Generalized resistance to thyroid hormone (GRTH), a syndrome of inherited tissue 
hyposensitivity to thyroid hormone, is linked to thyroid hormone receptor (TR) 
mutations. A typical feature of GRTH is variable severity of organ involvement 
among families that, surprisingly, does not correlate with the degree of 
T3-binding impairment of the corresponding in vitro synthesized mutant TRs. 
Furthermore, variations in the clinical severity among family members harboring 
identical TR beta mutations have been reported. We compared serum levels of 
thyroid hormones that maintained a normal TSH in members of a large family with 
GRTH divided in three groups: Group A, 8 affected subjects with a mutation 
replacing arginine-320 with a histidine in the T3-binding domain of TR beta; 
Group B, 11 first degree relatives (sibs and children of affected subjects) with 
no TR beta mutation; Group C, 16 controls related by marriage. TSH values were 
not different among the three groups. As expected, 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 same tests were also significantly higher in Group B vs 
Group C. The latter differences are not due to thyroid hormone transport in 
serum since TBG concentrations were not different. It is postulated that genetic 
variability of factors that contribute to the action of thyroid hormone modulate 
the phenotype of GRTH associated with TR beta mutations.