Point mutation (C446S) in the thyroid hormone receptor beta gene in a black South African kindred with thyroid hormone resistance syndrome

Objective. We describe a black South African kindred with thyroid hormone r esistance (RTH). Subjects. The two sibling propositi initially presented with hyperthyroidis m and were treated ablatively. Subsequent deterioration in their condition led to attendance at a specialist clinic. Method. Identification of a heterozygote mutation by nucleic acid sequencin g. Results. Both individuals were found to have a heterozygote missense mutati on (C446S) in exon 10 of the thyroid hormone receptor beta (TH beta) gene. This mutation, in which the normal Cys(446) is replaced with a serine, has not been reported previously. Three of the 13 remaining available family me mbers harboured the identical mutation. All 3 were clinically euthyroid but biochemically had elevated free thyroxine ( fT(4)) and free tri-iodothyron ine (fT(3)) levels in the presence of normal TSH, a finding compatible with RTH. Conclusion. This study demonstrates the importance of timely genetic diagno sis in the identification of RTH.