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 el evated thyroid hormone (TH) levels and decreased sensitivity to its action. We describe a child with extreme RTH and a severe phenotype. A 22-month-ol d female presented to the NIH with goiter, growth retardation, short statur e, and deafness. Additionally, the patient had hypotonia, mental retardatio n, visual impairment, and a history of seizures. Brain magnetic resonance i maging showed evidence of demyelination and bilateral ventricular enlargeme nt. The patient had markedly elevated free T-3 and free T-4 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 heterozygou s RTH patient. A T-3 stimulation test confirmed the diagnosis of RTH in the pituitary and peripheral tissues. Molecular analyses of the patient's geno mic DNA by PCR identified a single base deletion in exon 10 of her TR beta gene that resulted in a frameshift and early stop codon. This, in turn, enc oded a truncated receptor that lacked the last 20 amino acids. Cotransfecti on studies showed that the mutant TR was transcriptionally inactive even in the presence of 10(-6) M T-3 and had strong dominant negative activity ove r the wild-type receptor. It is likely that the severely defective TR beta mutant contributed to the extreme RTH phenotype and resistance in our patie nt.