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1.
Exp Suppl ; 111: 55-84, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588528

RESUMO

Thyroid hormone (TH) action is crucial for the development of several tissues.A number of syndromes are associated with reduced responsiveness to thyroid hormones, expanding the original definition of thyroid hormone resistance, firstly described by Refetoff and collaborators in 1967, which is characterized by elevated circulating levels of T4 and T3 with measurable serum TSH concentrations, as a consequence of mutations of thyroid hormone receptor beta (TRß), recently named as RTHß. More recently, another form of insensitivity to TH has been identified due to mutations in the thyroid hormone receptor alpha (TRα), named RTHα. In this chapter we will focus the discussion on the phenotype of RTHß and RTHα. These diseases share the same pathogenic mechanism caused by dominant negative mutations in TH receptor genes that reduce T3 binding or affect the recruitment of cofactors. As a consequence, thyroid hormone actions are impaired at the tissue level. The phenotypic manifestations of RTHß and RTHα are to some extent correlated with the degree of disruption and the tissue distribution of the TRs being characterized by variable coexistence of hypothyroid or thyrotoxic manifestations in RTHß or by a congenital hypothyroid features in RTHα despite normal TSH and borderline low free T4.


Assuntos
Receptores alfa dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Hormônios Tireóideos/sangue , Humanos , Fenótipo
2.
BMJ Case Rep ; 12(7)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31326901

RESUMO

The elevation of thyroid hormone with a normal or elevated thyroid-stimulation hormone (TSH) occurs uncommonly. This set a diagnosis challenge between TSH-secreting pituitary adenoma and resistance to thyroid hormone (RTH). We report a case of a young female patient with palpitations, with elevated thyroid hormone and non-suppressed TSH. TSH receptor antibody was undetectable. Thyroid ultrasound revealed mild heterogeneous goitre, and MRI revealed a microadenoma with 7.5 mm length in pituitary's left lobe. Pituitary hormones were within normal ranges. The thyrotropin-releasing hormone stimulation test showed normal TSH elevation, consistent with RTH. The genetic test revealed a mutation in heterozygosity in THRB gene (G344R) confirming RTH-beta. No pituitary surgery or thyroidectomy was performed nor were prescribed any antithyroid drugs. Inappropriate secretion of TSH requires a high level of clinical suspicion and the proper laboratory, genetic and radiological studies to conduct a correct diagnosis and prevent unnecessary and potential harmful therapies.


Assuntos
Adenoma/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Adenoma/genética , Diagnóstico Diferencial , Feminino , Testes Genéticos , Humanos , Imagem por Ressonância Magnética , Neoplasias Hipofisárias/genética , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Hormônios Tireóideos/sangue , Adulto Jovem
3.
Medicine (Baltimore) ; 98(9): e14675, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30817595

RESUMO

RATIONAL: Thyroid hormone resistance (RTH) is a rare disease that is characterised by a lowered sensitivity of the target organs to thyroid hormone. Herein, we present 3 cases of confirmed RTH, with the support of clinical lab results and/or gene sequencing at diagnosis. PATIENT CONCERNS: The 3 included patients were found to have elevated levels of free T3 (FT3), free T4 (FT4), and non-supressed levels of thyroid stimulating hormone (TSH). DIAGNOSIS: All patients were tested for thyroid antibodies, somatostatin suppression, vision and hearing at diagnosis. Electrocardiography (ECG), thyroid ultrasonography, and magnet resonance imaging (MRI) of the sellar region were also performed. Furthermore, gene sequencing was used to detect the thyroid hormone receptor beta (THRB) gene mutation. INTERVENTIONS: Patient treatment was individualised. Patients were given levothyroxine sodium or a low dose of thyroiodin, depending on the individual symptoms. OUTCOMES: After treatment, thyroid function was stable in 2 of the teenage patients. No evidence of worsening thyrotoxicosis was observed. LESSONS: Gene sequencing should be considered together with clinical lab results, including somatostatin suppression testing, before approaching a diagnosis of RTH.


