RESUMEN
BACKGROUND: APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). RESULTS: 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.
RESUMEN
EXPLORATION AND MANAGEMENT OF THYROID NODULES. Most thyroid nodules are benign (95%) and can benefit from clinical and ultrasound monitoring. Cancers (approximately 5% of nodules) could be suspected, particularly in subjects whose neck was irradiated, in cases of a hard, irregular, evolving nodule, or with very high serum calcitonin (> 100 pg/ml). It is crucial to recognize cancers when nodules exceed the supracentimeter stage. Thyroid ultrasonography is the most common, handy, safe, and cost-effective tool to image thyroid nodules. It classifies thyroid nodules according to the EU-TIRADS score, which comprises 5 categories associated with an increasing risk of malignancy. An ultrasound-guided fine needle aspiration (FNA) biopsy is performed only in nodules staged EU-TIRADS classes 5, 4, and 3 over 1, 1.5, and 2 cm, respectively. Cytologic analysis of FNA material classifies thyroid nodules according to the Bethesda system into 6 classes, each with its own prognostic value. The difficulties in cytological evaluation are related to the uninterpretable (Bethesda I) and indeterminate (especially III and IV) results, for which have to be discussed opportunities of reassessment and follow-up by scintiscans and cytological molecular markers. Management is imperfectly codifiable: from surveillance in the absence of suspicious elements initially to total thyroidectomy in their presence.
EXPLORATION ET PRISE EN CHARGE DES NODULES THYROÏDIENS. La plupart des nodules thyroïdiens sont bénins (95 %) et peuvent bénéficier d'une surveillance clinique et échographique. La malignité (5 % des nodules environ) est à suspecter, particulièrement chez les sujets dont le cou a été irradié, en cas de nodule dur, irrégulier, évolutif, avec une calcitoninémie très élevée (supérieure à 100 pg/mL). C'est au stade de nodule supracentimétrique qu'il importe de reconnaître les cancers. L'échographie est l'examen d'imagerie de référence ; elle permet de classer les nodules selon le score EU-TIRADS, composé de cinq catégories associées à un risque croissant de malignité. Les ponctions échoguidées en vue de l'analyse cytologique sont réservées aux catégories EU-TIRADS 5, 4 et 3 de plus de 1, 1,5 et 2 cm respectivement. Les caractéristiques cytologiques sont présentées selon la nomenclature de Bethesda en six classes dont chacune quantifie aussi le risque de malignité, en complément des données échographiques. Les difficultés de l'évaluation cytologique sont liées aux résultats ininterprétables (Bethesda I) et indéterminés (surtout Bethesda III et IV) pour lesquels se discutent l'opportunité de la réévaluation et de la surveillance, des scintigraphies dites de seconde intention, et également des marqueurs moléculaires sur le produit de cytoponction. La prise en charge est imparfaitement codifiable : de la surveillance en l'absence d'éléments suspects initialement à la thyroïdectomie totale en leur présence.
Asunto(s)
Neoplasias de la Tiroides , Nódulo Tiroideo , Humanos , Nódulo Tiroideo/diagnóstico , Nódulo Tiroideo/terapia , Nódulo Tiroideo/patología , Neoplasias de la Tiroides/patología , Estudios Retrospectivos , Ultrasonografía , Biopsia con Aguja Fina/métodosRESUMEN
BACKGROUND: The aim of this study was to evaluate the role of dual isotope 123Iodine/99mTc-MIBI thyroid scintigraphy (IMS) in discriminating between malignant and benign lesions in indeterminate nodules using quantitative analysis methods. METHODS: Thirty-five consecutive patients with thyroid nodules of indeterminate or non-diagnostic cytology and cold on 123Iodine scintigraphy (10 Bethesda I, 24 Bethesda III-IV, 1 in which cytology was impossible) underwent IMS between 2017 and 2019 with uptake quantification at two time points ahead of thyroidectomy: early and late. Images were analyzed by two blinded physicians. RESULTS: Twelve nodules were malignant and 23 benign on histopathology. Mean uptake values were lower in benign than in malignant nodules at both time points: early, 8.7±4.1 versus 12.9±3.5 (P=0.005); and late, 5.3±2.7 versus 7.7±1.1 (P=0.008). Interobserver reproducibility was excellent. The intraclass correlation coefficient was 0.86 in benign and 0.92 in malignant lesions for early uptake result (ER) and 0.94 and 0.85 respectively for late uptake result (LR). The optimal LR cut-off to exclude a diagnosis of malignancy was set at 5.9 . The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of this cut-off were, respectively, 100%, 65.2%, 60%, 100% and 77.1%. CONCLUSION: Despite some study limitations, quantitative analysis of 99mTc-MIBI thyroid scintigraphy had a good reproducibility, which could help to rule out malignancy in non-diagnostic or indeterminate thyroid nodules and thereby reducing the number of patients undergoing unnecessary surgery when LR is below 5.9.
