tissue responsiveness to thyroid hormone. It is usually due to mutations located at the ligand-binding domain and adjacent hinge region of the thyroid hormone receptor β (TRβ). We report the clinical and laboratory characteristics and the genetic analysis of a patient with this rare disorder and his family members.

METHODSThe clinical presentations and changes of thyroid function tests (TFTs) including magnetic resonance imaging (MRI) of pituitary and other laboratory tests were analysed. TFTs of his family's members were detected as well. Direct DNA sequencing of the TRβ gene was done for those with abnormal TFTs.

RESULTSThe RTH child had goiter, irritability, aggressiveness, and sudoresis. His TFTs showed high levels of circulating free thyroid hormones (FT(4) and FT(3)) and normal thyroid-stimulating hormone (TSH) concentrations. He felt worse when treated as hyperthyroidism (Grave disease) with thiamazole and his clinical presentations got improved obviously when treated as RTH with bromocriptine without obvious advert effect. We identified a novel missense mutation, A317D, located in exon 9 of the gene of this boy and his mother. His mother had not any clinical presentation, but having abnormal TFTs results.

CONCLUSIONSThis patient reported here was concordant with the criteria of RTH. The feature is dysfunction of hypothalamus-pituitary-thyroid axis. A novel mutation was found in the TRβ, A317D, of this family. This research verified the phenomena that there is a clinical heterogeneity within the same mutation of different RTH patients.

Child ; Diagnosis, Differential ; Humans ; Male ; Mutation, Missense ; Thyroid Hormone Receptors beta ; genetics ; Thyroid Hormone Resistance Syndrome ; diagnosis ; genetics ; therapy