Assuntos
Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Mutação , Testes de Função Tireóidea , Síndrome da Resistência aos Hormônios Tireóideos/sangue , Hormônios Tireóideos/sangue , Tireotoxicose/genética
4.
Hormones (Athens) ; 18(2): 223-227, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30747412

RESUMO

Thyroid hormone receptor alpha (THRA) gene mutation is a thyroid hormone resistance syndrome characterized by near-normal thyroid function tests and tissue-specific hypothyroidism. In this case study, we report a novel de novo p.G291S heterozygous mutation in the THRA gene was detected at mutation analysis. A 4-year-old male patient was admitted due to short stature, motor-mental retardation, and constipation. At physical examination, coarse facial appearance, eyelid edema, pallor, and umbilical hernia were observed. Primary thyroid hormone resistance should be considered in patients with phenotypically hypothyroid features. Laboratory analysis found moderate elevation in free triiodothyronine (T3) levels, normochromic normocytic anemia, and elevated creatine kinase levels. In conclusion, THRA gene mutation should be considered in patients with clinical hypothyroid findings and increased/moderately elevated free T3, decreased/ normal free thyroxine, normal thyroid-stimulating hormone levels, and increased muscle enzymes.


Assuntos
Mutação de Sentido Incorreto , Receptores alfa dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Substituição de Aminoácidos , Pré-Escolar , Análise Mutacional de DNA , Seguimentos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Testes de Função Tireóidea , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico
5.
J Endocrinol Invest ; 42(8): 941-949, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30707410

RESUMO

OBJECTIVE: Thyroid hormone resistance (RTH ß) is a rare genetic disorder characterized by an altered response of target tissue to the action of thyroid hormone. Few studies on RTH ß have been carried out in southern European populations. We aimed to describe the clinical and genetic characteristics at the time of diagnosis in a Spanish cohort of patients with genetically confirmed RTH ß, with ages ranging from newborns to adults. METHODS: Retrospective multicenter study of 28 patients who were genetically confirmed as RTH ß. Clinical and biochemical data were collected from the reference centers, and the studied variables included age, sex, anthropometric data, clinical characteristics and biochemical results. In the Basque country, a simultaneous analysis of TSH and T4 is carried out in the program for the screening of inborn errors of metabolism. A molecular analysis of the thyroid hormone beta (THRB) gene was performed. RESULTS: The total cohort included 20 adults and eight pediatric patients (six newborns). Of the total, 5 (17.8%) were diagnosed by clinical characteristics (goiter, hypertension or tachycardia), 13 (46.4%) were analyzed in the context of a family study and 10 (35.7%) were diagnosed after obtaining an altered fT4 and/or TSH level in a biochemical analysis performed due to clinical symptoms unrelated to RTH ß. Four of the newborns included in the series were diagnosed by the result of neonatal screening, which allows us to estimate a minimum local incidence of RTH ß of 1/18,750 live newborns. The genetic analysis showed the presence of 12 different heterozygous mutations in the THRB gene. CONCLUSIONS: We report the clinical and genetic characteristics of a Spanish RTH ß cohort, from neonates to adults. We also describe one novel mutation in the THRB gene as the cause of the disease. The simultaneous analysis of TSH and T4 carried out in the program for the screening of inborn errors of metabolism facilitates the early diagnosis of RTH ß in newborns and has allowed us to estimate a minimum local incidence of RTH of 1/18,750 live newborns.


Assuntos
Biomarcadores/análise , Resistência a Medicamentos/genética , Mutação , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Hormônios Tireóideos/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Espanha/epidemiologia , Síndrome da Resistência aos Hormônios Tireóideos/induzido quimicamente , Síndrome da Resistência aos Hormônios Tireóideos/epidemiologia , Síndrome da Resistência aos Hormônios Tireóideos/genética , Adulto Jovem
6.
J Pediatr Endocrinol Metab ; 32(2): 203-206, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30681972

