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.

The thyroid hormone receptor β-selective agonist GC-1 does not affect tolerance to exercise in hypothyroid rats

Objective Investigate the effect of GC-1 on tolerance to exercise in rats with experimental hypothyroidism. Materials and methods Hypothyroidism was induced with methimazole sodium and perchlorate treatment. Six groups with eight animals were studied: control group (C), hypothyroid group without treatment (HYPO); hypothyroidism treated with physiological doses of tetraiodothyronine (T4) or 10 times higher (10×T4); hypothyroidism treated with equal molar doses of GC-1 (GC-1) or 10 times higher (10×GC-1). After eight weeks, each animal underwent an exercise tolerance test by measuring the time (seconds), in which the rats were swimming with a load attached to their tails without being submerging for more than 10 sec. After the test, the animals were killed, and blood samples were collected for biochemical analysis, and the heart and soleus muscle were removed for weighing and morphometric analysis of the cardiomyocyte. Results Hypothyroidism significantly reduced tolerance to exercise and, treatment with GC-1 1× or T4 in physiological doses recover tolerance test to normal parameters. However, high doses of T4 also decreased tolerance to physical exercise. Conversely, ten times higher doses of GC-1 did not impair tolerance to exercise. Interestingly, hypothyroidism, treated or not with T4 in a physiological range, GC-1 or even high doses of GC-1 (10X) did not change cardiomyocyte diameters and relative weight of the soleus muscle. In contrast, higher doses of T4 significantly increased cardiomyocyte diameter and induced atrophy of the soleus muscle. Conclusion Unlike T4, GC-1 in high doses did not modify tolerance to physical exercise in the rats with hypothyroidism. .

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).

Modulation of thyroid hormone receptors, TRα and TRβ, by using different doses of triiodothyronine (T3) at different times / Modulação dos receptores de hormônio tireoidiano, TRα e TRβ, utilizando diferentes doses de triiodotironina (T3) em diferentes tempos

OBJECTIVE: To examine the effect of different doses of triiodothyronine (T3) on mRNA levels of thyroid hormone receptors, TRα and TRβ, at different times. MATERIALS AND METHODS: 3T3-L1 adipocytes were incubated with T3 (physiological dose: F; supraphysiological doses: SI or SII), or without T3 (control, C) for 0.5, 1, 6, or 24h. TRα and TRβ mRNA was detected using real-time polymerase chain reaction. RESULTS: F increased TRβ mRNA levels at 0.5h. After 1h, TRα levels increased with F and SI and TRβ levels decreased with SII compared with C, F, and SI. After 6h, both genes were suppressed at all concentrations. In 24h, TRα and TRβ levels were similar to those of C group. CONCLUSIONS: T3 action with F began at 1h for TRα and at 0.5h for TRβ. These results suggest the importance of knowing the times and doses that activate T3 receptors in adipocytes.

OBJETIVO: Examinar o efeito de diferentes doses de triiodotironina (T3) sobre a expressão gênica dos receptores TRα e TRβ em diferentes tempos. MATERIAIS E MÉTODOS: Adipócitos, 3T3-L1, foram incubados com T3 nas doses fisiológica (F, 10nM) e suprafisiológicas (SI, 100nM ou SII, 1000nM) ou veículo (controle, C) durante 0,5, 1, 6 ou 24h. mRNA dos TRs foram detectados utilizando PCR em tempo real. RESULTADOS: Níveis de TRβ aumentaram em F em 0,5h. Após 1h, níveis de TRα aumentaram em F e SI comparado ao C, enquanto TRβ diminuiu no SII comparado com C, F, e SI. Após 6h, ambos os genes foram suprimidos em todas concentrações. Em 24h, níveis de TRα e TRβ retornaram aos do C. CONCLUSÕES: Ação do T3 em F iniciou-se em 1h para TRα e 0,5h para TRβ. Esses resultados são importantes para determinar tempo inicial e dose de T3 em que os receptores de HT são ativados em adipócitos.

Is there a role for inherited TR βmutation in human carcinogenesis? / Qual o papel da mutação do TR β na carcinogênese da tireoide em humanos?

Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited disorder characterized by end-organ reduced sensitivity to thyroid hormone. This syndrome is caused by mutations of the thyroid hormone receptor (TR) β gene, and its clinical presentation is quite variable. Goiter is reported to be the most common finding. A close association of TRβ mutations with human cancers has become apparent, but the role of TRβ mutants in the carcinogenesis is still undefined. Moreover, higher TSH levels, described in RTH syndrome, are correlated with increased risk of thyroid malignancy, whereas TSH receptor stimulation is likely to be involved in tumor progression. We report here an illustrative case of a 29 year-old patient with RTH caused by a mutation in exon 9 (A317T) of TRβ gene, who presented multicentric papillary thyroid cancer. We review the literature on this uncommon feature, and discuss the potential role of this mutation on human tumorigenesis, as well as the challenges in patient follow-up.

