Nonautoimmune hyperthyroidism (NAH) inherited as an autosomal dominant trait can result from activating germline mutations in the thyrotropin receptor (TSHR) gene. Clinical features described include nonremitting thyrotoxicosis, absence of the features of autoimmune thyrotoxicosis, advanced bone age and increased growth velocity. We report a family with a heterozygous germline mutation of the TSHR gene resulting in the substitution of serine (AGC) by asparagine (AAC) at codon 505 (S505N). This mutation co-segregated with thyrotoxicosis, which was diagnosed in the children at the ages 20 months and 4 years and in their father at the age of 9 years. The two children were born prematurely by Caesarian section at 33 and 30 weeks following early rupture of the membranes. Their birth weights were 1750g (27 centile) and 790g (<3rd centile), respectively. A review of all previously reported cases of NAH associated with activating TSHR germline mutation showed that premature delivery and intrauterine growth retardation are consistent features of this disorder. The mean duration of gestation in NAH patients due to activating TSHR mutation was significantly lower than in patients with congenital hypothyroidism due to inactivating TSHR mutation (35.8 weeks vs. 39.4 weeks, p=0.003). In addition, the mean birth weight in patients with activating TSHR mutation was lower than in patients with inactivating TSHR mutation (2338 grams vs. 3470 grams, p=0.004). This suggests a possible role for the fetal thyroid axis in the regulation of fetal growth and possibly the timing of delivery.
22 - 24 Mar 2004
British Endocrine Societies