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.