Context Sequential conversion of Hashimoto's thyroiditis (HT) to Graves' disease (GD) is uncommon. Distinct immune paradigms, paucity of functioning tissue in long-standing HT, and infrequent conversion of blocking (TBAb) to stimulating (TSAb) thyrotrophin receptor antibody (TRAb) may account for this. Molecular and crystal structure analysis helps delineate TSH receptor (TSHR)/TRAb interactions in detail. Such fingerprinting helps determine the behaviour and characteristics of TRAb in longitudinal studies. Patient An 80-year-old woman taking thyroxine for long-standing HT became hyperthyroid. This persisted despite thyroxine withdrawal free T3 was 7.3 similar to pmol/l (2.65.7) and TSH<0.01mU/l (0.24.5) and TRAb highly positive. She had a goitre (ultrasound HT), pretibial myxoedema, with mild inactive Graves' orbitopathy. She had RAI treatment and is on thyroxine replacement. Measurements and Results Blood samples at presentation (A) and 1 similar to year (B) showed high TSAb and TPOAb activity but no TBAb. Experiments involving TSHR mutations confirmed that (i) TRAb had stable characteristics over 1 similar to year; (ii) TSHR mutation R255D caused complete inhibition and (iii) R109A caused marked reduction of cAMP production by M22 (TSHR-stimulating human monoclonal antibody) and A and B; (iv) mutations R80A, E107A and K129A while affecting M22 had little effect on A and B. Conclusions The reasons for an immunological paradigm shift in this elderly woman remain speculative. We believe that de-novo TSAb synthesis occurred converting her long-standing HT to GD although the mechanisms responsible remain unexplained. TRAb analysis confirmed stable autoantibody characteristics over 1year and variable effects of TSHR mutations on TRAb and M22 function.