Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: Evidence for a new inactivating mutation of the TSH receptor gene

Congenital hypothyroidism due to impaired thyroid response to TSH was origi nally described by Stanbury. A diagnosis of congenital hypothyroidism with thyroid unresponsiveness to TSH is accepted if the patient has congenital h ypothyroidism, the thyroid gland is in the normal position in the neck, the size of the thyroid is either normal or atrophic, the serum TSH level is i ncreased, the bioactivity of TSH is intact, and the response of the thyroid gland to TSH stimulation is decreased. In all originally described cases s erum thyroglobulin was undetectable. We describe a 22-yr-old female patient who was severely hypothyroid and mentally retarded. Serum T-4 and T-3 conc entrations were below the sensitivity of the methods, with elevated serum T SH levels. Serum thyroglobulin was undetectable. A normally shaped hypoplas tic gland located in the appropriate anatomical position in the neck was fo und at scintiscan. The gland did not respond after administration of bovine TSH in terms of I-131 uptake, serum thyroid hormones, and thyroglobulin se cretion. A diagnosis of congenital hypothyroidism due to TSH unresponsivene ss was formulated. Genetic analysis in the propositus showed a homozygous inactivating mutatio n of the TSH receptor that had not been previously described. The mutation consisted of the substitution of an isoleucine in place of a highly conserv ed threonine at position 477 in the first extracellular loop of the recepto r (T477I). The brother, one sister of the father (whose DNA was not availab le), the mother of the propositus, one sister, and the brother were heteroz ygous for T477I. All the heterozygous persons were unaffected. After transfection in COS-7 cells, the mutant receptor displayed an extreme ly low expression at cell surface. At variance with cells transfected with the wild-type TSH receptor, cells transfected with the mutant T477I did not show constitutive activity for the adenylyl cyclase pathway. A dramatic re duction in the amount of cAMP accumulation after bovine TSH challenge was o bserved in cells transfected with the mutant T477I receptor. A structural d efect in the mutant TSH receptor protein was probably responsible for the p oor routing of the receptor to the cell membrane. This is the first time th at a loss of function mutation of the TSH receptor is described in a patien t with severe congenital hypothyroidism and absent circulating thyroglobuli n due to TSH unresponsiveness and the first time that an inactivating mutat ion of the TSH receptor is described in the first extracellular loop.