Novel Thyrotropin Receptor Germline Mutation (Ile568Val) in a Saxonian Family with Hereditary Nonautoimmune Hyperthyroidism

Objective: Hereditary nonautoimmune hyperthyroidism is caused by activating thyrotropin receptor (TSHR) germline mutations. We describe a family from Saxony, Germany, with this condition. Recurrent thyrotoxicosis and goiter were prevalent in three generations, affecting in addition to the 16-year-old index patient, her father and late paternal grandmother. Hyperthyroidism in the girl was remarkable for its poor response to methimazole(40–60 mg/d) treatment. Methods and results: Molecular analysis of genomic DNA extracted from peripheral blood leucocytes showed a TSHR germline mutation in the girl and her father. This mutation results in a new amino acid exchange of valine for isoleucine in TSHR codon 568 (Ile568Val). Only the wild-type TSHR sequence was found in the girl's mother. On functional characterization in COS-7 cells, the novel Ile568Val TSHR mutation conferred constitutive activation of the cAMP pathway (2- to 3-fold increase of basal cyclic adenosine monophosphate [cAMP]), but not of the inositol phosphate cascade. As a consequence of the molecular findings, total thyroidectomy has been performed in the girl. She is now euthyroid on levothyroxine replacement therapy. Conclusion: This is the second Saxonian family with autosomal-dominant nonautoimmune hyperthyroidism, adding to a total of 13 families and 11 individuals with activating TSHR germline mutations worldwide. We suggest that the condition may indeed be more frequent than previously 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.