RESUMO
OBJECTIVE: Toxic thyroid adenoma (TA) is a common cause of hyperthyroidism. Mutations in the TSH receptor (TSHR) gene, and less frequently in the adenylate cyclase-stimulating G alpha protein (GNAS) gene, are well established causes of TA in Europe. However, genetic causes of TA remain unknown in a small percentage of cases. We report the first study to investigate mutations in TSHR, GNAS, protein kinase, cAMP-dependent, regulatory, type I alpha (PRKAR1A) and RAS genes, in a large series of TA from Galicia, an iodine-deficient region in NW Spain. DESIGN AND METHODS: Eighty-five TA samples were obtained surgically from 77 hyperthyroid patients, operated on for treatment of non-autoimmune toxic nodular goitre. After DNA extraction, all coding exons of TSHR, GNAS and PRKAR1A genes, and exons 2 and 3 of HRAS, KRAS and NRAS were amplified by PCR and sequenced. Previously unreported mutants were cloned in expression vectors and their basal constitutive activities were determined by quantification of cAMP response element (CRE)-luciferase activity in CO7 cells transfected with wild-type and mutant plasmids. RESULTS: TSHR gene mutations were found in 52 (61.2%) samples, GNAS gene mutations in 4 (4.71%) samples and no PRKAR1A or RAS mutations were found. Only three previously unreported mutations were found, two affecting the TSHR, A623F and I635V, and one affecting the G-protein alpha-subunit (Gsalpha), L203P. All mutant proteins showed higher CRE-luciferase activity than their wild-type counterparts. CONCLUSIONS: TA in a hyperthyroid population living in Galicia, a Spanish iodine-deficient region, harbours elevated frequencies of TSHR and GNAS mutations activating the cAMP pathway. However, the genetic cause of TA was undetermined in 34% of the TA samples.
Assuntos
Adenoma/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Genes ras/genética , Receptores da Tireotropina/genética , Neoplasias da Glândula Tireoide/genética , Adenoma/epidemiologia , Adulto , Idoso , Cromograninas , Doenças Endêmicas , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Hipertireoidismo/epidemiologia , Hipertireoidismo/genética , Iodo/deficiência , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Espanha , Neoplasias da Glândula Tireoide/epidemiologiaRESUMO
In up to a third of cases, central diabetes insipidus (DIC) is idiopathic although the percentage varies in different series. Since antibodies against magnicellular neurons were detected in some patients, a possible autoimmune basis for certain cases of apparently idiopathic DIC was speculated. Lymphocytic infundibuloneurohypophysitis, an inflammatory process that affects the infundibulum, pituitary stalk and neurohypophysis with distinctive radiologic, histologic and evolutive characteristics, has recently been described as a cause of central diabetes insipidus. We describe a patient in whom the clinical and radiologic characteristics suggest the diagnosis of DIC secondary to infundibuloneurohyphysitis.
