RESUMEN
Genetic and environmental determinants inducing Graves' disease are still poorly defined, especially those leading to the appearance of TSH receptor antibodies, which are both the hallmark of the disease and the keystone of its diagnosis. The treatment of Graves' disease is based on the use of antithyroid drugs and no therapeutic protocol has proven superior to the other. Surgical or radiometabolic treatments, largely restricted to relapses and to patients with comorbidities could be considered earlier provided we had reliable predictive markers for relapse. The treatment of Graves' orbitopathy relies first on a rigorous analysis of severity and activity of the disease. Intravenous steroids appear as a reference treatment in active forms. Evaluation of new therapeutics is in process. Graves' disease during pregnancy requires a multidisciplinary approach and an expert ultrasound evaluation of the fetus. Because of a suspected teratogenicity of carbimazole and methimazole, propylthiouracyl is the preferred drug used during early pregnancy.
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Enfermedad de Graves/diagnóstico , Enfermedad de Graves/terapia , Antitiroideos/uso terapéutico , Femenino , Predisposición Genética a la Enfermedad , Enfermedad de Graves/etiología , Humanos , Embarazo , Complicaciones del Embarazo , Recurrencia , Glándula Tiroides/patologíaRESUMEN
OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is a rare cause of congenital hypopituitarism. Limited data exist on the gonadotropic status and fertility of adult women with PSIS. Our study aims to describe pubertal development and the evolution of gonadotropic function and fertility in adult women with PSIS. DESIGN: A retrospective multicentric French study. METHODS: We described gonadotropic function in 56 adult women with PSIS from puberty onward. We compared live birth rates per woman with PSIS with age-matched controls from the large French epidemiological cohort (CONSTANCES). Additionally, we assessed height, body mass index (BMI), blood pressure, other metabolic parameters, and socioeconomic status. RESULTS AND CONCLUSIONS: Among 56 women with PSIS, 36 did not experience spontaneous puberty. Of these, 13 underwent ovarian stimulation, resulting in 7 women having a total of 11 children. In the subgroup with spontaneous puberty (n = 20), 4 had a total of 8 pregnancies, while 6 developed secondary gonadotropic deficiency. Women with PSIS had fewer children than controls (0.33 vs 0.63, P = .04). Median height was also lower (160.5 vs 165.0â cm, P < .0001). Although mean blood pressure was lower in women with PSIS compared with controls (111.3/65.9 ± 11.2/8.1 vs 118.7/72.1 ± 10.1/7.7â mmHg, P < .001), there were no significant differences in other metabolic parameters, notably BMI and lipid profile. Employment/academic status was not different in the 2 groups, but fewer women with PSIS were in relationships (42% vs 57.6% in controls, P = .02). The fertility prognosis in patients with PSIS needs optimization. Patients should be informed about the likelihood of declining gonadotropic function over time.
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Hipopituitarismo , Hipófisis , Humanos , Femenino , Adulto , Estudios Retrospectivos , Hipopituitarismo/sangre , Hipopituitarismo/epidemiología , Embarazo , Adulto Joven , Pubertad/fisiología , Francia/epidemiología , Adolescente , Estudios de Casos y ControlesRESUMEN
IMPORTANCE: A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches. OBJECTIVE: To study the efficacy of glucagon-like peptide-1 analogs compared with placebo in adults with obesity CRO. DESIGN: A double-blind multicenter superiority randomized clinical in trial in two parallel arms. SETTING: Eleven French University Hospital Centers. PARTICIPANTS: Adults with CRO (body mass index > 30 kg/m²) without the sign of recurrence of craniopharyngioma in the past year. INTERVENTIONS: Exenatide or placebo injected subcutaneously twice a day during 26 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life, and the tolerance profile. RESULTS: At week 26, weight decreased from baseline by a mean of -3.8 (SD 4.3) kg for exenatide and -1.6 (3.8) kg for placebo. The adjusted mean treatment difference was -3.1 kg (95% confidence interval [CI] -7.0 to 0.7, P = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared with placebo (estimated treatment difference in change from baseline to week 26: -2.3, 95% CI -4.5 to -0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in, respectively, 19 (95%) participants (108 events) and 14 (70%) participants (54 events). CONCLUSIONS AND RELEVANCE: Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity.