RESUMO

Background Resistance to thyroid hormone (RTH) commonly presents with goiter, attention deficit hyperactivity disorder (ADHD), short stature and tachycardia. However, due to its variable presentation with subtle clinical features, a third of the cases are mistreated, typically as hyperthyroidism. Case presentation A 15-year-old female with ADHD and oligomenorrhea was initially diagnosed as Hashimoto's thyroiditis but found to have a rare heterozygous mutation in c803 C>G (p Ala 268 Gly) in the THRß gene, confirming resistance to thyroid hormone. Conclusions Fluctuating thyroid function tests in addition to thyroid peroxidase antibody (TPO Ab) positivity complicated the diagnosis of RTH, initially diagnosed as Hashimoto's thyroiditis. A high index of suspicion is needed to prevent misdiagnosis and mistreatment.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Doença de Hashimoto/diagnóstico , Oligomenorreia/diagnóstico , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Diagnóstico Diferencial , Feminino , Genes erbA/genética , Doença de Hashimoto/genética , Doença de Hashimoto/metabolismo , Humanos , Mutação , Oligomenorreia/genética , Oligomenorreia/metabolismo , Prognóstico , Testes de Função Tireóidea , Síndrome da Resistência aos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/metabolismo
7.
Thyroid ; 29(3): 449-451, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30458118

RESUMO

Resistance to thyroid hormone beta (RTHß) is a syndrome characterized by high serum levels of thyroid hormone and unsuppressed serum thyrotropin concentrations. RTHß is caused by mutations in the thyroid hormone receptor beta (THRB) gene, which are mostly clustered in three "hot" regions along the gene. Here, a report is given on a family with RTHß caused by a novel mutation in the THRB gene (c.1069 G>C, p.G357R) occurring outside the historically known "hot" regions.


Assuntos
Mutação , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Adulto , Idoso , Criança , Saúde da Família , Feminino , Bócio/complicações , Humanos , Hipertireoidismo/sangue , Masculino , Pessoa de Meia-Idade , Linhagem , Tireotropina/sangue
8.
Endokrynol Pol ; 70(1): 124-130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30450533

RESUMO

INTRODUCTION: Resistance to thyroid hormone (RTHß) is a rare syndrome of impaired tissue responsiveness to thyroid hormones (THs). The disorder has an autosomal dominant or recessive pattern of inheritance. Most of the reported mutations have been detected in the thyroid hormone receptorß gene (THRß). CASE REPORT: Authors present an eight-month-old infant with poor linear growth, decreased body weight, tachycardia, positive family history, and neonatal features suggestive of RTHß. Both our patient and his mother had elevated free thyroxine, free triiodothyronine, and non-suppressed thyrotropin (TSH) concentration. The fluorescent sequencing analysis showed a heterozygous mutation c.728G>A in TRß gene. This pathogenic variant is known to be associated with THR. CONCLUSIONS: The clinical presentation of RTHb is variable, ranging from isolated biochemical abnormalities to symptoms of thyrotoxicosis or hypothyroidism. The syndrome should be suspected in patients with increased serum TH level, accompanied by a normal or elevated TSH concentration. The affected patients require individualised management.


Assuntos
Mutação , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Análise Mutacional de DNA , Humanos , Lactente , Masculino , Síndrome da Resistência aos Hormônios Tireóideos/sangue , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/sangue
9.
Isr Med Assoc J ; 20(11): 679-686, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30430796

RESUMO

BACKGROUND: Reduced sensitivity to thyroid hormone (RSTH) syndrome describes a group of rare heterogeneous genetic disorders. Precise diagnosis is essential to avoid unnecessary treatment. OBJECTIVES: To identify and characterize previously undiagnosed patients with RSTH in Israel. METHODS: Patients with suspected RSTH throughout Israel were referred for study. After clinical evaluation, genomic DNA was obtained and all coding exons of the thyroid hormone receptor beta (THRB) gene were sequenced. If mutations were found, all available blood relatives were evaluated. The common polymorphism rs2596623, a putative intronic regulatory variant, was also genotyped. Genotype/phenotype correlations were sought, and the effect of mutation status on pregnancy outcome was determined. RESULTS: Eight mutations (one novel; two de-novo, six dominant) were identified in eight probands and 13 family members. Clinical and genetic features were similar to those reported in other populations. Previous suggestions that rs2596623 predicts clinical features were not confirmed. There was no evidence of increased risk of miscarriage or fetal viability. Mothers carrying a THRB mutation tended to have increased gestational hypertension and low weight gain during pregnancy. Their affected offspring had increased risk of small-for-gestational age and poor postnatal weight gain. CONCLUSIONS: Clinical heterogeneity due to THRB mutations cannot be explained by the variant rs2596623. Mothers and newborns with THRB mutations seem to be at increased risk of certain complications, such as gestational hypertension and poor intrauterine and postnatal growth. However, these issues are usually mild, suggesting that routine intervention to regulate thyroid hormone levels may not be warranted in these patients.


