Endocrine Abstracts

Context: Familial gestational hyperthyroidism caused by mutations of TSH receptor gene, hypersensitive to hCG, is rare. Only two mutations at the same amino acid (lys183Arg, Lys183Asn) in the leucine-rich region of the extracellular N-terminal domain of the TSH receptor have been reported.

Patients: A 38-year-old woman was seen during the first trimester of her second pregnancy for weight loss (5 kgs), nausea and vomiting. Thyroid function test revealed thyrotoxicosis with increased fT₃=8.3 ng/dl (2.4–4.1 ng/dl) and free T₄=2.3 ng/dl (0.8–1.3 ng/dl) concentrations and low TSH (<0.03 mU/l) levels without anti-TSH receptor antibody. Thyroid ultrasound showed a normal-sized thyroid gland with diffuse hyper-vascularization. Thyrotoxicosis persisted at 2nd trimester (fT₃=7.0 ng/dl, fT₄=1.3 ng/dl) and improved spontaneously during the 3rd trimester (T₃=3.5 ng/dl, fT₄=1.3 ng/dl). She gave birth to a girl (3300 gr, 48 cm). Interestingly she presented similar symptoms with a loss of 6 kgs during the first trimester of her first pregnancy with low TSH and normal fT₃ and fT₄ levels. Her mother had two children and reported similar symptoms during her first pregnancy. At the age of 66 years, she had normal thyroid function (TSH=0.92 mU/l) and high gonadotropin (LH=26.8 IU/l, FSH=85.7 IU/l) levels.

Results: DNA sequencing of this woman and her mother, led to identify a heterozygous variant (c.1789 G>A) changing Valine to Isoleucine residue at codon 597 in the exon 10 of the TSH receptor. Functional studies of this mutant receptor showed high constitutive activity in regard to the basal level of cAMP and IP3 production (2 to 2.5-fold higher) while responses to TSH were reduced compared to that of wild type receptor (average 50%), and related to low cell surface expression (28% of the wild type receptor). This Val597Ile mutant presented a dose-dependent increase in cAMP in response to chorionic gonadotrophin and luteinizing hormone whereas the wild type receptor was insensitive to those hormones except at high concentration of chorionic gonodotrophin.

Conclusion: We describe familial gestational hyperthyroidism due to a new variant in TSH receptor gene with hCG hypersensitivity. This amino-acid, located in the 5th transmenbrane helix of the receptor, is highly conserved among the receptors for TSH and LH in different species. We analyzed clinical and hormonal data related to the increased constitutive activity of the Val507Ile receptor and thyroid hypersentivity to HCG and LH in women of this family.