REVISTA ARGENTINA DE ENDOCRINOLOGÍA Y METABOLISMO
Rivolta, C. M.1; Feijoo, M. C.2; Targovnik, H. M.1*; Funes, A.2
El síndrome de resistencia a hormonas tiroideas (RTH) se caracteriza por una disminución de la respuesta a las hormonas tiroideas por parte de los tejidos y se debe a mutaciones en la isoforma b del receptor de hormonas tiroideas (THRb). Las moléculas THRb defectivas interfieren con la función de los receptores normales produciendo este síndrome con modo de herencia autosómico dominante. El paciente evaluado, una mujer de 16 años, acudió a la consulta por bajo peso, nerviosismo, palpitaciones, hipersudoración y bocio difuso. Las pruebas bioquímicas revelaron elevada T4 libre de 3,61 ng/dl (valores normales: 0,7-2,3), T3 total de 352 ng/dl (valores normales: 80-200) y TSH no suprimida de 0,99 mU/L (valores normales: 0,32-5,0). Su padre y sus dos hermanas también tenían hallazgos bioquímicos compatibles con RTH. El diagnóstico de RTH fue confirmado por la secuenciación del gen THRb. En el exón 10 se identificó una transversión heterocigota (1357C>A) resultando en la sustitución de prolina por treonina (P453T). Esta alteración estaba presente en la paciente, en su padre y dos hermanas. La técnica de «Single Strand Conformation Polymorphism» (SSCP) fue empleada para validar dicha mutación. La sustitución P453T caracterizada aquí constituye el segundo caso de mutación en el gen de THRb, identificada en población argentina. R
The syndrome of resistance to thyroid hormone (RTH) is characterized by an variable tissue hyposensitivity to thyroid hormone 1 – 1 4. Different mutations located in the ligand-binding (LBD) or hinge domains of the thyroid hormone receptor b (THRb) gene have been identified in the RTH phenotype 1 5 – 3 1. Consistent with the dominant mode of transmission, mutant THRbs interfere with the function of the wild type receptor by a dominant negative mechanism 32-35. The affected individuals display unsupressed TSH levels despite elevated serum free T4 and T3, reflecting resistance to the normal negative feedback mechanisms within the hypothalamus and pituitary 5. RTH patients are clinically euthyroid or even hypothyroid depending on the severity of the mutation 5-8. We describe the clinical and molecular analysis of a family with RTH. The propositus, a 16-years-old woman, came to medical attention because of weight loss, nervousness, palpitations and excessive sweating. Those symptoms were associated with a difuse goiter. Biochemical tests revealed an elevated free T4 of 3.61 ng/dl (normal range, 0.7-2.3), a total T3 of 352 ng/dl (normal range, 80-200), and a non-supressed TSH of 0.99 mU/L ( n o rmal range, 0.32-5). Administration of exogeneous T4 or T3 did not result in the usual TSH suppression , leading to the clinical diagnosis of RTH. Her father and two sisters also had biochemical findings compatible with RTH (Table 1). The diagnosis of RTH was confirmed by sequencing the THRb gene. An heterozigous transversion 1357C>A was identified in exon 10 resulting in substitution of proline 453 by treonine (P453T). This change was present in the propositus, her father and sisters (Figure 1). Single Strand Conformation Polymorphism (SSCP) was used to validate the mutation found. So, the product of PCR corresponding to exon 10 of the propositus was electrophoresed in a 10% polyacrylamide gel next to the fragments obtained from 8 normal and no related controls. The silver staining revealed the presence of two fragments in the patient corresponding one of them to the allele carrying the mutation and the other to the normal allele (Figure 2). No mutations were dentified in exon 9 of the THRb gene. The substitution P453T in the first domain of the LDB of the THRb gene characterized in this work is the second mutation identified in argentine population. The molecular diagnosis of RTH is important to determinate the appropriate treatment in those symptomatic patients to ameliorate features of hyper or hypothyroidism.