GENETIC AND CLINICAL-FEATURES OF 42 KINDREDS WITH RESISTANCE TO THYROID-HORMONE - THE NATIONAL-INSTITUTES-OF-HEALTH PROSPECTIVE-STUDY

Objective: To determine the genetic and clinical features of resistanc e to thyroid hormone in a study from a single institution. Design: Pro spective, controlled study. Setting: National Institutes of Health. Pa tients: 104 patients with resistance to thyroid hormone from 42 kindre ds and 114 unaffected relatives sharing the patients' environmental an d genetic backgrounds. Measurements: Thyroid, cardiovascular, psychome tric, hearing, speech, and growth testing; thyroid tests done at basel ine and after TSH-releasing hormone stimulation; and DNA analysis for detection of mutations in the thyroid hormone receptor beta (TR beta) gene (exons 9 and 10). Assessment of tissue-specific compensation for resistance. Results: Inheritance was autosomal dominant in 22 families , sporadic in 14 families, and unknown in 6 families. We found mutatio ns in 25 kindreds (64 patients); 16 mutations were in exon 9 and 9 wer e in exon 10 of the TR beta gene. In persons with resistance to thyroi d hormone, we measured the increased incidence of goiter (65%), attent ion-deficit hyperactivity disorder (60%), IQ less than 85 (38%), speec h impediment (35%), and short stature (18%). We also described new cli nical features, such as frequent ear, nose, and throat infections (56% ); low weight-for-height in children (32%); hearing loss (21%); and ca rdiac abnormalities (18%). Genotype, age, whether the mother had resis tance to thyroid hormone, and sex influenced the phenotype. Tissue res istance varied from kindred to kindred and involved, in decreasing ord er, the pituitary gland, the brain, the bone, the liver, and the heart . Conclusions: This study underscores the incidence of classic feature s of resistance to thyroid hormone, describes new clinical characteris tics of this condition for the first time, and stresses the heterogene ity of the phenotype.