CONSTITUTIVELY ACTIVE GERMLINE MUTATION OF THE THYROTROPIN RECEPTOR GENE AS A CAUSE OF CONGENITAL HYPERTHYROIDISM

Congenital hyperthyroidism is a rare, transient disease usually caused by transmission of thyrotropin receptor autoantibodies from the mothe r with Graves' disease to her child. We report a German women and her two sons who had congenital, but persistent hyperthyroidism without an y signs of autoimmunity. Direct sequencing of the polymerase chain rea ction-amplified exon 10 of the thyrotropin receptor genomic DNA reveal ed in the mother and both sons a transition of GCC to GTC, resulting i n an exchange of alanine 623 to valine. This germline mutation in a hi ghly conserved region of the thyrotropin receptor resulted in a consti tutive activation of the cyclic adenosine monophosphate-generating cas cade with resulting hyperthyroidism. Analysis of the family for a corr esponding BstXI restriction-site polymorphism revealed heterozygosity for this mutation in the affected family members, but not in the fathe r or other relatives. We conclude that whenever congenital hyperthyroi dism is persistent and parameters of autoimmunity are absent, a consti tutively active thyrotropin receptor mutation should be considered. Tr eatment appears to require aggressive means such as total thyroidectom y or ablation by (131)iodine because two subtotal thyroidectomies in t he mother were insufficient to control the disease.