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Homozygosity for a Dominant Negative Thyroid Hormone Receptor Gene Responsible for Generalized Resistance to Thyroid Hormone^*

Division of Pediatric Endocrinology, Department of Pediatrics, University of South Florida College of Medicine Tampa, Florida 33612 All Children's Hospital St. Petersburg, Florida 33731 the Department of Medicine, East Carolina University School of Medicine Greenville, North Carolina 27858

Address all correspondence and requests for reprints to: Barry B. Bercu, M.D., Department of Pediatrics, All Children's Hospital, 801 Sixth Street South, St. Petersburg, Florida 33731–8920.

Generalized resistance to thyroid hormones (GRTH) commonly results from mutations in the T₃-binding domain of the c-erbAβ thyroid hormone receptor gene. We have reported on a novel deletion mutation in c-erbAβ in a kindred, S, with GRTH. One patient from this kindred was the product of a consanguineous union from two affected members and was homozygous for the β-receptor defect. This patient at 3.5 weeks of age had unprecedented elevations of TSH, free T₄, and free T₃ (TSH, 389 mU/L; free T₄, 330.8 pmol/L; free T₃, 82,719 fmol/L). He displayed a complex mixture of tissue-specific hyperthyroidism and hypothyroidism. He had delayed growth (height age, 1 yr at chronological age 2 yr) and skeletal maturation (bone age, 4 months), and developmental delay (developmental age, 8 months), but he was quite tachycardia The homozygous patient of kindred S is markedly different from a recently reported patient with no c-erbA β-receptor. This difference indicates that a dominant negative form of c-erbAβ in man can inhibit at least some thyroid hormone action mediated by the c-erbA -receptors.

^* Presented in part to the Society for Pediatric Research, Anaheim, CA, 1987 and 1990.

Received January 14, 1991.

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