Abstract
Congenital hyperthyroidism is a rare, transient disease usually caused
by transmission of thyrotropin receptor autoantibodies from the mother
with Graves' disease to her child. We report a German women and her
two sons who had congenital, but persistent hyperthyroidism without
any signs of autoimmunity. Direct sequencing of the polymerase chain
reaction-amplified exon 10 of the thyrotropin receptor genomic DNA
revealed in the mother and both sons a transition of GCC to GTC,
resulting in an exchange of alanine 623 to valine. This germline
mutation in a highly conserved region of the thyrotropin receptor
resulted in a constitutive activation of the cyclic adenosine monophosphate-generating
cascade with resulting hyperthyroidism. Analysis of the family for
a corresponding BstXI restriction-site polymorphism revealed heterozygosity
for this mutation in the affected family members, but not in the
father or other relatives. We conclude that whenever congenital hyperthyroidism
is persistent and parameters of autoimmunity are absent, a constitutively
active thyrotropin receptor mutation should be considered. Treatment
appears to require aggressive means such as total thyroidectomy or
ablation by 131iodine because two subtotal thyroidectomies in the
mother were insufficient to control the disease.
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