A síndrome da resistência aos hormônios tireoidianos (RHT) é caracterizada por redução da sensibilidade aos hormônios da tireoide. A apresentação clínica é variável, sendo a presença de bócio a manifestação mais frequentemente descrita. A associação de mutação no receptor β e neoplasias em humanos vem sendo demonstrada recentemente, porém o mecanismo pelo qual a mutação desse receptor está envolvida na carcinogênese não está completamente definido. Além disso, níveis elevados de TSH sérico, descritos na RHT, estão associados a aumento do risco de câncer de tireoide, e o estímulo do TSH está provavelmente envolvido na patogênese desses carcinomas. Este artigo relata o caso de um homem de 29 anos com RHT, com análise molecular demonstrando mutação no éxon 9, códon 317, e carcinoma papilar de tireoide. Revisamos a literatura dos casos relatados os quais descrevem associação entre RHT e câncer de tireoide e discutimos os desafios do tratamento e seguimento desses pacientes.

A new mutation in the thyroid hormone receptor gene of a Chinese family with resistance to thyroid hormone / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Resistance 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.</p><p><b>METHODS</b>The 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.</p><p><b>RESULTS</b>The 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.</p><p><b>CONCLUSIONS</b>This 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.</p>

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.

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.

E449X mutation in the thyroid hormone receptor β associated with autoimmune thyroid disease and severe neuropsychomotor involvement / Mutação E449X no receptor β do hormônio tireoidiano associada com doença tireoidiana auto-imune e retardo neuropscicomotor grave

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.

OBJETIVOS: Descrever aspectos clínicos e moleculares de um paciente com resistência ao hormônio tireoidiano (RHT) portador da mutação E449X associada a doença tireoideana auto-imune e retardo neuropscicomotor grave. MÉTODOS: Relatamos um caso incluindo achados clínicos, laboratoriais e análise molecular de um paciente brasileiro com RHT. RESULTADOS: Paciente masculino, 23 anos de idade, apresentou-se com distúrbio de hiperatividade, déficit de atenção, retardo no desenvolvimento neuropsicomotor e bócio. Desde 1 ano e 8 meses de idade, sua mãe procurou assistência médica para investigação do retardo do desenvolvimento neuropsicomotor associado com irritabilidade, agressividade, cefaléia recorrente, sudorese profusa, diarréia intermitente, polifagia, bócio e perda de peso. Avaliação laboratorial evidenciou TSH normal e aumento do T3, T4 e anticorpos antimicrossomal e antitireoglobulina. Doses crescentes de levotiroxina foram prescritas, máximo de 200 µg/dia, sem significativas alterações em seu quadro clínico-laboratorial. Doses crescentes de tiratricol foram introduzidas com melhora clínica evidente da agressividade, da hiperatividade, do tremor de extremidades e maior ganho de peso. O estudo molecular revelou uma mutação nonsense no éxon 10, no qual a substituição da guanina pela tirosina no nucleotídeo 1345 (códon 449) gerou um stop códon TAA, confirmando o diagnóstico da RHT. CONCLUSÃO: Este paciente tem um grave retardo neuropiscomotor não observado em um relato único anterior com a mesma mutação. Isto pode refletir a falta de relação genotipo-fenótipo nos casos afetados com esta síndrome sugerindo que a variabilidade genética de outros fatores, além do receptor do hormônio tireoidiano (HT), possa modular o fenótipo da RHT.

A novel mutation of thyroid hormone receptor beta (I431V) impairs corepressor release, and induces thyroid hormone resistance syndrome / Uma nova mutação no TR beta (I431V) prejudica a liberação de correpressores e induz síndrome de resistência ao hormônio tireoideano

Resistance to thyroid hormone (RTH) is a rare disorder characterized by variable tissue hyporesponsiveness to thyroid hormone, usually caused by mutations in the thyroid hormone receptor beta (TRβ). We describe a large Brazilian family harboring a novel mutation affecting TRβ gene and inducing RTH. A 14-year-old girl was found to have elevated free T4 and free T3 plasma concentrations in coexistence with unsuppressed TSH and a questionable goiter. The diagnosis of RTH was verified by identification of a novel mutation (I431V) in the TRβ gene. Sixteen asymptomatic relatives of the proposita are also affected by the mutation. Functional studies showed that I431V mutation exerts dominant-negative effect on wild type TRβ, mainly by impairment of ligand-dependent release of corepressor SMRT. The presence of this mutation reduces potency, but does not affect efficacy of thyroid hormone action, in accordance with the clinical picture of eumetabolism of the affected individuals.

