RESUMEN
OBJECTIVE: Thyroxine-binding globulin (TBG) is the major human thyroid hormone transport protein, encoded by the SERPINA7 gene (Xq22.2). We aim to investigate the molecular basis of partial TBG deficiency (TBG-PD) in a female, by evaluating the X-chromosome inactivation pattern as well as the mutant protein structural modeling. DESIGN AND METHODS: Sequencing of the coding region of the SERPINA7 gene was performed in a female with a TBG-PD phenotype and her first-degree relatives. The proband presented with low serum levels of total T3 (TT3) and total T4 (TT4), serum TSH level of 5.4⯵UI/mL (normal range, 0.35-5.5), and serum TBG level of 5.5â¯mg/L (normal range, 13.6-27.2). X-chromosome inactivation pattern was evaluated by methylation analysis of the androgen receptor gene (Xq11.2). Structural analysis of the SERPIN family was performed using Pymol and Areaimol, and PFSTATS for conservation analysis and family-wide investigation of equivalent positions in human homologs. Modeller was used for point mutation structural modeling. RESULTS: A novel missense SERPINA7 mutation (p.R35W; c.163Câ¯>â¯T) was found in heterozygosity in the proband, and in hemizygosity in her affected siblings. The proband X-chromosome inactivation ratio was 20:80. The substitution of an arginine by a tryptophan is predicted to disrupt the protein surface and main electrostatic interactions. Tryptophans are extremely rare (0.1%) in this position. CONCLUSIONS: We report a new SERPINA7 variant associated with TBG-PD in three siblings. We named this variant TBG-Brasilia. The X-chromosome inactivation pattern may have accounted for the rare phenotypic expression in a female. The hydrophobic nature of the mutant is predicted to create an apolar patch at the surface, which results in protein aggregation and/or misfolding, potentially responsible for thyroid hormone transport defect.
Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/genética , Globulina de Unión a Tiroxina/deficiencia , Adulto , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Modelos Moleculares , Mutación Missense , Linaje , Mutación Puntual , Conformación Proteica en Hélice alfa , Dominios Proteicos , Globulina de Unión a Tiroxina/química , Globulina de Unión a Tiroxina/genética , Inactivación del Cromosoma XRESUMEN
OBJECTIVE: To analyze the association between the indirect methods of evaluating insulin resistance (IR) and blood pressure, anthropometric and biochemical parameters in a population of polycystic ovary syndrome (PCOS) patients. METHODS: Cross-sectional study performed at the Hospital Universitário de Brasília (HUB, in the Portuguese acronym) involving PCOS patients diagnosed from January 2011 to January 2013. Four indirect methods, namely, fasting blood insulin level, fasting glucose/insulin ratio (G/I), homeostatic model-assessment-insulin resistance (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI), were used to obtain the IR diagnosis. The data were analyzed using the test of proportions, the Chi-square test, and Fisher exact test, when indicated. RESULTS: Out of the 83 patients assessed, aged 28.79 ± 5.85, IR was found in 51.81-66.2% of them using the G/I ratio and the QUICKI, respectively. The test of proportions did not show a significant difference between the methods analyzed. The proportion of IR diagnoses was statistically higher in obese women than in women with normal body mass index (BMI). We observed a statistically significant association between all the methods for diagnosing IR and BMI, waist circumference (WC) and lipid accumulation product (LAP). With regards to arterial hypertension (AH), we observed a significant association according to three methods, with the exception of the ratio G/I. CONCLUSION: Insulin resistance prevalence varied according to the diagnostic method employed, with no statistical difference between them. The proportion of IR diagnoses was statistically higher in obese women than in women with normal BMI. We observed a significant association between IR and WC, BMI, LAP, as well as dyslipidemia and AH in a high proportion of patients.