Assuntos
Complicações na Gravidez/epidemiologia , Resultado da Gravidez , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Hormônios Tireóideos/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Hipertensão Induzida pela Gravidez/genética , Lactente , Recém-Nascido , Israel , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Gravidez , Complicações na Gravidez/genética , Análise de Sequência de DNA , Síndrome da Resistência aos Hormônios Tireóideos/genética , Adulto Jovem
11.
Horm Res Paediatr ; 90(5): 283-290, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30497070

RESUMO

BACKGROUND/AIMS: Syndromes of reduced sensitivity to thyroid hormone can be caused by innate resistance to thyroid hormone (RTH), thyroid hormone cell transporter defects, or thyroid hormone metabolism defects. This study was performed to describe clinical, endocrinological, and molecular characteristics of patients with disorders associated with impaired sensitivity to thyroid hormone due to THRB or SLC16A2 mutations. METHODS: This study included 5 probands (1 male and 4 females) with RTH and 6 patients with Allan-Herndon-Dudley syndrome (AHDS). Clinical features and endocrine findings were reviewed retrospectively. Molecular analysis of two candidate genes, THRB or SLC16A2, confirmed the diagnosis. RESULTS: Among RTH patients, median age at diagnosis was 5.6 years. Three patients were classified as having generalized RTH, whereas the other 2 patients were regarded as having isolated pituitary RTH. Three novel heterozygous mutations and 2 known mutations in THRB were identified from 5 independent pedigrees. All mutations were located in the major ligand-binding domain. In AHDS patients, delayed development was apparent between 3 and 6 months of age. Direct sequencing of SLC16A2 identified 6 hemizygous missense mutations in each patient: p.I188N, p.G221R, p.A224V, p.G276R, p.W398R, and p.G401R. CONCLUSIONS: This study identified 3 novel mutations in THRB in RTH patients and 1 novel mutation in SLC16A2 in AHDS patients. Routine neonatal screening based on the TSH assay has a limited role in detecting RTH or AHDS. Therefore, genetic testing of the candidate genes THRB and SLC16A2 should be performed for diagnosis of RTH and AHDS in patients with the suggestive clinical phenotype.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/genética , Atrofia Muscular/genética , Mutação , Fenótipo , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Hipotonia Muscular/diagnóstico , Atrofia Muscular/diagnóstico , Estudos Retrospectivos , Avaliação de Sintomas , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico
12.
Thyroid ; 28(12): 1708-1722, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30235988

RESUMO

BACKGROUND: Thyroid hormone receptors (TRs) are tightly regulated by the corepressors nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptors. Three conserved corepressor/NR signature box motifs (CoRNR1-3) forming the nuclear receptor interaction domain have been identified in these corepressors. Whereas TRs regulate multiple normal physiological and developmental pathways, mutations in TRs can result in endocrine diseases and be associated with cancers due to impairment of corepressor release. Three mutants that are located in helix H11 of TRs are of special interest: TRα-M388I, a mutant associated with the development of renal clear cell carcinomas (RCCCs), and TRß-Δ430 and TRß-Δ432, two deletion mutants causing resistance to thyroid hormone syndrome. METHODS: Several cell-based and biophysical methods were used to measure the affinity between wild-type and mutant TRα and TRß and all the CoRNR motifs from corepressors to quantify the effects of different thyroid hormone analogues on these interactions. This study was coupled with the measurement of interactions between wild-type and mutant TRs in the context of a heterodimer with RXR to a NCoR fragment in the presence of the same ligands. Structural insights into the binding mode of corepressors to TRs were assessed in parallel by nuclear magnetic resonance spectroscopy. RESULTS: The study shows that TRs interact more avidly with the silencing mediator of retinoic acid and thyroid hormone receptors than with NCoR peptides, and that TRα binds most avidly to S-CoRNR3, whereas TRß binds preferentially to S-CoRNR2. In the studied TR mutants, a transfer of the CoRNR-specificity toward CoRNR1 was observed, coupled with a significant increase in the binding strength. In contrast to 3,5,3'-triiodothyronine (T3), the agonist TRIAC and the antagonist NH-3 were very efficient at dissociating the abnormally strong interactions between mutant TRßs and corepressors. A strong impairment of T3-binding for TRß mutants was shown compared to TRIAC and NH-3 and could explain the different efficiencies of the different ligands in releasing corepressors from the studied TRß mutants. Consequently, TRIAC was found to be more effective than T3 in facilitating coactivator recruitment and decreasing the dominant activity of TRß-Δ430. CONCLUSION: This study helps to clarify the specific interaction surfaces involved in the pathologic phenotype of TR mutants and demonstrates that TRIAC is a potential therapeutic agent for patients suffering from resistance to thyroid hormone syndromes.