A resistência ao hormônio tireoideano (RHT) é uma doença rara, causada por variável hiporresponsividade dos tecidos aos hormônios tireoideanos, usualmente causada por mutações no receptor beta do hormônio tireoideano (TRβ). Descrevemos uma grande família brasileira portadora de uma nova mutação afetando o gene do TRβ, induzindo RHT. Uma paciente de 14 anos de idade apresentou concentrações plasmáticas elevadas de T4 e T3 livres, associadas a TSH não-suprimido e bócio questionável. O diagnóstico de RHT foi estabelecido pela identificação da mutação I431V no gene do TRβ. Dezesseis parentes assintomáticos da probanda também são afetados pela mutação. Estudos funcionais mostram que a mutação I431V exerce efeito dominante negativo sobre o TR selvagem, basicamente, por prejudicar a liberação do correpressor SMRT ligante-dependente. A presença desta mutação reduz a potência, mas não afeta a eficácia da ação do hormônio tireoideano, o que está de acordo com a apresentação clínica de eumetabolismo dos indivíduos afetados.

A case of pituitary resistance to thyroid hormone with nonfunctioning pituitary microadenoma / 대한내과학회지

Resistance to thyroid hormone (RTH) is an autosomal dominant disorder that's characterized by inappropriate normal or elevated TSH levels despite of the elevated thyroid hormone levels. RTH is distinguished from the TSH secreting pituitary adenoma by performing the TRH stimulation test, TSH alpha subunit measurement and sellar MRI. A 23 year old woman visited our hospital complaining of fatigue, palpitation and heat intolerance and she had an anterior neck mass. She had elevated total T3, free T4 and TSH levels. The serum TSH levels were increased during the TRH stimulation test before and after T3 suppression. The serum TSH alpha subunit showed a normal response and the serum TSH alpha subunit/TSH molar ratio did not increase over 1.0 with TRH stimulation. Thyroid hormone receptor beta gene mutation was identified. Although a left pituitary microadenoma was revealed on sellar MRI, the patient was diagnosed as having pituitary RTH with a nonfunctioning pituitary microadenoma. We report here on a patient with pituitary RTH and a nonfunctioning pituitary microadenoma, and this is the first such case in Korea.

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.

Depresión refractaria y resistencia periférica a hormona tiroidea: el efecto de altas dosis de triyodotironina / Refractory depression and peripheral resistance to thyroid hormone: the effect of high doses of triodothyronine

We describe a 39-year-old woman with a severe chronic mood disorder, refractory to antidepressive treatment, who showed a marked improvement after a self prescription of very high doses of liothyronine (T3). A modified Refetoff protocol was carried out to study the rol of high doses of thyroid hormones on her clinical and biochemical responses. Depression severity and change was assessed by the HAM-D and MADRS rating scales. Sequencing of thyroid receptors TRalpha1 and TRbeta1 was done and no abnormal findings were obtained. At the final stage of the study plasma T3 and free T3 were >800 ng/dl (80-180) and 1.409 pg/dl (230-420),respectively. No changes in the cardiovascular parameters, alcaline phosphatase isoenzymes or ferritine were observed. An improvement in mood was confirmed by a marhed drop in the rating scales scores (HAM-D 24 to 8; MADRS 40 to 11). These results support the existence in this patient of a peripheral resistance to thyroid hormone (RTH) and the response of depressive symptoms to high dosis of T3 Screening for RTH in refractory chronic depression may pro vide access to alternative and more efficacious treatments for this psychiatric condition.

Describimos el caso de una mujer de 39 años portadora de un trastorno del ánimo crónico y refractario a tratamiento, que experimentó una marcada mejoría de sus síntomas depresivos luego de auto-prescribirse altas dosis de liotiranina (T3). Se le sometió a un protocolo de Refetoff modificado a fin de estudiar los efectos de altas dosis de hormona tiroidea en sus síntomas clínicos y en variables bioquímicas. La severidad y cambio en la intensidad de la depresión se evaluó mediante la aplicación de las escalas HAM-D y MADRS. Se secuenciaron los receptores de hormona tiroidea TRalfa1 y TRbeta1, sin hallazgos anormales. Al final del estudio los niveles plasmáticos de T3 y T31ibre fueron >800 ng/dl (80-180) y 1.409 pg/dl (230-420), respectivamente. No hubo cambios en los parámetros cardiovasculares, fosfatasas alcalinas ni ferritina. Una marcada mejoría del ánimo fue confirmada por la disminución de los puntajes de las escalas aplicadas (HAM-D24 a 8; MADRS 40 a 11). Estos resultados apoyan la existencia de una resistencia periférica a hormona tiroidea (RHT) en esta paciente y la respuesta de los síntomas anímicos a altas dosis de liotironina. La búsqueda de RHT en pacientes con depresión crónica refractaria podría dar acceso a tratamientos alternativos más eficaces para esta condición psiquiátrica.