Asunto(s)
Radioisótopos de Yodo , Cintigrafía/métodos , Tecnecio Tc 99m Sestamibi , Neoplasias de la Tiroides/diagnóstico por imagen , Nódulo Tiroideo/diagnóstico por imagen , Adulto , Anciano , Biopsia con Aguja Fina , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/cirugía , Nódulo Tiroideo/patología , Nódulo Tiroideo/cirugía , UltrasonografíaRESUMEN
BACKGROUND: Levothyroxine sodium marketed in France was reformulated following a French National Agency for Medicines and Health Products Safety request for a more stringent potency specification. Despite previously established purity and bioequivalence of the new and old formulations, reports of adverse events substantially increased following reformulation. This analysis evaluated the nature and relevance of the medically confirmed safety reports. METHODS: Spontaneous and solicited individual case safety reports in France were retrieved from 26 March 2015 to 30 June 2016 (old formulation) and 26 March 2017 to 30 June 2018 (new formulation). Rates of reports and adverse events were calculated for the overall patient population and for at-risk subgroups. Adverse events delineated by thyroid-stimulating hormone levels were evaluated. RESULTS: A total of 295 and 42 775 reports for the old formulation and new formulation, respectively, were retrieved, with 149 and 5503 medically confirmed. The most common medically confirmed adverse events were consistent with the known safety profile of levothyroxine, with generally comparable rates between both formulations (range of differences, 1.8-4.1%). Most cases were not serious (old formulation, 65.8%; new formulation, 78.7%). Reporting rates were similar or higher for the old formulation within subgroups of at-risk patients. Nature/distributions of adverse events by thyroid-stimulating hormone levels as determined by both the marketing authorization holder of levothyroxine and the French National Agency for Medicines and Health Products Safety were similar. CONCLUSIONS: The new formulation safety profile aligns with the established profile of the old formulation of levothyroxine. The benefit-risk profile is unchanged, such that the benefits of using the new formulation in the approved indications outweigh the risks associated with the treatment.
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Composición de Medicamentos/estadística & datos numéricos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Tiroxina/efectos adversos , Francia/epidemiología , Humanos , Estudios Retrospectivos , Equivalencia TerapéuticaAsunto(s)
Hipotiroidismo/inmunología , Hipotiroidismo/metabolismo , Receptores de Tirotropina/inmunología , Adulto , Anciano , Autoanticuerpos/inmunología , Femenino , Humanos , Inmunoglobulinas Estimulantes de la Tiroides/inmunología , Yoduro Peroxidasa/inmunología , Masculino , Persona de Mediana Edad , Receptores de Tirotropina/análisis , Receptores de Tirotropina/metabolismo , Tirotropina/inmunologíaRESUMEN
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene.
Asunto(s)
Candida albicans/fisiología , Candidiasis Mucocutánea Crónica/inmunología , Carcinoma de Células Escamosas/inmunología , Neoplasias de la Boca/inmunología , Mutación/genética , Poliendocrinopatías Autoinmunes/inmunología , Células Th17/inmunología , Factores de Transcripción/genética , Insuficiencia Suprarrenal , Animales , Autoanticuerpos/metabolismo , Fluconazol/uso terapéutico , Humanos , Hipoparatiroidismo , Poliendocrinopatías Autoinmunes/tratamiento farmacológico , Proteína AIRERESUMEN
Graves' disease is the most frequent cause of hyperthyroidism. Many questions remain about the choice of diagnostic evaluations and treatment strategy according to clinical context (age, gender, pregnancy, etc.) and about the best management of the main extrathyroidal complication that is Graves orbitopathy. The exact pathogenic mechanisms are not fully clear. They associate genetic factors, interactions between endogenous and environmental factors, and immune system dysregulation. Graves' orbitopathy is one of the consequences of this partial understanding. Iatrogenic Graves' disease induced by the new targeted therapies are described and could help to better understand the molecular pathways involved in the disease and to develop new therapeutic approaches.