Assuntos
Proteínas Correpressoras/metabolismo , Mutação , Receptores dos Hormônios Tireóideos/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/química , Anisotropia , Humanos , Cinética , Ligantes , Espectroscopia de Ressonância Magnética , Proteínas Nucleares/metabolismo , Peptídeos/química , Ligação Proteica , Receptores dos Hormônios Tireóideos/genética , Proteínas Repressoras/genética , Espectrometria de Fluorescência , Glândula Tireoide/metabolismo , Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/genética
13.
Endocrine ; 62(3): 628-638, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30027432

RESUMO

AIM: Resistance to thyroid hormone (RTH), characterized by persistent hyperthyroxinemia with non-suppressed thyrotropin (TSH), is mostly caused by mutations in thyroid hormone receptor beta gene (THRB). Two differential diagnoses should be considered due to similar clinical and laboratory findings: TSH-producing pituitary adenoma (TPA) and Familial Dysalbuminemic Hyperthyroxinemia (FDH). The aim of this study is to describe our single tertiary center experience in the molecular diagnosis of RTH in Brazilian patients, analyzing their clinical and laboratory characteristics and the most common differential diagnosis. SUBJECTS AND METHODS: We enrolled 30 subjects with clinical and laboratory features of RTH. Patient´s evaluations included clinical examination, thyroid hormone profile and imaging tests. Sequencing analysis for THRB hot spot region was conducted on all patients, and those without mutations in beta isoform of the thyroid hormone receptor (TRß) (non-TR-RTH) were investigated for albumin gene (ALB) mutation. RESULTS: Seventeen patients presented mutations in TRß (RTHß); six were non-TR-RTH, three had a diagnosis of FDH with a mutation in ALB, and four were diagnosed with TPA. Two characteristics were different to what is commonly described in the literature: higher serum TSH levels in RTHß patients when compared to the non-TR-RTH group, but this difference did not extend to free T4 (FT4) level; also the percentage of non-TR-RTH was higher than what was reported in other series. CONCLUSION: In the present series, most cases were RTHß with higher levels of TSH. We described three novel mutations in THRB (p.M313V, p.R320G and p.R438P) and the first patients with FDH molecular diagnosis (p.R242H) documented in Brazil.


Assuntos
Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Testes de Função Tireóidea , Receptores beta dos Hormônios Tireóideos/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Adulto Jovem
14.
Methods Mol Biol ; 1801: 225-240, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29892828

RESUMO

Resistance to thyroid hormone beta (RTHß) is a syndrome characterized by reduced responsiveness of peripheral tissues to thyroid hormone (TH). Affected individuals have consistently high TH levels and non-suppressed thyrotropin in the absence of acute illness, drugs, or alterations in TH binding proteins. Depending on the tissue, features of TH excess and deficiency may coexist, although most individuals have a euthyroid, normal metabolic state at the expense of high TH levels. In most cases the disorder is associated with germline mutations in the THRB gene. In the last decades, advances in genetics have expanded our knowledge on the etiology and pathophysiology of the syndrome and have shed more light on the molecular mechanisms of TH action. This review provides an update on the genetics of RTHß, summarizes the clinical and biochemical presentation of the syndrome, and describes the methodology used to diagnose and manage individuals with RTHß.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Receptores beta dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Biomarcadores , Humanos , Padrões de Herança , Mutação , Transdução de Sinais , Avaliação de Sintomas , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Hormônios Tireóideos/metabolismo
15.
Methods Mol Biol ; 1801: 241-245, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29892829

RESUMO

Resistance to thyroid hormone alpha is an emerging syndrome, with up to now a limited number of published cases. Some features are common to most of the patients, but there is still some work to provide a comprehensive description of the full spectrum of the syndrome. A survey of the strategy to screen for and characterize the mutations in TR α gene is given.


