Thyroid Hormone Resistance in a Preterm Infant with a Novel THRB Mutation

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.

A Case with Thyroid Hormone Resistance Syndrome

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.

Expression and significance of thyroid hormone receptors mRNA of residents exposed to arsenic via drinking water / 中华地方病学杂志

Objective To detect thyroid hormone receptors (TRs) mRNA expression of subjects exposed to different levels of arsenic,to further study the endocrine disturbing effect of arsenic.Methods Molecular epidemiological method was used,in drinking water type of endemic arsenic poisoning areas,which were divided into control (＜ 10 μg/L),low (10-＜ 100 μg/L),medium (100-＜ 200 μg/L) and high (≥200 μg/L) dose groups based on the drinking water arsenic concentrations.According to the gender stratification,a total of 273 (control,low,medium and high dose groups were 58,49,66,100,respectively) residents were chosen.To carry out the questionnaire,urine arsenic determination,electrocardiographic examination.Real-time PCR was used to detect blood TRs mRNA expression.Results TRα mRNA relative expression levels in the control,low,medium and high dose groups were (12.2 ± 5.7) × 10-4,(12.2 ± 5.0) × 10-4,(12.3 ± 5.4) × 10-4,(12.2 ± 4.3) × 10-4,respectively,the differences were not statistically significant (F =0.109,P ＞ 0.05).TRβ mRNA relative expression levels were all low,the control,low,medium and high dose groups were (5.7 ± 4.1) × 10-6,(8.6 ± 7.6) × 10-6,(6.3 ± 4.2) × 10-6 and (6.2 ± 3.8) ×10~,respectively,the differences were statistically significant (F =2.938,P ＜ 0.05).The levels of TRβ mRNA relative expression changed with increased content of arsenic in water and urine trends in inverse U-shaped curves (R2 =0.035,0.067,all P ＜ 0.05).TRβ mRNA relative expression in low dose group was higher than that in control group,the difference was statistically significant (P ＜ 0.05);TRβ mRNA relative expression in high dose group was lower than that in low dose group,the difference was statistically significant (P ＜ 0.05).Arsenic induced arrhythmia which most displayed sinus bradycardia;the prevalence of arrhythmia in the control,low,medium and high dose groups were 12.1％ (7/58),10.2％ (5/49),13.6％ (9/66),19.4％ (19/98),respectively,the differences were not statistically significant (x2 =2.877,P＞ 0.05).Heart rate was positively associated with the level of TRβ mRNA relative expression in lg value (r =0.218,P ＜ 0.05).Conclusion Chronic arsenic exposure can disturb TRβ mRNA expression;there is a possible relationship between TRβ mRNA abnormal expression and arrhythmia caused by arsenic.

Effects of high iodine on mRNA expression of thyroid hormone receptor and protein kinase A and sodium iodide symporter in peripheral blood of patients with thyroid diseases during lacatation / 中华地方病学杂志

Objective To observe the effect of high iodine on mRNA expression of thyroid hormone receptor (TSHR),protein kinase A (PKA) and sodium iodide symporter (NIS) in peripheral blood of patients with thyroid diseases during lacatation.Methods A total of 99 breast-feeding women were selected as observation objects in Shanxi Province's sufficient iodine and high iodine areas,and they were divided into case group and control group according to whether suffer from thyroid disease.In high iodine areas,there were 21 patients and 19 healthy controls.In sufficient iodine areas,there were 30 patients and 29 healthy controls.Peripheral blood of all the observation objects was collected,and mRNA expression of TSHR,PKA and NIS was detected by real-time quantitative PCR.Results The case group [median (M):0.099,0.994] and the control group (M:0.240,0.738) in the high iodine areas were respectively compared with the case group (M:3.087,1.127) and the control group (M:1.823,0.842) in the sufficient iodine areas.The TSHR mRNA expression was significantly decreased (Z =-5.034,-4.010,all P ＜ 0.01);the PKA mRNA expression had a downward trend,and the difference was not statistically significant (Z =2.895,-0.343,all P＞ 0.05).The NIS mRNA expression of the case group in high iodine areas (M:0.485) was obviously lower than that of the the case group in sufficient iodine regions (M:2.680,Z=-3.311,P ＜ 0.01).The control group in high iodine areas (M:0.470) was compared with the control group in sufficient iodine areas (M:0.835),and the difference was not statistically significant (Z =-1.882,P ＞ 0.05).The NIS and the TSHR mRNA were positively correlated [correlation coefficient (r) =0.741,P ＜ 0.01];the NIS and the PKA mRNA was also positively correlated (r =0.293,P ＜ 0.01);but the TSHR mRNA was not significantly correlated with the PKA mRNA (r =-0.081,P ＞ 0.05).Conclusion Lactating women may have protected themselves and their babies through TSH-TSHR-cAMP-PKA signaling pathway that regulating iodine levels.

