The Syndromes of Resistance to Thyroid Hormone Beta / 罕见病研究

The syndrome of resistance to thyroid hormone(RTH) is a rare syndrome caused by the mutation of thyroid hormone receptor (TR) gene, which reduces the sensitivity of target organs to thyroid hormone (TH) and leads to the dysfunction of TH. Thyroid hormone resistance syndrome β (RTHβ) is caused by the mutations in the THRB gene. The main characteristics of RTHβ are increased thyroxine (T4) in the circulating blood, normal or elevated levels of triiodothyronine(T3), paired with normal or high thyroid-stimulating hormone (TSH) concentration. Clinically, it is easy to misdiagnose RTHβ as hyperthyroidism, and give anti-thyroid drugs, radioactive 131I therapy or surgery, which then leads to the aggravation of TH resistance, so the correct diagnosis of the disease is critical. In this paper, the molecular mechanism, clinical characteristics, diagnosis and treatment of RTHβ are summarized.

Research on THRβ gene mutation in a patient with thyroid hormone resistance syndrome using whole-exome sequencing / 中华内分泌代谢杂志

Objective:To assess clinical and genetic features in a patient with thyroid hormone resistance syndrome(RTH) and explore the pathogenic mechanism.Methods:The clinical data of the proband was collected. The genomic DNA was extracted from peripheral blood samples of the patients. The pathogenic variant was identified using whole-exome sequencing and confirmed by Sanger sequencing. Then the function of the mutation sites was detected by bioinformatics.Results:The patient presented with chest distress, palpitation, and persistent atrial fibrillation, along with elevated levels of serum free triiodothyronine(FT 3), free thyroxine(FT 4), and thyroid stimulating hormone(TSH), which suggested RTH clinically. The genetic analysis identified a heterozygous mutant of THRβ(c.1313G>A) gene at exon 8, which was a missense mutation causing the substitution of arginine to histidine at 438 position of the protein(p.R438H). Its inheritance pattern was unknown. This mutation was considered as a new one that had not been reported. Conclusion:A novel pathogenic THRβ gene mutation was found in the patient with RTH, which might be the cause of this disease. This variant c. 1313G>A is located in the ligand binding domain of THRβ, which might result in low protein activity.

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.

Pedigree analysis of a pituitary-resistance to thyroid hormone syndrome family caused by heterozygous A317T mutation in thyroid hormone receptor β gene / 中华内分泌代谢杂志

To study thyroid hormone receptor β(THRβ)gene mutation in a pituitary-resistance to thyroid hormone syndrome family. The peripheral blood samples of the patient, his sister, parents, and 4 maternal relatives were collected. Then serum was isolated for detecting thyroid hormone levels with chemiluminescence immunoassay, and DNA was extracted for PCR, and 10 exons of THRβ gene were sequenced. The patient and his mother had the hyperthyroid symptom for many years and his mother with atrial fibrillation. The G→A heterozygous transition mutation was confirmed by exon sequencing at nucleotide 949 within exon 9 of THRβ gene in the patient and his mother, which was a missense mutation causing a substitution of Alanine to Threonine(A317T). No mutation was found in THRβ gene in other family members. This is the first Chinese family reported with pituitary thyroid hormone resistance syndrome caused by a A317T mutation in the thyroid hormone receptor β gene.

Clinical characteristics of thyroid hormone resistance syndrome in two cases with different subtypes / 中华儿科杂志

Objective@#To analyze the clinical characteristics of children with two types of thyroid hormone resistance (RTH) syndrome, and to detect the variants of thyroid hormone receptor alpha(TRα) and TRβ gene in children.@*Method@#Two children with RTH were reported in regard to clinical manifestation, laboratory examination and genetic variants. Some related reports in literature were reviewed.@*Result@#Case 1 was a girl, 10 years old, with thyroid enlargement for several days and without thyrotoxicosis. Laboratory work-up revealed that free thyroxine (FT4) was 65.77 pmol/L (reference 12-22) , free triiodothyronine (FT3) was 15.36 pmol/L (reference 3.1-6.8) and thyroid stimulating hormone (TSH) level was normal. There was a likely pathogenic missense variant detected in TRβ gene and this patient was diagnosed with RTHβ. Case 2 was a boy, 3 years old, with classic features of hypothyroidism(growth retardation, developmental retardation, skeletal dysplasia) but had only borderline-abnormal thyroid hormone levels. Targeted sequencing showed a de novo heterozygous nonsense variant in TRα gene which is a pathogenic variant and this patient been diagnosed with RTHα.@*Conclusion@#Thyroid enlargement is a common clinical manifestation of RTHβ, with laboratory work-up reveals elevated FT4 and FT3 levels but TSH level is normal. The clinical manifestations of RTHα are similar to those of hypothyroidism, but the thyroid hormone levels are almost normal. The gene sequence and the pathogenicity analysis for TRα and TRβ will help to make a definitive diagnosis.

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.

Monogenic Thyroid Disorder / 대한갑상선학회지

Monogenic disorder is a single gene disorder resulted of a single mutated gene. Monogenic disorder has benefits in early diagnosis and precious prediction of disease course. Furthermore, monogenic disorder could provide an informative knowledge to the understanding of related pathophysiology. Thyroid monogenic disorder could occur in various steps, such as thyroid development, hormonogenesis, TSH-receptor signaling, thyroid hormone transport and end organ response. Here, we reviewed of congenital hypothyroidism, congenital hyperthyroidism and thyroid hormone resistance syndrome.

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.

Two cases of thyroid hormone resistance syndrome with review of literature / 中华内分泌代谢杂志

The clinical features,laboratory data,and therapeutic efficacy of two patients with thyroid hormone resistance syndrome(THRS)were reported.Two cases manifested growth retardation,raised serum TT_3,FT_3levels,and decreased~(131)I uptake.One patient presented with bird face deformity,nerve deafness,and raised TSH level.The superphysiological dosage of exogenous thyroxin inhibited the synthesis and release of thyrotropin.Thyroxin treatment proved to be effective for the patients.THRS is a disease related to thyroid hormone receptor gene mutation.The final diagnosis of this disease depends on gene analysis.

Progress in the study of molecular mechanisms in thyroid hormone insensitive syndrome / 中华内分泌代谢杂志

Thyroid hormone insensitive syndrome is an inherited disease characterized by decreased target tissue responsiveness to thyroid hormone. Most cases are due to thyroid hormone receptor β gene mutation. Two novel types of thyroid hormone insensitive syndrome were recently identified, which are caused by gene mutations of MCT8, a specific thyroid hormone transporter, and SBP2 in the synthesis of deiodinase.

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.

Thyroid hormone resistance syndrome caused by V458A mutation in the thyroid hormone receptor ? gene / 中华内分泌代谢杂志

Objective To study the genotype of the thyroid hormone receptor ? (THRB) gene in a patient with thyroid hormone resistance syndrome. Methods The peripheral blood samples of the patient and his parents were collected, then DNA was isolated. PCR and direct sequencing techniques were performed to determine if there were mutations in their THRB gene. Results No mutation was found in exon 1-9. There was a point mutation in exon 10 of THRB which is a T to C transition in nucleotide 1658 resulting in the replacement of the normal Val (GTG) with an Ala (GCG) (V458A). The mutation was located in exon 10 of THRB gene and was a heterozygote. No mutation was found in THRB gene of his parents.Conclusion The gene diagnosis confirms that the patient has a mutation V458A located in the ligand binding area of THRB.