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Genetic and Clinical Features of 42 Kindreds with Resistance to Thyroid Hormone: The National Institutes of Health Prospective Study

Francoise Brucker-Davis, MD; Monica C. Skarulis, MD; Marcy B. Grace, BA; Jacques Benichou, MD, PhD; Peter Hauser, MD; Edythe Wiggs, PhD; and Bruce D. Weintraub, MD
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From the National Institutes of Health, National Institute of Diabetes, Digestive, and Kidney Disease, and National Cancer Institute, Bethesda, Maryland. Acknowledgments: The authors thank the study participants, their families, and their referring physicians and the nurses and fellows of the Clinical Center of the National Institutes of Health. They also thank Mitchell Gail MD, PhD, for expert statistical advice; David Pee, MPhil, for expert statistical computing; Suvimol Hill, MD, for bone age determination; Anita Pickus, MA, for audiologic assessment; Julio Panza, MD, for echocardiographic analysis; Pedro Martinez, MD, for attention-deficit hyperactivity disorder testing; and Jacob Robbins, MD, Rosemary Wong, MD, Richard Eastman, MD, and Miriam Levav, PhD, for critical review of the manuscript. Requests for Reprints: Bruce D. Weintraub, MD, National Institutes of Health, MCEB, 10 Center Drive, MSC 1758, Building 10, Room 8D14, Bethesda, MD 20892-1758. Current Author Addresses: Drs. Brucker-Davis, Skarulis, Wiggs, and Weintraub and Ms. Grace: Molecular and Cellular Endocrine Branch, NIDDK, National Institutes of Health, 10 Center Drive, MSC 1758, Bethesda, MD 20892-1758.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1995;123(8):572-583. doi:10.7326/0003-4819-123-8-199510150-00002
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Objective: To determine the genetic and clinical features of resistance to thyroid hormone in a study from a single institution.

Design: Prospective, controlled study.

Setting: National Institutes of Health.

Patients: 104 patients with resistance to thyroid hormone from 42 kindreds and 114 unaffected relatives sharing the patients' environmental and genetic back-grounds.

Measurements: Thyroid, cardiovascular, psychometric, hearing, speech, and growth testing; thyroid tests done at baseline and after TSH-releasing hormone stimulation; and DNA analysis for detection of mutations in the thyroid hormone receptor β (TR β) 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 mutations in 25 kindreds (64 patients); 16 mutations were in exon 9 and 9 were in exon 10 of the TR β gene. In persons with resistance to thyroid hormone, we measured the increased incidence of goiter (65%), attention-deficit hyperactivity disorder (60%), IQ less than 85 (38%), speech impediment (35%), and short stature (18%). We also described new clinical features, such as frequent ear, nose, and throat infections (56%); low weight-for-height in children (32%); hearing loss (21%); and cardiac abnormalities (18%). Genotype, age, whether the mother had resistance to thyroid hormone, and sex influenced the phenotype. Tissue resistance varied from kindred to kindred and involved, in decreasing order, the pituitary gland, the brain, the bone, the liver, and the heart.

Conclusions: This study underscores the incidence of classic features of resistance to thyroid hormone, describes new clinical characteristics of this condition for the first time, and stresses the heterogeneity of the phenotype.

Ann Inten Med. 1995; 123:572-583.


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Figure 1.
Degree of resistance to thyroid hormone in various organs in patients with resistance to thyroid hormone.

The variables studied were basal and TSH-releasing hormone-stimulated TSH levels for the pituitary gland; full-scale IQ for the brain; percentile of the height and bone age for the bone; cholesterol, testosterone binding globulin, and ferritin levels for the liver; resting pulse for the heart; and basal metabolic rate for the metabolism. For the pituitary gland, the liver, the heart, and the metabolism, the results were from patients with no history of thyroidectomy who were not receiving thyroid medication. Patients receiving cardiac medication were excluded for the evaluation of the heart. TSH equals thyroid-stimulating hormone.

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