Resistance to thyroid hormone due to a novel mutation of thyroid hormone receptor beta gene

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).

Síndrome de resistencia a las hormonas tiroideas: reporte de un caso / Syndrome of resistance to thyroid hormone: a case report

El síndrome de resistencia a las hormonas tiroideas es una entidad poco frecuente que se caracteriza por concentraciones elevadas de tiroxina libre y triyodotironina libre, tirotropina normal o ligeramente elevada, en ausencia de cualquier otra enfermedad, medicación o antagonista que causen alteraciones sobre la función tiroidea. Se reporta un caso de una mujer a quien se le realizó diagnóstico de resistencia a las hormonas tiroideas con base en los antecedentes personales, las manifestaciones clínicas y los hallazgos de laboratorio; además, se realiza una revisión de la literatura, con énfasis en el diagnóstico y el tratamiento de la enfermedad.

The syndrome of resistance to thyroid hormones is a rare disease characterized by high levels of both free thyroxin and free triiodothyronine, as well as normal or slightly elevated levels of thyrotropin in absence of any disease, medication or antagonist that cause alterations on thyroid function. It is reported a case of a woman who was diagnosed with syndrome of resistance to thyroid hormones based on personal history, signs and symptoms, and laboratory findings. In addition, a literature review is presented, with emphasis in diagnosis and treatment of the disease.

Case of Thyroid Hormone Resistance Syndrome with a Mutation in the Thyroid Hormone Receptor Beta Gene / 대한내과학회지

In thyroid hormone resistance syndrome (THR) TSH levels are normal or elevated despite thyroid hormone levels being elevated. THR is distinguished from TSH-producing pituitary adenoma by TRH stimulation and alpha-subunit tests, thyroid hormone receptor (TR) beta gene analysis, and sellar MRI. A 24-year old man with diffuse goiter visited our hospital complaining of fatigue, heat intolerance, palpitation, and weight loss. He had elevated total T3 and free T4 levels, but normal TSH levels. Serum TSH levels during TRH stimulation tests performed before and after T3 suppression showed normal and non-suppressible responses, respectively. The serum basal alpha-subunit test result was normal. A TR beta gene R438H mutation was identified, and a pituitary mass with cystic change was identified by sellar MRI. We report a case of THR with a mutation (R438H) in the TR beta gene, the first case of its kind in Korea.

Effect of thyroid hormones on the expression of thyroid hormone receptor isoforms in human osteogenic sarcoma cell line MG-63 / 中华内分泌代谢杂志

Objective To examine the expression of thyroid hormone receptor isoforms (TR α1, α2, β1, and β2) in human osteoblast-like cell line MG-63 at the mRNA level and the effect of thyroid hormone (T3 or T4 ) on the expression. Methods Realtime quantitative PCR was performed. Results The expression of TRα1 mRNA was the highest, that was 10. 70± 0.45, TRβ1 was 5.75 ± 0. 10, TRβ2 was 3.34 ± 0. 08, and TRα2 was very low, only (3.66 ±0. 59) × 10-2. Only the expression of TRαl and TRα2 mRNA was down regulated significantly by the treatment of 10-10 ～ 10-6 mol/L T3, and there was a negative correlation between the expression of TRα1 or TRα2 mRNA and the concentration of T3. Conclusion TRα1 plays a primary role in mediating the effects of thyroid hormones in skeletal development.

The thyroid hornone receptor in human osteogenic sarcoma cell line MG-63 cell-T3 binding studies with nuclear extracts / 中华内分泌代谢杂志

To establish a method for radioligand binding assay of thyroid hormone receptors(TR)in human osteoblast-like osteosarcoma cell line MG-63 and to estimate the kinetic parameters of putative receptors. The MG-63cell was cultured in Ham's F12, the soluble TR was prepared from the intact nuclear extracts. The binding properties between TR and T3 were performed by using the traditional Scatchard analysis. The apparent Ka of TR in MG-63 is 7.68× 109 L/mol, and MBC(111. 25+ 10.77)fmol/mg protein. The study indicated that MG-63 cells possessed high affinity and limited-capacity of TR in its nuclear extracts. This may serve as the starting and basic work about TR in bone cell.

