TSH receptor gene mutations and familial gestational hyperthyroidism.

‘Gestational hyperthyroidism’ is a clinical condition characterized by thyrotoxicosis and hyperemesis gravidarum and generally occurs in 1–2% of all normal pregnancies. It represents an extreme degree of morning nausea and vomiting in early pregnancy, accompanied by weight loss, ketonemia, acetonuria, and profound volume depletion. Within the last decade, the association of abnormal thyroid function tests (suppressed thyrotropin (TSH) levels and high free thyroxine (FT4) concentrations) with hyperemesis gravidarum has been increasingly recognized and the severity of the hyperemesis has been linked to the biochemical severity of the hyperthyroidism (1–3), even though a precise correlation between these two conditions is still unclear. Gestational hyperthyroidism has been attributed to the thyrotropic action of choriogonadotropin (CG) (3–6). During early pregnancy, the high circulating levels of CG could be responsible for the transient thyroid stimulation leading to hyperemesis. The mechanism known as ‘specificity spillover’ could explain the ability of CG to stimulate the TSH receptor. The specificity spillover is related to the structural homology between CG and TSH molecules, and also between their mutual receptors. Using FRTL-5 cells, it was shown that highly purified CG increased iodide uptake and cAMP production (7), and induced thymidine incorporation and c-myc mRNA expression as indirect indices of cell growth (8). In addition, in cultured human thyroid follicles CG displaces TSH from its receptor and is able to stimulate adenylyl cyclase, iodide uptake, organification, and tri-iodothyronine (T3) secretion (9). These data clearly indicate that CG possesses TSH-like activity. This characteristic of the CG molecule and the high degree of homology among glycoprotein hormone (TSH, follicle-stimulating hormone (FSH) and luteinizing hormone (LH)/CG) receptors, which belong to the family of closely related G-protein coupled receptors, is responsible for the hyperthyroidism found in trophoblastic diseases, as well as in CG-producing tumors, such as choriocarcinomas. However, many but not all pregnant women with gestational hyperthyroidism have high serum concentrations of CG (6, 10), indicating that other factors, such as the glycosylation of the molecule, could contribute to the hyperthyroidism in pregnant women with normal CG circulating levels (11, 12). In this regard, it has been demonstrated that deglycosylation and/or desialylation of CG enhances its thyrotropic potency to bind TSH receptor and stimulate cAMP production and growth response in FRTL-5 cells (13, 14). More recently, Rodien and coworkers (15) have shown that another mechanism can be involved in the pathogenesis of hyperemesis gravidarum and hyperthyroidism associated with normal serum CG concentrations. These authors reported on a 10-week pregnant woman and her mother who had recurrent gestational hyperthyroidism and normal serum CG concentrations. The proband had two miscarriages accompanied by severe nausea and vomiting, and two full-term pregnancies characterized by hyperemesis and hyperthyroidism. On physical examination she presented weight loss of 5 kg, small and diffuse goiter, tachycardia, excessive sweating, tremors and absence of ophthalmopathy. Laboratory tests revealed the presence of suppressed TSH (<0.07 mU/l; normal value 0.2–6 mU/l) and elevated serum FT4 and total T3 (TT3) concentrations (60 pmol/l and 9.8 nmol/l; normal value 11–24 pmol/l and 1.0–2.8 nmol/l respectively) associated with normal circulating levels of CG (70 U/ml: normal range for the first trimester of pregnancy, 38-173 U/ml). Anti-thyroid autoantibodies were negative. During both pregnancies, the patient was treated with propylthiouracil until the delivery and then the therapy was discontinued. She became rapidly euthyroid without symptoms or signs of hyperthyroidism out of the gestational period. Her mother reported a similar history of miscarriage followed by two full-term pregnancies characterized by hyperemesis gravidarum and recurrent hyperthyroidism. The presence of familial gestational hyperthyroidism suggested a genetic defect transmitted by Mendelian inheritance. TSH receptor gene mutations were considered possible causes of the disease. In effect, a substitution of guanine for adenine at codon 183 on exon 7 of the TSH receptor gene was found in the proband and the mother. Both patients were heterozygous for this mutation, which results in the replacement of a lysine residue with an arginine (K183R) in the extracellular N-terminal domain of the TSH receptor. Functional studies in COS-7 cells demonstrated that the mutant receptor was more sensitive to CG (4-fold increase in cAMP production after stimulation by CG at the maximal dose of 1000 U/ml) than the wild-type receptor, thus accounting for the occurrence of hyperthyroidism despite the presence of normal CG European Journal of Endocrinology (1999) 141 93–94 ISSN 0804-4643 H IG H L IG H T