OBJETIVO: Analisar a associação entre os métodos indiretos de avaliação de resistência à insulina (RI) e parâmetros pressóricos, antropométricos e bioquímicos em uma população de pacientes com síndrome dos ovários policísticos (SOP). MéTODOS: Estudo transversal realizado no Hospital Universitário de Brasília (HUB), envolvendo pacientes que apresentaram o diagnóstico de SOP no período de janeiro de 2011 a janeiro de 2013. O diagnóstico de RI foi obtido por meio de quatro métodos indiretos: insulinemia de jejum, relação glicemia de jejum/insulinemia de jejum (G/I), avaliação da resistência à insulina através do modelo homeostático (HOMA-IR) e índice quantitativo de sensibilidade à insulina (QUICKI). Os dados foram analisados utilizando o teste de proporções, o teste do Qui-quadrado e o teste exato de Fisher, quando indicado. RESULTADOS: Foram avaliadas 83 pacientes com idade média de 28,79 ± 5,85 anos. A RI foi diagnosticada em 51,8166,27% dos casos pela relação G/I e QUICKI, respectivamente, e o teste de proporções não evidenciou diferença significativa entre os métodos analisados. A proporção de diagnósticos de RI foi estatisticamente maior em mulheres obesas em comparação à proporção de mulheres com índice de massa corporal (IMC) normal. Foi observada uma associação estatisticamente significativa entre todos os métodos diagnósticos de RI e IMC, circunferência da cintura (CC) e produto de acumulação lipídica (LAP). Quanto à hipertensão arterial (HA), foi observada associação significativa de acordo com três métodos, com exceção da relação G/I. CONCLUSãO: A prevalência de RI variou conforme o método diagnóstico utilizado, mas não houve diferença estatística entre eles. A proporção de diagnósticos de IR foi maior nas mulheres obesas do que naquelas com peso normal. Foi observada associação significativa entre RI e CC, IMC e LAP, assim como com dislipidemia e HA em uma proporção elevada de pacientes.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Resistencia a la Insulina , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/metabolismo , Adulto , Presión Sanguínea , Enfermedades Cardiovasculares/epidemiología , Estudios Transversales , Femenino , Humanos , Síndrome del Ovario Poliquístico/fisiopatología , Factores de RiesgoRESUMEN
Pheochromocytoma (PCC) is a tumor derived from adrenomedullary chromaffin cells. Prognosis of malignant PCC is generally poor due to local recurrence or metastasis. We aim to report a case of malignant PCC with 18-year survival and discuss which factors may be related to mortality and long-term survival in malignant pheochromocytoma. The patient, a 45-year-old man, reported sustained arterial hypertension with paroxysmal episodes of tachycardia, associated with head and neck burning sensation, and hand and foot tremors. Diagnosis of PCC was established biochemically and a tumor with infiltration of renal parenchyma was resected. No genetic mutation or copy number variations were identified in SDHB, SDHD, SDHC, MAX and VHL. Over 18 years, tumor progression was managed with 131I-MIBG (iodine-metaiodobenzylguanidine) and 177Lutetium-octreotate therapy. Currently, the patient is asymptomatic and presents sustained stable disease, despite the presence of lung, para-aortic lymph nodes and femoral metastases. Adequate response to treatment with control of tumor progression, absence of significant cardiovascular events and other neoplasms, and lack of mutations in the main predisposing genes reported so far may be factors possibly associated with the prolonged survival in this case. Early diagnosis and life-long follow-up in patients with malignant pheochromocytoma are known to be crucial in improving survival.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/mortalidad , Feocromocitoma/mortalidad , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/genética , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mutación , Feocromocitoma/diagnóstico por imagen , Feocromocitoma/genética , Pronóstico , Supervivencia , Factores de Tiempo , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
SUMMARY Pheochromocytoma (PCC) is a tumor derived from adrenomedullary chromaffin cells. Prognosis of malignant PCC is generally poor due to local recurrence or metastasis. We aim to report a case of malignant PCC with 18-year survival and discuss which factors may be related to mortality and long-term survival in malignant pheochromocytoma. The patient, a 45-year-old man, reported sustained arterial hypertension with paroxysmal episodes of tachycardia, associated with head and neck burning sensation, and hand and foot tremors. Diagnosis of PCC was established biochemically and a tumor with infiltration of renal parenchyma was resected. No genetic mutation or copy number variations were identified in SDHB, SDHD, SDHC, MAX and VHL. Over 18 years, tumor progression was managed with 131I-MIBG (iodine-metaiodobenzylguanidine) and 177Lutetium-octreotate therapy. Currently, the patient is asymptomatic and presents sustained stable disease, despite the presence of lung, para-aortic lymph nodes and femoral metastases. Adequate response to treatment with control of tumor progression, absence of significant cardiovascular events and other neoplasms, and lack of mutations in the main predisposing genes reported so far may be factors possibly associated with the prolonged survival in this case. Early diagnosis and life-long follow-up in patients with malignant pheochromocytoma are known to be crucial in improving survival.