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1.
Am J Med Genet A ; 194(7): e63576, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38407483

RESUMEN

Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel occurrence of a MEN2A patient's family in which the siblings inherited three different RET 634 genotypes: wild type (p.Cys634), p.Cys634Gly or p.Cys634Arg heterozygous pathogenic variants. We hypothesized that germline/gonadal mosaicism, derived from an inherited + early somatic mutation in the mother or a double de novo mutation during maternal embryogenesis, led to this rare event in the RET gene. Exome analysis of the proband's deceased mother's paraffin-embedded thyroid tissue confirmed the three nucleotides in the same 634 codon position. For the first time, we describe germline/gonadal mosaicism in RET, generating a second pathogenic amino acid change in the same codon causing MEN2A. Our finding shows that RET parental mosaicism, confirmed by somatic exome sequencing, might explain discrepant genotype cases in siblings with inherited cancers.


Asunto(s)
Mutación de Línea Germinal , Mosaicismo , Neoplasia Endocrina Múltiple Tipo 2a , Linaje , Proteínas Proto-Oncogénicas c-ret , Humanos , Neoplasia Endocrina Múltiple Tipo 2a/genética , Neoplasia Endocrina Múltiple Tipo 2a/patología , Proteínas Proto-Oncogénicas c-ret/genética , Mutación de Línea Germinal/genética , Femenino , Masculino , Adulto , Sustitución de Aminoácidos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Genotipo , Secuenciación del Exoma
2.
Arch Endocrinol Metab ; 64(5): 514-520, 2021 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-34033290

RESUMEN

OBJECTIVE: Graves' disease (GD) is the main cause of hyperthyroidism among adults. It is an autoimmune condition classically marked by the Merserburg Triad (goiter, thyrotoxicosis, and orbitopathy), but the change in presentation of GD over time has rarely been studied. To determine changes in the clinical presentation of patients with GD in the last 30 years. METHODS: The study evaluated 475 patients diagnosed with GD between 1986 and 2016 in a single center. Patients were evaluated regarding epidemiological aspects, thyroid function, inflammatory activity of the eyes evaluated by the Clinical Activity Score; CAS, severity evaluated by NOSPECS classification and thyroid volume estimated by ultrasonography. RESULTS: Patients assessment identified an increase in the mean age of diagnosis of GD (p < 0.02), a reduction in thyroid volume (p < 0.001) and less intense orbital involvement from 2007-2016 compared to 1986-2006 (p = 0.04). The number of smoking patients was smaller from 2007 to 2016 (28.7%) than 1986 to 2006 (42.8% p = 0.001). The TSH and TRAb values did not had significant changes. CONCLUSION: GD presentation appears to be changed in the last years compared to the typical initial presentation. There is a less frequent inflammatory involvement of orbital tissue, smaller goiters, a lower number of smokers and diagnosis at older age.


Asunto(s)
Enfermedad de Graves , Tirotoxicosis , Adulto , Anciano , Brasil/epidemiología , Enfermedad de Graves/epidemiología , Humanos , Estudios Retrospectivos
3.
Arch. endocrinol. metab. (Online) ; 64(5): 514-520, Sept.-Oct. 2020. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1131126

RESUMEN

ABSTRACT Objective Graves' disease (GD) is the main cause of hyperthyroidism among adults. It is an autoimmune condition classically marked by the Merserburg Triad (goiter, thyrotoxicosis, and orbitopathy), but the change in presentation of GD over time has rarely been studied. To determine changes in the clinical presentation of patients with GD in the last 30 years. Subjects and methods The study evaluated 475 patients diagnosed with GD between 1986 and 2016 in a single center. Patients were evaluated regarding epidemiological aspects, thyroid function, inflammatory activity of the eyes evaluated by the Clinical Activity Score; CAS, severity evaluated by NOSPECS classification and thyroid volume estimated by ultrasonography. Results Patients assessment identified an increase in the mean age of diagnosis of GD (p < 0.02), a reduction in thyroid volume (p < 0.001) and less intense orbital involvement from 2007-2016 compared to 1986-2006 (p = 0.04). The number of smoking patients was smaller from 2007 to 2016 (28.7%) than 1986 to 2006 (42.8% p = 0.001). The TSH and TRAb values did not had significant changes. Conclusion GD presentation appears to be changed in the last years compared to the typical initial presentation. There is a less frequent inflammatory involvement of orbital tissue, smaller goiters, a lower number of smokers and diagnosis at older age.


