Diverse Abnormalities of the c-erbAβ Thyroid Hormone Receptor Gene in Generalized Thyroid Hormone Resistance
The syndrome of generalized thyroid hormone resistance (GTHR) was first described in 1967 in a kindred, G, with elevated free thyroid hormones and absence of the typical clinical features of hyperthyroidism (1). The proband, a 6-year-old girl, demonstrated stippled epiphyses, dysmorphic features (bird-like facies, pigeon breast, and winged scapulae) and deaf-mutism. The syndrome was transmitted as a recessive trait and affected members were the product of a consanguineous union. As children, affected members had intelligence quotients within the ranges normally seen in hearingimpaired individuals (1,2). Although minimal delay of bone age was observed in affected members, final adult height was above the parental mean. Interestingly, affected members showed a paradoxical increase of serum TSH in response to the administration of suppressive doses of T3 (3) and no significant effect of antithyroid drugs on the level of TSH (2). This constellation of clinical findings in the original kindred--stippled epiphyses, somatic abnormalities, and deafmutism--has never been reported in other kindreds with GTHR. However, less severe hearing defects, learning disabilities and growth retardation are not uncommon.
KeywordsThyroid Hormone Thyroid Hormone Receptor Thyroid Hormone Level Affected Member Thyroid Hormone Action
Unable to display preview. Download preview PDF.
- 1.S. Refetoff, L.T. DeWind, L.J. DeGroot. Familial syndrome combining deaf mutism, stippled epiphyses, goiter, and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J. Clin. Endocrinol. Metab 27 :279–294 (1967).Google Scholar
- 5.J.A. Magner, P. Petrick, M. Menezes-Ferreira, B.D. Weintraub. Familial generalized resistance to thyroid hormones: report of three kindreds and correlation of patterns of affected tissues with the binding of [125I] triiodothyronine to fibroblast nuclei. J. Endocrinol Invest 9: 459–69 (1986).PubMedGoogle Scholar
- 8.S.J. Usala, J.B. Menke, T.L. Watson, J. Berard, W.E.L. Bradley, A.E. Bale, R.W. Lash, B.D. Weintraub. A new point mutation in the T3-binding domain of the c-erbAß thyroid hormone resistance is tightly linked to generalized thyroid hormone resistance. J. Clin. Endocrinol. Metab.,(1991) (in press).Google Scholar
- 11.J. Sap, A. Munoz, K. Damm, Y. Goldberg, J. Ghysdael, A. Leutz, J. Beng, B. Vennstrom. The c-erbAß protein is a high-affinity receptor for thyroid hormone. Nature (Lond.) 324: 635–40 (1986).Google Scholar
- 12.C. Weinberger, C.C. Thompson, E.S. Ong, R. Lebo, D.J. Gruol, R.M. Evans. The c-erbA gene encodes a thyroid hormone receptor. Nature (Lond.) 324: 641–46 (1986).Google Scholar
- 14.H.G. Fein, K.D. Burman, Y.Y. Djuh, S.J. Usala, R.C.Google Scholar
- Smallridge. Linkage between the syndrome of generalized thyroid hormone resistance (GTHR) and the human c-erbAß gene is present in multiple kindreds. Endocrinology Suppl. 122:T-1 (abstract) (1989).Google Scholar
- 15.A. Sakurai, K. Takeda, K. Ain, P. Ceccarelli, A. Nakai, S. Seino, G.I. Bell, S. Refetoff, L.J. DeGroot. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor D. Proc. Natl. Acad. Sci. USA. 86: 8977–8981 (1989).PubMedCrossRefGoogle Scholar
- 17.S.J. Usala, F.E. Wondisford, T.L. Watson, J.B. Menke, B.D. Weintraub. Thyroid hormone and DNA binding properties of a mutant c-erbAß receptor associated with generalized thyroid hormone resistance. Biochem. Biophy. Res. Commun. 171: 575580 (1990).Google Scholar
- 18.S.J. Usala, J.B. Menke, T.L. Watson, F.E. Wondisford, B.D. Weintraub, J. Berard, W.E.C. Bradley, S. Ono, O.T. Mueller, B.B. Bercu. A homozygous deletion in the c-erbA13 thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor. Mol. Endocrinol. (1991) (in press).Google Scholar
- 19.K. Takeda, S. Balzano, A. Sakurai, L.J. DeGroot, S. Refetoff. Screening of 19 unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor 13 gene and the detection of a new mutation. J. Clin. Invest. (1991) (in press).Google Scholar
- 20.S. Ono, I.D. Schwartz, A.W. Root, B. Bercu. Evolution of hypothalamic-pituitary-thyroid function in a suspected homozygotic child from a kindred with generalized resistance to thyroid hormone. Clin. Res. (Abstract) 38: 48A (1990).Google Scholar