Clinical case seminar: Extreme thyroid hormone resistance in a patient with a novel truncated TR mutant

Resistance to thyroid hormone (RTH) is a syndrome in which patients have elevated thyroid hormone (TH) levels and decreased sensitivity to its action. We describe a child with extreme RTH and a severe phenotype. A 22-month-old female presented to the NIH with goiter, growth retardation, short stature, and deafness. Additionally, the patient had hypotonia, mental retardation, visual impairment, and a history of seizures. Brain magnetic resonance imaging showed evidence of demyelination and bilateral ventricular enlargement. The patient had markedly elevated free T₃ and free T₄ levels of more than 2000 pg/dl (normal, 230-420 pg/dl) and more than 64 pmol/liter (normal, 10.3-20.6 pmol/liter), respectively, and TSH of 6.88 mU/liter (normal, 0.6-6.3 mU/liter). These are the highest TH levels reported for a heterozygous RTH patient. A T₃ stimulation test confirmed the diagnosis of RTH in the pituitary and peripheral tissues. Molecular analyses of the patient's genomic DNA by PCR identified a single base deletion in exon 10 of her TRβ gene that resulted in a frameshift and early stop codon. This, in turn, encoded a truncated receptor that lacked the last 20 amino acids. Cotransfection studies showed that the mutant TR was transcriptionally inactive even in the presence of 10^-6 M T₃ and had strong dominant negative activity over the wild-type receptor. It is likely that the severely defective TRβ mutant contributed to the extreme RTH phenotype and resistance in our patient.