MULTIPLE GENETIC-FACTORS IN THE HETEROGENEITY OF THYROID-HORMONE RESISTANCE

Generalized resistance to thyroid hormone (GRTH), a syndrome of inheri ted tissue hyposensitivity to thyroid hormone, is linked to thyroid ho rmone receptor (TR) mutations. A typical feature of GRTH is variable s everity of organ involvement among families that, surprisingly, does n ot correlate with the degree of T3-binding impairment of the correspon ding in vitro synthesized mutant TRs. Furthermore, variations in the c linical severity among family members harboring identical TRbeta mutat ions have been reported. We compared serum levels of thyroid hormones that maintained a normal TSH in members of a large family with GRTH di vided in three groups: Group A, 8 affected subjects with a mutation re placing arginine-320 with a histidine in the T3-binding domain of TRbe ta; Group B, 11 first degree relatives (sibs an children of affected s ubjects) with no TRbeta mutation; Group C, 16 controls related by marr iage. TSH values were not different among the three groups. As expecte d, total and free T4 and T3, and rT3 levels were significantly higher in Group A vs Groups B and C. However, with the exception of T3, the s ame tests were also significantly higher in Group B vs Group C. The la tter differences are not due to thyroid hormone transport in serum sin ce TBG concentrations were not different. It is postulated that gene c variability of factors that contribute to the action of thyroid hormo ne modulate the phenotype of GRTH associated with TRbeta mutations.