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Craneofaringioma , Neoplasias Hipofisarias , Adulto , Humanos , Exenatida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Calidad de Vida , Craneofaringioma/complicaciones , Craneofaringioma/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Pérdida de Peso , Conducta Alimentaria , Neoplasias Hipofisarias/tratamiento farmacológico , Método Doble CiegoRESUMEN
Pituitary deficiency, or hypopituitarism, is a rare chronic disease. It is defined by insufficient synthesis of one or more pituitary hormones (growth hormone, TSH, ACTH, LH-FSH, prolactin), whether or not associated with arginine vasopressin deficiency (formerly known as diabetes insipidus). In adult patients, it is usually acquired (notably during childhood), but can also be congenital, due to abnormal pituitary development. The present study focuses on congenital pituitary deficiency in adults, from diagnosis to follow-up, including special situations such as pregnancy or the elderly. The clinical presentation is highly variable, ranging from isolated deficit to multiple deficits, which may be part of a syndromic form or not. Diagnosis is based on a combination of clinical, biological (assessment of all hormonal axes), radiological (brain and hypothalamic-pituitary MRI) and genetic factors. Treatment consists in hormonal replacement therapy, adapted according to the period of life and the deficits, which may be progressive. Comorbidities, risk of complications and acute decompensation, and the impact on fertility and quality of life all require adaptative multidisciplinary care and long-term monitoring.
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Hipopituitarismo , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/terapia , Francia/epidemiología , Adulto , Femenino , Embarazo , Terapia de Reemplazo de Hormonas/métodos , Masculino , Anciano , Hipófisis/anomalíasRESUMEN
Immune checkpoint inhibitors (ICIs) are currently the key therapy for several cancers. Among immune-related adverse events, thyroid dysfunction is the most frequent. We review this thyroid dysfunction, with recent data on epidemiology, diagnostic considerations, management and risk factors.
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Inhibidores de Puntos de Control Inmunológico , Enfermedades de la Tiroides , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/terapiaRESUMEN
Thyrotropic adenomas (TSH-PitNET) are the rarest pituitary tumours. Most TSH-PitNETs are secreting adenoma, with a biological picture of inappropriate TSH secretion (moderately elevated TSH, elevated FT3 and FT4). Patients present most often clinical hyperthyroidism, but with more moderate symptoms than in peripheral hyperthyroidism. Biological diagnosis is not always easy. The main differential diagnoses are interfering antibody assay interactions, dysalbuminemia and thyroid hormone resistance syndrome. Misdiagnosis is common. However, the diagnosis is easier when macroadenomas are involved (80% of cases), with symptoms of optic chiasm compression, headache and signs of hypopituitarism. Treatment is initially based on surgery. In case of failure, somatostatin analogues are very effective in controlling tumor volume and secretion, although there is a risk of thyroid insufficiency, which is usually transient.
Asunto(s)
Adenoma , Antineoplásicos , Hipertiroidismo , Neoplasias Hipofisarias , Humanos , Tirotropina , Neoplasias Hipofisarias/terapia , Neoplasias Hipofisarias/tratamiento farmacológico , Adenoma/terapia , Adenoma/tratamiento farmacológico , Hipertiroidismo/diagnósticoRESUMEN
INTRODUCTION: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH. METHODS: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded. RESULTS: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L. CONCLUSION: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.
Asunto(s)
Hipotiroidismo Congénito , Humanos , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/genética , Mutación , Genómica , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
CONTEXT: Resistance to thyroid hormone ß syndrome (RTHß) is caused by pathogenic variants in the THRB gene, but such variants are found in only 85% of cases. We report the case of a patient with RTHß phenotype but for whom we found a pathogenic variant of the THRB gene in a mosaic state. CASE DESCRIPTION: The patient is a 52-year-old woman with clinical and biological signs of RTHß. Symptoms included asthenia, cardiac palpitations, and diarrhea. Repeated thyroid function tests showed an elevated serum TSH, elevated serum free T4, and variably normal or slightly elevated serum fT3. Pituitary magnetic resonance imaging was normal, and the thyrotropin-releasing hormone test result was compatible with the diagnosis of RTHß syndrome. Initial Sanger sequencing on blood samples could not highlight the presence of a mosaic variant because of insufficient sensitivity. When next-generation sequencing became accessible, blood samples were retested and we found a known pathogenic variant: c.949Gâ >â A; p.(ala317Thr), with an allelic frequency of 12%. Other samples from tissues of different embryological origin were also tested and found an allelic frequency of 5.7%, 17.9%, 9.9%, 6.4%, and 0% on urine tests, oral swab, nasal mucosa swab, skin biopsy, and conjunctival swab, respectively. Cloning confirmed the allelic frequency observed. CONCLUSIONS: We highlight that a pathogenic variant in a mosaic state in the THRB gene may be the cause of an authentic RTHß syndrome. High-throughput sequencing of multiple tissues eases the detection of pathogenic variant in a mosaic state and allows the correct diagnosis of patients with true RTHß, thus avoiding patient mismanagement.