Identification of a de novo mutation (H435Y) in the THRB gene in a Korean patient with resistance to thyroid hormone / 소아과

The syndrome of resistance to thyroid hormone (RTH) is characterized by reduced tissue sensitivity to thyroid hormone (TH). In the majority of subjects, RTH is caused by mutations in the thyroid hormone receptor beta (TRbeta) gene, located on the chromosome locus 3p24.3. RTH is inherited in an autosomal dominant manner. The clinical presentation of RTH is variable, but common features include elevated serum levels of thyroid hormone (TH), a normal or slightly increased thyrotropin (thyroid stimulating hormone, TSH) level that responds to thyrotropin releasing hormone (TRH), and goiter. We report a 4 year-old girl, who was clinically euthyroid in spite of high total and free T4, and T3 concentrations, while TSH was slightly increased. Sequence analysis of the thyroid hormone receptor beta gene (THRB) confirmed a heterozygous C to T change at nucleotide number 1303, resulting in a substitution of histidine by tyrosine at codon 435 (H435Y). Further analysis of her parents revealed that the H435Y variation was a de novo mutation since neither parents had the variation. Her parents' TH and TSH levels were within normal range.

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.

Study on TR beta gene mutation in a thyroid hormone resistance syndrome family / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To detect the gene mutation of thyroid hormone receptor beta (TR beta) in a family with thyroid hormone resistance syndrome.</p><p><b>METHODS</b>The genomic DNA was extracted from peripheral blood leukocytes of the patient, 14 family members and 7 healthy subjects. The exons 7-10 of TR beta gene were amplified by PCR. The products of PCR were purified and sequenced directly to detect the gene mutation.</p><p><b>RESULTS</b>Five members of this family were confirmed to have the C to G transition mutation at nucleotide 1642 site within exon 10 of TR beta gene, which was a missense mutation causing the substitution of Proline to Alanine (P453A); and also to have the C to T transition mutation at nucleotide 1020 within exon 7 of TR beta gene, which was a synonymous mutation that didn't cause the change of amino acid at this position (F245F). The two mutations were heterozygote. No mutation in the exons 7-10 of TR beta gene were identified in other family members.</p><p><b>CONCLUSION</b>A family with thyroid hormone resistance syndrome caused by TR beta gene mutation is first founded in Chinese people.</p>

A Case of Thyroid Hormone Resistance (RTH) / 대한소아내분비학회지

Thyroid hormone resistance (RTH) is a rare autosomal dominant disease characterized by reduced tissue sensitivity to thyroid hormone. Approximately 90% of subjects with RTH have mutation in the thyroid hormone receptor beta (TRbeta) gene. Approximately 10% of subjects diagnosed as having RTH do not carry mutation in the TRbeta gene. We report a 12-year-old male. The patient was euthyroid in spite of high total and free T4 and T3 concentrations, while TSH is slightly increased. TSH response to TRH stimulation was normal, and TSH values to TRH stimulation after T3 suppression revealed partial response. Sequence analysis of TRbeta gene showed no mutation. We report a case of RTH without mutations in the TRbeta gene.

A Case of Syndrome of Resistance to Thyroid Hormone Associated with Mutation(M313T) in Thyroid Hormone Receptor Beta Gene / 대한내분비학회지

Syndrome of resistance to thyroid hormone(RTH) is inherited by an autosomal dominant trait, and characterized by elevated thyroid hormone levels with reduced responsiveness of the pituitary and peripheral tissues to thyroid hormone action. All of the reported RTH patients have various mutations in the ligand-binding domain coding region of the thyroid hormone receptor beta gene. A 21-year-old man visited our hospital complaining of fatigue. He had mild thyroid goiter and intermittent palpitation. Thyroid function test showed elevated total T3, free T4, and TSH levels. Levels of TSH free a-subunit and basal pituitary hormones, except prolactin, were normal. MRI of the sellar region showed no abnormal finding. TSH response to TRH stimulation was normal, and TSH values to TRH stimulation after T3 suppression revealed partial response. Sequeuce analysis of the thyroid hormone receptor beta gene confirmed a heterozygous missense mutation in exon 9; and the amino acid alteration was a substitution of a threonine(ACG) for a methionine(ATG) at codon313. Sequeuce analysis of the parents showed no mutation.We report the first case of a man with RTH caused by a de novo mutation(M313T) in TRbeta gene, confirmed by sequeuce analysis.