Asunto(s)
Humanos , Adulto , Anciano , Tirotoxicosis , Brasil/epidemiología , Enfermedad de Graves/epidemiología , Estudios Retrospectivos
4.
Thyroid ; 25(12): 1282-90, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26414885

RESUMEN

BACKGROUND: Low doses of antithyroid drugs (ATD) for extended periods may be an alternative for Graves' disease (GD) patients who relapse after a course of ATD. METHODS: Patients with GD relapse (n = 238) after discontinuation of ATD therapy for 12-24 months were retrospectively analyzed in a nonrandomized study. Radioiodine (RAI) treatment and L-thyroxine replacement was used in 114 patients, and a low dose of methimazole (MMI; 2.5-7 mg/daily) was used in 124 patients. Thyroid dysfunction, Graves' ophthalmopathy (GO) evolution, quality of life (QoL), and body weight were evaluated during the follow-up. RESULTS: The mean follow-up was 80.8 ± 35.3 months for the RAI group, and 71.3 ± 40.3 months for the low-dose MMI group. No notable side effects were observed in either group. Thyroid dysfunction was predominant in the RAI group (p < 0.001), and euthyroidism was more common in the MMI group (p < 0.001). GO deterioration was mainly evaluated by clinical activity score (CAS)--it was higher in the RAI group (p < 0.0005) over all periods of follow-up. Multivariate logistic analysis showed that RAI treatment was associated with no improvement in CAS during follow-up (24 months: OR = 3.51 [CI 1.02-12.03], p < 0.05; 36 months: OR = 8.46 [CI 1.47-48.58], p < 0.05; 48 months: OR = 19.52 [CI 1.70-223.10], p < 0.05; 60 months: OR = 21.1 [CI 1.5-298], p < 0.05). Kaplan-Meier survival analysis confirmed this finding (p < 0.0003). Assessment of QoL using the Short Form Health Survey's 36 parameters in stable euthyroid patients (at least six months) was similar in both groups. The RAI group patients gained more weight (p < 0.005), particularly after 24 months of follow-up. CONCLUSIONS: The use of low doses of MMI is efficient and safe, and offers better outcomes for GO than RAI treatment. Prolonged low doses of MMI may be an alternative choice for relapsed GD patients, particularly for GO patients or for patients who refuse a definitive treatment.


Asunto(s)
Antitiroideos/administración & dosificación , Enfermedad de Graves/terapia , Oftalmopatía de Graves/terapia , Metimazol/administración & dosificación , Adulto , Femenino , Terapia de Reemplazo de Hormonas , Humanos , Radioisótopos de Yodo/uso terapéutico , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Tiroxina/uso terapéutico , Resultado del Tratamiento
5.
Clin Nucl Med ; 37(3): 241-4, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22310249

RESUMEN

AIM: To investigate the effectiveness of 2 fixed iodine (¹³¹I) doses for the treatment for Graves hyperthyroidism and their impact on eye disease. METHODS: We prospectively examined 76 patients who received a fixed dose of 370 MBq (group 1) and 52 patients who received 555 MBq ¹³¹I (group 2). Patients were followed up for 12 months and considered in remission when they were in a stable euthyroid or hypothyroid state in the absence of antithyroid drugs 12 months after ¹³¹I administration. Eight patients with active eye disease received a daily dose of 0.5 mg/kg prednisone per kilogram of body weight at the time of radioiodine therapy for 1 month. RESULTS: The remission rate obtained was similar in groups 1 (73.7%) and 2 (80.8%; P = 0.35). Hypothyroidism was diagnosed in 56.5% of the 370-MBq group and 71.1% of the 555-MBq group patients (P = 0.13). There was no correlation among clinical features, thyroid uptake, antibody levels, serum hormones levels, and outcome. However, logistic regression analysis demonstrated that patients with large thyroid glands had 2.4 times less chance to go into remission (odds ratio; 95% confidence interval = 1.18-4.96). None of the patients developed eye disease during any fixed-dose treatment regimen or worsened their previously diagnosed ophthalmopathy. CONCLUSIONS: Fixed doses of 370 MBq and 555 MBq ¹³¹I provided similar remission rates; however, outcome was influenced by the thyroid size. We propose that 370 MBq ¹³¹I should be the routine treatment dose for all Graves disease patients, reserving a dose of 555 MBq ¹³¹I to palpable large goiters, without any additional concern to eye disease.


Asunto(s)
Enfermedad de Graves/radioterapia , Radioisótopos de Yodo/administración & dosificación , Adulto , Distribución de Chi-Cuadrado , Femenino , Humanos , Modelos Logísticos , Masculino , Prednisona/administración & dosificación , Estudios Prospectivos , Inducción de Remisión , Estadísticas no Paramétricas , Pruebas de Función de la Tiroides , Resultado del Tratamiento
7.
Femina ; 36(11): 691-695, nov. 2008. tab
Artículo en Portugués | LILACS | ID: lil-508551

RESUMEN

A fisiopatologia multifatorial da síndrome dos ovários policísticos (SOP) encontra-se estabelecida, assim como sua associação com a resistência insulina (RI) e, conseqüentemente, com a síndrome metabólica (SM). Entretanto, a avaliação da SM e do risco cardiovascular (RCV) inerente a este estado tem sido dificultado pela multiplicidade de critérios que definem a SM e pela dificuldade de diagnóstico laboratorial da RI incluso nos critérios. O objetivo deste artigo é revisar, de forma acessível à prática clínica, os critérios diagnósticos atuais para a SOP, associada ou não à SM, possibilitando o embasamento para opções terapêuticas que permitam não apenas tratar a anovulação crônica, como também reduzir o risco cardiovascular das mulheres com SOP.