Asunto(s)
Genes erbA , Síndrome de Resistencia a Hormonas Tiroideas , Humanos , Mosaicismo , Mutación , Receptores beta de Hormona Tiroidea/genética , Síndrome de Resistencia a Hormonas Tiroideas/diagnóstico , Síndrome de Resistencia a Hormonas Tiroideas/genética , Hormonas TiroideasRESUMEN
Cushing's syndrome is defined by prolonged exposure to glucocorticoids, leading to excess morbidity and mortality. Diagnosis of this rare pathology is difficult due to the low specificity of the clinical signs, the variable severity of the clinical presentation, and the difficulties of interpretation associated with the diagnostic methods. The present consensus paper by 38 experts of the French Society of Endocrinology and the French Society of Pediatric Endocrinology and Diabetology aimed firstly to detail the circumstances suggesting diagnosis and the biologic diagnosis tools and their interpretation for positive diagnosis and for etiologic diagnosis according to ACTH-independent and -dependent mechanisms. Secondly, situations making diagnosis complex (pregnancy, intense hypercortisolism, fluctuating Cushing's syndrome, pediatric forms and genetically determined forms) were detailed. Lastly, methods of surveillance and diagnosis of recurrence were dealt with in the final section.
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Síndrome de Cushing , Endocrinología , Niño , Consenso , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiología , Femenino , Glucocorticoides , Humanos , EmbarazoRESUMEN
Thyroid hormones exert their action by binding to their thyroid hormone receptors among other mechanisms. They are involved in different cardiac functions, including contractility and rhythm. The mutation of thyroid hormone receptor ß is the main cause of thyroid hormone resistance. The cardiac phenotype of mutated patients has been studied in several cohorts of patients with different mutations. Tachycardia, palpitation and cardiac arrhythmia frequently appear; atrial flutter/fibrillation is found in up to 20%. Cardiac systolic and diastolic functions are impaired compared to hyperthyroid or euthyroid subjects, but cases of heart failure have not been reported. No correlation between genotype and cardiac phenotype has been found. Patients with a mutation of thyroid hormone receptor α frequently present bradycardia and systolic and diastolic functions that are similar to those of hypothyroid subjects. Levothyroxine treatment partly improves these parameters.
Asunto(s)
Cardiopatías/etiología , Síndrome de Resistencia a Hormonas Tiroideas/complicaciones , Animales , Cardiopatías/diagnóstico , Cardiopatías/genética , Cardiopatías/terapia , Pruebas de Función Cardíaca , Humanos , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas de Unión al ARN/genética , Simportadores/genética , Receptores alfa de Hormona Tiroidea/genética , Receptores beta de Hormona Tiroidea/genética , Síndrome de Resistencia a Hormonas Tiroideas/diagnóstico , Síndrome de Resistencia a Hormonas Tiroideas/genética , Síndrome de Resistencia a Hormonas Tiroideas/terapiaRESUMEN
CONTEXT: Radioiodine-refractory thyroid cancers have poor outcomes and limited therapeutic options (tyrosine kinase inhibitors) due to transient efficacy and toxicity of treatments. Therefore, combinatorial treatments with new therapeutic approaches are needed. Many studies link G protein-coupled receptors (GPCRs) to cancer cell biology. OBJECTIVE: To perform a specific atlas of GPCR expression in progressive and refractory thyroid cancer to identify potential targets among GPCRs aiming at drug repositioning. METHODS: We analyzed samples from tumor and normal thyroid tissues from 17 patients with refractory thyroid cancer (12 papillary thyroid cancers [PTCs] and 5 follicular thyroid cancers [FTCs]). We assessed GPCR mRNA expression using NanoString technology with a custom panel of 371 GPCRs. The data were compared with public repositories and pharmacological databases to identify eligible drugs. The analysis of prognostic value of genes was also performed with TCGA datasets. RESULTS: With our transcriptomic analysis, 4 receptors were found to be downregulated in FTC (VIPR1, ADGRL2/LPHN2, ADGRA3, and ADGRV1). In PTC, 24 receptors were deregulated, 7 of which were also identified by bioinformatics analyses of publicly available datasets on primary thyroid cancers (VIPR1, ADORA1, GPRC5B, P2RY8, GABBR2, CYSLTR2, and LPAR5). Among all the differentially expressed genes, 22 GPCRs are the target of approved drugs and some GPCRs are also associated with prognostic factors. DISCUSSION: For the first time, we performed GPCR mRNA expression profiling in progressive and refractory thyroid cancers. These findings provide an opportunity to identify potential therapeutic targets for drug repositioning and precision medicine in radioiodine-refractory thyroid cancer.
