Mutations of the thyrotropin receptor (TSHr) can be loss of function o
r gain of function. Loss-of-function mutations can affect a variety of
loci in the TSHr gene. Their most common manifestation is resistance
to TSH; they may also be the cause of a subset of cases of congenital
hypothyroidism. Gain-of-function mutations are of greater theoretical
interest. Somatic mutations constitutively activating the TSHr are the
major cause of benign toxic thyroid adenomas, and of some cases of mu
ltinodular goiters. They underlie hereditary toxic thyroid hyperplasia
, and have been found in cases of sporadic congenital non-autoimmune h
yperthyroidism. A role for TSHr polymorphisms in Graves' disease has n
ot been documented.