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 to 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 phenotype. DNA was amplified and the TRP gene was sequenced. Linkage analysis assessed linkage between the TRP gene and RTH phenotype. Results: Direct sequencing of the TRP gene failed to identify any anomaly in the coding exons. Linkage analysis demonstrated that the RTH phenotype was not linked to the TRP gene in this family. Conclusion : TR beta 1 and TR beta 2 genes were not defective in this family. Multiple mechanisms might account for this situation at the pre-receptor, receptor and post-receptor levels. The most likely hypothesis is the involvement of an abnormal nuclear cofactor serving a specific function in the regulation of thyroid hormone action.