The multifactorial pathophysiology of the Polycystic Ovary Syndrome is established, as well as its association with insulin resistance and consequently with the Metabolic Syndrome. On the other hand, the evaluation of the Metabolic Syndrome and Cardiovascular risk (CV), inherent to this illness, has been made difficult due to the multiplicity of criteria that define the Metabolic Syndrome and the difficulty of the insulin resistance laboratorial diagnosis, which is included in those criteria. The purpose of this article is to review, in an accessible form the clinic practice, the current diagnosis criteria of the Polycystic Ovary Syndrome, whether associated or not with the Metabolic Syndrome, making possible to set the basis for the therapeutical options that allows not only the chronic anovulation treatment, but also to reduce the cardiovascular risk for women with polycystic ovary syndrome.


Asunto(s)
Femenino , Enfermedades Cardiovasculares/etiología , Enfermedades Metabólicas , Síndrome Metabólico , Resistencia a la Insulina/fisiología , Síndrome del Ovario Poliquístico/diagnóstico , Síndrome del Ovario Poliquístico/fisiopatología , Síndrome del Ovario Poliquístico/terapia , Estilo de Vida , Metformina/uso terapéutico
8.
Clin Endocrinol (Oxf) ; 68(6): 982-7, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17980001

RESUMEN

OBJECTIVE: Cigarette smoking is a well-recognized risk factor of Graves' disease and, particularly, Graves' ophthalmopathy. Hence, germline polymorphisms of detoxification genes and genes belonging to the major DNA repair-apoptosis pathways might have an important role in disease susceptibility. In addition, as some of these genes are regulated by thyroid hormones, they may affect the patients' outcomes. We aimed to assess the influence of the GST, CYP and TP53 gene polymorphisms in the risk of Graves' disease and its outcome. DESIGN: Prospective case-control study. PATIENTS: A PCR-based strategy was used for GSTT1, GSTM1, GSTP1, CYP1A1 and TP53 codon 72 genotypes in a group of 400 Graves' disease patients, and to compare them to 574 control individuals with similar environmental exposure features. RESULTS: GSTM1 and GSTT1 genotypes were equally distributed in cases and controls, respectively. However, GSTP1 (P < 0.0001), CYP1A1 (P < 0.0033) and Pro/ProTP53 (P < 0.0035) variants appeared more frequently in Graves' disease patients than in controls. A multivariate analysis indicated that cigarette smoking and inheritance of GSTP1, CYP1A1 and Pro/ProTP53 variants were important risk factors for Graves' disease, but only smoking appeared as an independent risk factor for Graves' ophthalmopathy. There was no association between clinical features, including ophthalmopathy or treatment outcome, and the studied genotypes. CONCLUSION: We concluded that GSTP1, CYP1A1 and TP53, but not GSTT1 and GSTM1 germline polymorphisms, may be associated with smoking-related Graves' disease susceptibility and configure a risk profile for the disease. However, these polymorphisms do not influence the patients' response to treatment.


Asunto(s)
Enfermedad de Graves/genética , Polimorfismo Genético , Fumar/genética , Adulto , Antitiroideos/uso terapéutico , Estudios de Casos y Controles , Citocromo P-450 CYP1A1/genética , Femenino , Genotipo , Glutatión Transferasa/genética , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/radioterapia , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteína p53 Supresora de Tumor/genética , Adulto Joven
9.
Thyroid ; 14(7): 525-30, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15307942

RESUMEN

In order to assess the effect of propylthiouracil (PTU) or methimazole (MMI) pretreatment on patient outcome after radioiodine therapy, we examined 100 patients with Graves' disease 3, 6, 9, and 12 months after administration of a 10-mCi standard single dose of 131I. They were assigned to one of three groups: no drug (ND) treatment (30 cases); MMI (45 cases); and PTU (25 cases). Antithyroid drugs (ATD) were withdrawn 15 days before radioiodine administration. The groups were similar concerning age, gender, ATD pretreatment duration, goiter size, and initial serum triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), antithyroid autoantibody levels, 24-hour radioiodine uptake and 131I dose administered per gram of thyroid tissue. ND and MMI groups presented a similar rate of cure of 73.3% and 77.8% respectively (p = NS). In contrast, the PTU group showed a rate of cure of only 32% (p < 0.05). Logistic regression analysis indicated that PTU administration (p = 0.003) and thyroid size (p = 0.02) were the variables related to radioiodine therapy failure. Our data demonstrate that the chance of 131I treatment failure is higher in individuals using PTU than in patients using MMI or not using any ATD before radioiodine (odds ratio [OR] 5.84; 95% confidence interval [CI] 1.82-18.76) suggesting that PTU should be avoided in the treatment of patients with Graves' disease.


Asunto(s)
Antitiroideos/administración & dosificación , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/radioterapia , Radioisótopos de Yodo/uso terapéutico , Propiltiouracilo/administración & dosificación , Adolescente , Adulto , Anciano , Terapia Combinada , Contraindicaciones , Relación Dosis-Respuesta en la Radiación , Femenino , Estudios de Seguimiento , Enfermedad de Graves/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pruebas de Función de la Tiroides
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