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Adenocarcinoma Folicular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Cáncer Papilar Tiroideo/metabolismo , Neoplasias de la Tiroides/metabolismo , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patología , Adulto , Anciano , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Medicina de Precisión , Receptores Acoplados a Proteínas G/genética , Estudios Retrospectivos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Glándula Tiroides/metabolismo , Glándula Tiroides/patología , Neoplasias de la Tiroides/genéticaRESUMEN
OBJECTIVE: Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL. DESIGN: Retrospective study. METHODS: Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency. RESULTS: Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4-7) and for a median duration of 3 months (2.5-3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency. CONCLUSIONS: SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.
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Adenoma/complicaciones , Hipertiroidismo/tratamiento farmacológico , Hipotiroidismo/inducido químicamente , Neoplasias Hipofisarias/complicaciones , Receptores de Somatostatina/uso terapéutico , Adenoma/metabolismo , Adulto , Femenino , Humanos , Hipertiroidismo/etiología , Ligandos , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/metabolismo , Estudios Retrospectivos , Tirotropina/metabolismoRESUMEN
INTRODUCTION: Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. PATIENTS AND METHODS: The PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. The primary end-point was time to treatment failure (TTF) defined as the time from randomisation to permanent discontinuation of pazopanib, due to any cause. One hundred randomised patients were needed to demonstrate an increase from 50% (CP) to 70% (IP) (hazard ratio (HR) 0.515, 80% power) in the rate of patients still under treatment 6 months (6m-SuT) post-randomisation. Secondary end-points included the overall response rate (ORR), progression-free survival (PFS) under pazopanib and safety. RESULTS: RAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6-month pazopanib treatment and showed 35.6% (95% CI 28.2-43.6) best response rate and 89.4% (83.5-93.7) disease control rate. One hundred patients were randomised (IP:50; CP:50). With a median follow-up of 31.3 months, median TTF was not statistically different between arms (IP:14.7, 95% confidence interval (CI) 9.3-17.4; CP:11.9, 95% CI 7.5-15.6) months (HR 0.79, 0.49-1.27). 6m-SuT rates were similar (IP:80% 66.0-88.7%; CP:78% 63.8-87.2%). Median PFS under pazopanib were not statistically different (IP:5.7 4.8-7.8; CP: 9.2 7.3-11.1) months (HR 1.36, 0.88-2.12). Pazopanib-related adverse events grade 3-4 occurred in 36 (IP: 19, 38%; CP: 17, 34%) randomised patients. Seven pazopanib-related deaths occurred. CONCLUSIONS: Intermittent administration of pazopanib did not demonstrate significant superiority in efficacy or tolerance compared with continuous treatment. An intermittent administration scheme cannot be recommended outside clinical trials. This study was registered with ClinicalTrial.gov, number NCT01813136.
Asunto(s)
Indazoles/administración & dosificación , Radioisótopos de Yodo/uso terapéutico , Pirimidinas/administración & dosificación , Sulfonamidas/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Indazoles/efectos adversos , Masculino , Persona de Mediana Edad , Pirimidinas/efectos adversos , Sulfonamidas/efectos adversos , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/radioterapia , Insuficiencia del TratamientoRESUMEN
OBJECTIVE: Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management. METHODS: A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center. RESULTS: Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156)). CONCLUSION: Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.
