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Extreme Thyroid Hormone Resistance in a Patient with a Novel Truncated TR Mutant

Diabetes and Molecular Regulation and Neuroendocrinology Sections, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; University of Maryland School of Medicine (J.L.), Baltimore, Maryland 21201; Portland Veterans Affairs Medical Center, Department of Psychiatry, Oregon Health Sciences University (P.H.), Portland, Oregon 97201; and Department of Medicine, Centre Hospitalier, Universite de Nice (F.B.-D.), Nice, France

Address all correspondence and requests for reprints to: Paul M. Yen, M.D., Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, National Institutes of Health, Building 10, Room 8D12, Bethesda, Maryland 20892. E-mail: pauly{at}intra.niddk.nih.gov

Abstract

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 TRß 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 TRß mutant contributed to the extreme RTH phenotype and resistance in our patient.

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