Resistance to thyroid hormone in a family with no TR beta gene anomaly: pathogenic hypotheses

Syndromes of resistance to thyroid hormone (RTH) are almost always linked t o a defective triiodothyronine-receptor beta gene (TRP). Only six families with RTH exhibiting a normal TRP gene have been reported so far. We report another and discuss possible mechanisms. Patients and methods:. We studied a kindred expressing a typical RTH phenot ype. DNA was amplified and the TRP gene was sequenced. Linkage analysis ass essed linkage between the TRP gene and RTH phenotype. Results: Direct sequencing of the TRP gene failed to identify any anomaly i n the coding exons. Linkage analysis demonstrated that the RTH phenotype wa s not linked to the TRP gene in this family. Conclusion : TR beta 1 and TR beta 2 genes were not defective in this famil y. Multiple mechanisms might account for this situation at the pre-receptor , receptor and post-receptor levels. The most likely hypothesis is the invo lvement of an abnormal nuclear cofactor serving a specific function in the regulation of thyroid hormone action.