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Neoplasias de las Glándulas Suprarrenales , Ganglioneuroma , Adolescente , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/terapia , Adulto , Edad de Inicio , Anciano , Bélgica/epidemiología , Niño , Preescolar , Estudios de Cohortes , Redes Comunitarias , Femenino , Estudios de Seguimiento , Francia/epidemiología , Ganglioneuroma/diagnóstico , Ganglioneuroma/epidemiología , Ganglioneuroma/terapia , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Resistance to thyroid hormone (RTH) is a syndrome characterized by impaired sensitivity of tissues to thyroid hormone (TH). The alteration of TH-binding proteins, such as in Familial Dysalbuminemic Hyperthyroxinemia (FDH), can mimic the abnormal serum thyroid tests typical of RTH. We aimed to characterize a population referred to our center with suspected RTH and estimate the proportion of patients with FDH. For 303 different families, we collected clinical and hormonal data and sequenced the thyroid hormone receptor ß gene (THRB) and exon 7 of the albumin gene (ALB). We found 56 THRB variants (i.e., 38% of the 303 index cases, called RTHß group). Among the samples screened for FDH variants, 18% had the variant R218H in ALB (FDH group); in addition, 71% of the cases had neither variant (non-FDH/RTHß group). Patients with FDH had significantly lower free T3 (fT3) and free T4 (fT4) levels and more often an isolated elevation of fT4 than RTHß patients. Clinically, patients with FDH had fewer symptoms than patients with RTHß. Our study suggests that FDH should be systematically considered when examining patients suspected of having RTH. In most cases, they present no clinical symptoms, and their biochemical alterations show an elevation of fT4 levels, while fT3 levels are 1.11 times below the upper limit of the assay.
RESUMEN
Resistance to thyroid hormone alpha (RTHα) is a rare and under-recognized genetic disease caused by mutations of THRA, the gene encoding thyroid hormone receptor α1 (TRα1). We report here two novel THRA missense mutations (M259T, T273A) in patients with RTHα. We combined biochemical and cellular assays with in silico modeling to assess the capacity of mutant TRα1 to bind triiodothyronine (T3), to heterodimerize with RXR, to interact with transcriptional coregulators, and to transduce a T3 transcriptional response. M259T, and to a lower extent T273A, reduces the affinity of TRα1 for T3. Their negative influence is only reverted by large excess of T3. The severity of the two novel RTHα cases originates from a reduction in the binding affinity of TRα1 mutants to T3 and thus correlates with the incapacity of corepressors to dissociate from TRα1 mutants in the presence of T3.
Asunto(s)
Mutación Missense , Receptores alfa de Hormona Tiroidea/genética , Síndrome de Resistencia a Hormonas Tiroideas/genética , Preescolar , Simulación por Computador , Dimerización , Femenino , Heterocigoto , Humanos , Lactante , Recién Nacido , Recien Nacido Prematuro , Ligandos , Mutación , Fenotipo , Síndrome de Resistencia a Hormonas Tiroideas/sangre , Hormonas Tiroideas , Tiroxina/metabolismo , Activación Transcripcional , Transfección , Triyodotironina/metabolismoRESUMEN
Resistance to thyroid hormones syndrome is defined as increased thyroxine (T4) and triiodothyronine (T3) concentrations associated with normal or sometimes increased thyrotropin (TSH) concentration. This is usually due to a pathogenic variant with loss of function of the gene coding for thyroid hormone receptor ß (THRB). This discrepancy in thyroid hormones (TH) and TSH concentrations is also frequently observed in the presence of analytical interference, notably alteration of TH transport proteins in serum. During 2017, 58 samples were sent to our laboratory in the Angers University Hospital Rare Thyroid and Hormone Receptor Disease Reference Center in order to identify an etiology for discrepant TSH and TH results. We sequenced the genes involved in TH regulation, action and transport (THRB,THRA, SECISBP2, SLC16A, ALB, TTR, SERPINA7). Free T4 and free T3 assay were performed with a second immunoassay (Siemens ADVIA Centaur). A genetic cause of discrepancy in TH and TSH concentrations, with mutation in THRB, was found in 26% of cases (15/58). Biological interference due to TH serum transport protein variant was found in 24% (14/58) of cases. No pathogenic variants were found in the other genes studied. Biological interference was also suspected in 26% of cases without genetic variant, in which the biological discrepancy was not confirmed by a second analytical technique (15/58). Finally, no etiology for the biological discrepancy could be found in 24% of cases (14/58). Clinically, patients in whom biological discrepancy was due to analytic interference were more often asymptomatic, and patients with no identified etiology tended to be older. To limit diagnostic errors associated with the finding of discrepant TSH and TH, we recommend initially conducting a second thyroid function test (TSH, free T4 and free T3) with a different assay, and then screening for a genetic variant in gene coding for thyroid hormone receptor ß (THRB) and the TH serum transport proteins (ALB, TTR, SERPINA7).
