Familial non-autoimmune hyperthyroidism due to a novel TSHR germline mutation (Ile568Val)

A 16 yr. old girl presented with a 4 month history of overt hyperthyroidism and goitre. She had a strong family history of recurrent hyperthyroidism affecting both her father and her paternal grandmother. The grandmother had undergone partial thyroidectomy at age 25 for toxic multinodular goitre and had suffered 3 relapses of hyperthyroidism, which were poorly controlled by further sugery and antithyroid medication. The father underwent thyroid surgery at 34 yr. and had a first relapse of hyperthyroidism at 38 yr., for which he received RIT. At 43 yr. he has subclinical hyperthyroidism. Hyperthyroidism in the girl was remarkable for its poor response to methimazole (40–60mg/d). Thyroid ultrasound showed a diffusely enlarged gland with normal echogeneity. TSAB and TPO-Ab were negative. Molecular analysis of genomic DNA extracted from peripheral blood leucocytes showed a TSHR germline mutation in codon 568 with a novel amino acid exchange of valine for isoleucine in the girl and her father. Only the wild-type TSHR sequence was found in the mother. Constitutively activating properties have previously been described for the Ile568Thr mutation, located in the 2nd extracellular TSHR loop. As a consequence of the molecular findings, the girl will undergo total thyroidectomy in October 2004.

This is the second Saxonian family with autosomal-dominant non-autoimmune hyperthyroidism, adding to a total of 13 families and 11 individuals with activating TSHR germline mutations world-wide. Functional characterization of the novel Ile568Val TSHR germline mutation is in progress. We suggest that the condition may indeed be more frequent than hitherto thought and that consequent assessment of a family history in children as well as adults with thyroid autonomy will contribute to ensure correct diagnosis and adequate treatment of patients with activating TSHR germline mutations.