Assuntos
Mutação , Receptores alfa dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Animais , Animais Geneticamente Modificados , Biomarcadores , Criança , Biologia Computacional/métodos , Análise Mutacional de DNA , Modelos Animais de Doenças , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Testes Genéticos , Humanos , Receptores alfa dos Hormônios Tireóideos/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/sangue , Hormônios Tireóideos/metabolismo
16.
Medicine (Baltimore) ; 97(21): e10544, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29794730

RESUMO

RATIONALE: In patients with pituitary thyroid hormone resistance, the ability of the pituitary gland to detect (and down-regulate) the increase of triiodothyronine is selectively impaired, while the periphery remains sensitive to triiodothyronine levels, producing symptoms of peripheral thyrotoxicity. Subsequently, there is no feedback of pituitary production of thyroid-stimulating hormone (TSH), which is responsible for this hyperthyroidism. PATIENT CONCERNS: We report a case of a 46-year-old Chinese woman diagnosed with a thyroid nodule, with normal thyroid function. She underwent conventional subtotal thyroidectomy, and replacement therapy (levothyroxine) was used for as convention. However, it was later proven that she had pituitary resistance to thyroid hormone, as supra-physiological doses of levothyroxine were required to normalize TSH levels, which resulted in peripheral thyrotoxicity. DIAGNOSES: Based on the patient's symptoms, laboratory tests results, imaging examinations, and genetic analysis (which noted a gene mutation), a diagnosis of pituitary resistance to thyroid hormones was confirmed. INTERVENTIONS: The dose of levothyroxine was adjusted periodically and ß-adrenergic blocker was used as symptomatic treatment. OUTCOMES: The outcome in the reported case has been satisfactory despite the persistence of non-suppressed TSH. LESSONS: An inappropriate level of TSH should always be evaluated. We found a new mutation (H435A) of the thyroid hormone receptor beta gene, which allowed for the establishment of a definitive diagnosis.


Assuntos
Doenças da Hipófise/genética , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Tiroxina/administração & dosagem , Diagnóstico Diferencial , Feminino , Humanos , Hipertireoidismo/tratamento farmacológico , Hipertireoidismo/genética , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Mutação , Doenças da Hipófise/diagnóstico , Hipófise/fisiopatologia , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Síndrome da Resistência aos Hormônios Tireóideos/tratamento farmacológico , Hormônios Tireóideos/sangue , Tireoidectomia , Tireotropina/sangue
17.
Thyroid ; 28(1): 139-150, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29205102

RESUMO

BACKGROUND: Resistance to thyroid hormone due to THRA mutations (RTHα) is a recently discovered genetic disease, displaying important variability in its clinical presentation. The mutations alter the function of TRα1, one of the two nuclear receptors for thyroid hormone. METHODS: The aim of this study was to understand the relationship between specific THRA mutations and phenotype. CRISPR/Cas9 genome editing was used to generate five new mouse models of RTHα, with frameshift or missense mutations. RESULTS: Like human patients, mutant mice displayed a hypothyroid-like phenotype, with altered development. Phenotype severity varied between the different mouse models, mainly depending on the ability of the mutant receptor to interact with transcription corepressor in the presence of thyroid hormone. CONCLUSION: The present mutant mice represent highly relevant models for the human genetic disease which will be useful for future investigations.


Assuntos
Genes erbA/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Animais , Sistemas CRISPR-Cas , Camundongos , Mutação , Fenótipo
18.
Zhonghua Er Ke Za Zhi ; 55(12): 953-956, 2017 Dec 02.
Artigo em Chinês | MEDLINE | ID: mdl-29262478

RESUMO

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 TRß 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 (FT(4)) was 65.77 pmol/L (reference 12-22) , free triiodothyronine (FT(3)) 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 TRß gene and this patient was diagnosed with RTHß. 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 RTHß, with laboratory work-up reveals elevated FT(4) and FT(3) 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 TRß will help to make a definitive diagnosis.