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Errores Diagnósticos/estadística & datos numéricos , Mutación/genética , Pruebas de Función de la Tiroides/métodos , Receptores beta de Hormona Tiroidea/genética , Síndrome de Resistencia a Hormonas Tiroideas/diagnóstico , Síndrome de Resistencia a Hormonas Tiroideas/genética , Adolescente , Adulto , Anciano , Proteínas Portadoras/sangre , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Síndrome de Resistencia a Hormonas Tiroideas/sangre , Tirotropina/sangre , Tiroxina/sangre , Triyodotironina/sangreAsunto(s)
Mutación de Línea Germinal , Neoplasias Cardíacas/genética , Paraganglioma/genética , Succinato Deshidrogenasa/genética , Adulto , Neoplasias Cardíacas/complicaciones , Neoplasias Cardíacas/metabolismo , Humanos , Hipertensión/etiología , Masculino , Norepinefrina/sangre , Norepinefrina/orina , Paraganglioma/complicaciones , Paraganglioma/metabolismoRESUMEN
Thyroid pathology is the most frequent form of endocrinopathy during tyrosine kinase inhibitor (TKI) treatment. Dysthyroidism occurs in 10% to 80% of cases, depending on diagnostic criteria. In patients with intact thyroid gland prior to TKI treatment, incidence of dysthyroidism is 30-40%, with subclinical presentation in half of cases. It mainly involves hypothyroidism, preceded in 20-40% of cases by transient thyrotoxicosis that may go overlooked. The pathophysiological mechanism is "vascular" thyroiditis induced by the anti-angiogenic action of TKIs. Between 20% and 60% of patients receiving levothyroxine ahead of TKI treatment show increased levothyroxine requirements. TKIs should not be discontinued because of onset of thyroid dysfunction. Treatment is symptomatic in case of thyrotoxicosis, and levothyroxine replacement therapy is initiated in case of symptomatic hypothyroidism or TSH>10mIU/L. During TKI treatment, TSH should be assayed monthly, or at end of off-period (i.e., day 1 of new cycle after interruption), for the first 6 months, then every 2-3 months or in case of clinical signs of dysthyroidism. In patients already treated for hypothyroidism, TSH should be assayed monthly for 3 months, then every 3 months throughout treatment. At TKI termination, remission of hypothyroidism is possible but unpredictable, and progressive discontinuation of levothyroxine may be considered under monitoring. Teamwork between oncologists and endocrinologists improves screening and treatment of thyroid dysfunction, enabling the patient to be better accompanied during treatment.
Asunto(s)
Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/etiología , Consenso , Humanos , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Proteínas Tirosina Quinasas , Enfermedades de la Tiroides/epidemiología , Pruebas de Función de la TiroidesRESUMEN
Thyroid pathologies are the most common forms of endocrinopathy under anticancer immunotherapy. Frequency ranges from 3% to 22% for hypothyroidism and 1% to 11% for thyrotoxicosis. Risk is higher with anti-PD-1 than anti-CTLA-4 treatment and higher again with associated treatment. Pathophysiology mainly consists in silent inflammatory thyroiditis, which accounts for the usual presentation of transient thyrotoxicosis followed by hypothyroidism. Therapeutic strategy usually consists in monitoring with or without symptomatic treatment in case of thyrotoxicosis, and levothyroxine replacement therapy in case of symptomatic hypothyroidism or TSH>10 mIU/L. Screening for dysthyroidism should be systematic ahead of treatment and before each immunotherapy injection for the first 6 months, then at a lower rhythm. It comprises clinical assessment and TSH assay. Onset of thyroid dysfunction should not interrupt immunotherapy, being mainly transient, easy to treat and mild. Teamwork between oncologists and endocrinologists improves screening and management, so as better to accompany the patient during treatment.