Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone.
Generalized resistance to thyroid hormones (GRTH) commonly results from mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene. We have reported on a novel deletion mutation in c-erbA beta 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 beta-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 3/12 yr at chronological age 2 9/12 yr) and skeletal maturation (bone age, 4 months), and developmental delay (developmental age, 8 months), but he was quite tachycardic. The homozygous patient of kindred S is markedly different from a recently reported patient with no c-erbA beta-receptor. This difference indicates that a dominant negative form of c-erbA beta in man can inhibit at least some thyroid hormone action mediated by the c-erbA alpha-receptors.
Department of Pediatrics, University of South Florida College of Medicine, Tampa 33612.
S
S
Ono
I D
ID
Schwartz
O T
OT
Mueller
A W
AW
Root
S J
SJ
Usala
B B
BB
Bercu
D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002675:Child, Preschool; D002872:Chromosome Deletion; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004262:DNA Restriction Enzymes; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011519:Proto-Oncogenes; D011877:Radionuclide Imaging; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D012867:Skin / Q000378:metabolism; D013959:Thyroid Diseases / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics*; D013961:Thyroid Gland / Q000000981:diagnostic imaging; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D011518:Proto-Oncogene Proteins; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D004247:DNA; D004262:DNA Restriction Enzymes; D013974:Thyroxine