Asunto(s)
Ambiente , Enfermedad de Graves/diagnóstico , Enfermedad de Graves/epidemiología , Enfermedad de Graves/etiología , Edad de Inicio , Susceptibilidad a Enfermedades/complicaciones , Susceptibilidad a Enfermedades/epidemiología , Susceptibilidad a Enfermedades/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/complicaciones , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Humanos , Enfermedad Iatrogénica/epidemiología , Fenómenos del Sistema Inmunológico/fisiología , Infecciones/complicaciones , Infecciones/epidemiologíaRESUMEN
Lymph node involvement (LNI) is one of the most important prognostic factors for poor survival in medullary thyroid carcinoma (MTC). At diagnosis, LNI is found in over 50% of sporadic MTCs, and especially in large tumours. Cervical lymph node dissection is therefore mandatory during MTC surgery. However, some large tumours (responsible for high preoperative basal calcitonin levels) are found to lack LNI, and can be cured definitely. Preoperative detection of these particular tumours might spare patients from undergoing extensive cervical dissection. The objective of the present retrospective study of a series of large sporadic MTCs was to identify clinical, biological and pathological factors that were predictive of LNI. Consecutive cases of large, sporadic MTCs (measuring at least 1 cm in diameter) were retrieved and reviewed. The levels of several mature microRNAs (miRs) in paraffin-embedded samples were assessed using qPCR. Of the 54 MTCs, 26 had LNI and 28 were pN0. Relative to pN0 patients, patients with LNI had a significant higher preoperative basal calcitonin level (p = 0.0074) and a greater prevalence of infiltrative margins (p < 0.0001), lymphovascular invasion (p = 0.0004), extrathyroidal extension (p < 0.0001), a higher pT stage (p = 0.0003) and more abundant desmoplastic stroma (p = 0.0006). Tumour expression levels of miR-21 (p = 0.0008) and miR-183 (p = 0.0096) were higher in the LNI group. The abundance of desmoplastic stroma (p = 0.007) and the miR-21 expression level (p = 0.0026) were independent prognostic factors for LNI. The abundance of desmoplastic stroma and high levels of miR-21 expression were strong indicators of LNI, and may thus help the surgeon to choose the extent of cervical lymph node dissection for large, sporadic MTCs with no preoperatively obvious LNI.
Asunto(s)
Carcinoma Medular/patología , Carcinoma Neuroendocrino/patología , Ganglios Linfáticos/patología , Glándula Tiroides/patología , Neoplasias de la Tiroides/patología , Adulto , Anciano , Femenino , Humanos , Escisión del Ganglio Linfático/métodos , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosAsunto(s)
Contaminación de Medicamentos , Medios de Comunicación de Masas , Pánico , Opinión Pública , Tiroxina/efectos adversos , Composición de Medicamentos/métodos , Composición de Medicamentos/normas , Excipientes/efectos adversos , Francia , Terapia de Reemplazo de Hormonas/efectos adversos , Terapia de Reemplazo de Hormonas/métodos , Humanos , Difusión de la Información , Farmacovigilancia , Tiroxina/administración & dosificaciónRESUMEN
Oral disorders were observed in children with congenital hypothyroidism, lately apparent because of difficulties of feeding, swallowing disorders, and macroglossia. Macroglossia was also a component of the severe acquired myxedema, particularly observed in hypothyroidism related to autoimmune atrophic thyroiditis beyond menopause. Lingual ectopy in children and adults could determine respiratory gene or swallowing difficulties, and were detectable by visual examination and the endobuccal touch. Expression of these events was completely minimized since the neonatal screening of congenital hypothyroidism, also by the common practice in adults of serum TSH determinations. Congenital and acquired hormonal deficits are now early detected and correct with suppletive doses of levothyroxine. Oral expression of hyperthyroidism is poor, even if thyrotoxicosis is sometimes revealed by increased thirst. Caution is required for dental care, mainly due to changes in the hemostatic functions. Finally, a genetic predisposition to the medullary thyroid cancer may be revealed by an oral and neuromatosis. Radioisotopic therapy of thyroid cancers is likely to alter the salivation.