Assuntos
Hipotireoidismo , Síndrome da Resistência aos Hormônios Tireóideos , Criança , Pré-Escolar , Códon sem Sentido , Feminino , Bócio , Heterozigoto , Humanos , Masculino , Testes de Função Tireóidea , Receptores beta dos Hormônios Tireóideos , Síndrome da Resistência aos Hormônios Tireóideos/complicações , Síndrome da Resistência aos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/patologia , Tiroxina , Tri-Iodotironina
19.
BMJ Case Rep ; 20172017 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-29183897

RESUMO

A 13-½-year-old boy was referred to the Department of Endocrinology as a case of thyrotoxicosis for initiation of antithyroid medication. His chief complaint was a swelling in front of the neck, which was incidentally noted by his mother 2 weeks prior to presentation. He denied any history of symptoms suggestive of hyperthyroidism or ophthalmological involvement. His physical examination was unremarkable except for a grade 2 goitre. Thyroid function test revealed elevated free triiodothyronine and tetraiodothyronine in the face of an unsuppressed thyroid-stimulating hormone level. Technetium-99 uptake scan showed increased uptake indicating enhanced thyroid activity. However, he was clinically euthyroid. This raised the possibility of resistance to thyroid hormones, which was confirmed by documenting similar thyroid function test abnormalities in other members of his family and genetic testing. The family was reassured of the benign nature of the condition.


Assuntos
Testes de Função Tireóidea , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Adolescente , Diagnóstico Diferencial , Bócio , Humanos , Masculino , Tecnécio , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/fisiopatologia , Síndrome da Resistência aos Hormônios Tireóideos/genética , Hormônios Tireóideos/sangue
20.
J Clin Endocrinol Metab ; 102(9): 3517-3525, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28911146

RESUMO

Context: Patients with resistance to thyroid hormone (TH) α (RTHα) are characterized by growth retardation, macrocephaly, constipation, and abnormal thyroid function tests. In addition, almost all RTHα patients have mild anemia, the pathogenesis of which is unknown. Animal studies suggest an important role for TH and TH receptor (TR)α in erythropoiesis. Objective: To investigate whether a defect in TRα affects the maturation of red blood cells in RTHα patients. Design, Setting, and Patients: Cultures of primary human erythroid progenitor cells (HEPs), from peripheral blood of RTHα patients (n = 11) harboring different inactivating mutations in TRα (P398R, F397fs406X, C392X, R384H, A382fs388X, A263V, A263S), were compared with healthy controls (n = 11). During differentiation, erythroid cells become smaller, accumulate hemoglobin, and express different cell surface markers. We assessed cell number and cell size, and used cell staining and fluorescence-activated cell sorter analysis to monitor maturation at different time points. Results: After ∼14 days of ex vivo expansion, both control and patient-derived progenitors differentiated spontaneously. However, RTHα-derived cells differentiated more slowly. During spontaneous differentiation, RTHα-derived HEPs were larger, more positive for c-Kit (a proliferation marker), and less positive for glycophorin A (a differentiation marker). The degree of abnormal spontaneous maturation of RTHα-derived progenitors did not correlate with severity of underlying TRα defect. Both control and RTHα-derived progenitors responded similarly when differentiation was induced. T3 exposure accelerated differentiation of both control- and RTHα patient-derived HEPs. Conclusions: Inactivating mutations in human TRα affect the balance between proliferation and differentiation of progenitor cells during erythropoiesis, which may contribute to the mild anemia seen in most RTHα patients.


Assuntos
Anemia/genética , Eritropoese/genética , Regulação da Expressão Gênica , Receptores alfa dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/genética , Adolescente , Adulto , Anemia/epidemiologia , Anemia/fisiopatologia , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Eritrócitos/metabolismo , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Valores de Referência , Papel (figurativo) , Células-Tronco/citologia , Células-Tronco/fisiologia , Síndrome da Resistência aos Hormônios Tireóideos/epidemiologia , Síndrome da Resistência aos Hormônios Tireóideos/fisiopatologia , Adulto Jovem
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