A Case of Resistance to Thyroid Hormone with Thyroid Cancer

Resistance to thyroid hormone (RTH) is an autosomal dominant hereditary disorder that is difficult to diagnose because of its rarity and variable clinical features. The magnitude of RTH is caused by mutations in the thyroid hormone receptor beta (TRbeta) gene. We recently treated a 38-yr-old woman with RTH who had incidental papillary thyroid carcinoma. She presented with goiter and displayed elevated thyroid hormone levels with an unsuppressed TSH. She was determined to harbor a missense mutation of M310T in exon 9 of the TRbeta gene, and diagnosed with generalized RTH. This mutation has not yet been reported in Korea. RTH is very rare and easily overlooked, but should be considered in patients who present with goiter and elevated thyroid hormone levels with an unsuppressed TSH. The association between thyroid cancer and RTH needs further study.

Resistance to Thyroid Hormone with Missense Mutation (V349M) in the Thyroid Hormone Receptor Beta Gene

Resistance to thyroid hormone (RTH) is a syndrome characterized by reduced sensitivity to the thyroid hormone. It is generally caused by mutations in the thyroid hormone receptor beta (TRbeta) gene. On the basis of its clinical features, two different forms of this syndrome have been described: generalized resistance and pituitary resistance. A total of 122 TRbeta gene mutations have been identified thus far. A 38-year-old woman presented with intermittent palpitation. Thyroid function tests revealed elevated levels of free T4 and TSH. TSH alpha-subunit levels were 0.41 mIU/mL, and magnetic resonance images of the sellar region evidenced no abnormal findings. The TSH response to TRH stimulation was found to be normal. The sequence analysis of the TRbeta gene verified a missense mutation in exon 11, and the observed amino acid alteration was a substitution of a valine for a methionine at codon 349. We report the first case of a woman with RTH, which was found to be caused by a missense mutation (V349M) in the TRbeta gene.

A Newly Identified Insertion Mutation in the Thyroid Hormone Receptor-beta Gene in a Korean Family with Generalized Thyroid Hormone Resistance

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 response to thyroid hormone. 90% of RTH subjects, when studied at the level of the gene, have been found to harbor mutations in the thyroid hormone receptor-beta(THRB) gene. These affected individuals have been shown to possess a variety of missense mutations, resulting from changes in a single nucleotide in the THRB gene that corresponds to amino acid alternation. However, insertion or deletion mutations in the THRB gene sequence are quite rare, and have been observed in only a very few cases. In this study, we describe two such cases, in which two members of the same family were determined to harbor an insertion mutation in exon 10, and had also been diagnosed with generalized RTH. This insertion mutation, specifically the insertion of a cytosine at nucleotide 1358 of the THRB gene, is, to the best of our knowledge, the first such mutation reported among RTH patients in Korea.

EXPRESSION OF THYROID HORMONE RECEPTOR mRNA DURING THE HUMAN BRAIN DEVELOPMENT / 解剖学报

Objective To observe the variations of thyroid hormone receptors(RTs) mRNA experession during the human brain devlopment. Methods We investigated the ontogeny of TR isoforms in the first and second trimester human fetal different brain areas by semi-quantitative reverse transcriptase-polymerase chain reaction analysis. When we amplified the TR? 2 by PCR, the other sequence was amplified at the same time, it is about 100pb less than the RT? 2, so we cloned it into pGEM-T easy vector to determine its sequence. Results In the first and second trimester human fatal brain, RTs mRNAs were detected in cerebrum, cerebellum, brain, stem, hippocampus, spinal cord, thalamus. TRs mRNAs were relatively higher in cerebrum, cerebellum, hippocampus. In the first trimester human fatal brain, the TR? isoforms mRNAs were higher than TR? 1, In the second trimester human fatal brain, the TR? 2 and TR? 1 were higher than TR? 1. An additional truncated species was detected with the TR? 2 primer set. We submitted its sequencing results to Genbank, comparing it with TR? 2 by BLAST software, the results showed that it is identical to TR? 2 with the exception that it is missing 42 amino acids at 371-412 of TR? 2 sequence, so it is the human TR? 3. At the same time we acquired the Genbank accession number AF522368. Conclusion The spatial and temporal expressions of TR isoforms mRNAs exist in CNS development. We firstly assure the different sequence between human TR?2 and TR?3.