Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation

OBJECTIVE Nonautoimmune hyperthyroidism (NAH), a rare autosomal dominantly inherited condition characterized by nonremitting thyrotoxicosis and the absence of features of autoimmune thyrotoxicosis, can result from activating germline mutations in the thyrotropin receptor (TSHR) gene. We report clinical and genetic features of a new family with NAH, and highlight that premature delivery and low birth weight are important characteristics of this condition. PATIENTS AND METHODS Thyrotoxicosis was diagnosed in two children at the ages 20 months and 4 years and in their father at the age of 9 years. Both children were born prematurely by Caesarian section at 33 and 30 weeks following early rupture of the membranes. Their birth weights were 1750 g (27th centile) and 790 g (< 3rd centile), respectively. Mutation analysis of the TSHR gene was performed in both children and their parents by direct DNA sequencing. RESULTS A heterozygous germline mutation of the TSHR gene resulting in the substitution of serine (AGC) by asparagine (AAC) at codon 505 (S505N) was found, which co-segregated with thyrotoxicosis in the family. A review of all previously reported cases of NAH due to an activating TSHR germline mutation showed that the mean duration of gestation in these patients was significantly lower than in patients with inactivating TSHR mutations causing congenital hypothyroidism (35.8 weeks vs. 39.4 weeks, P = 0.003). In addition, the mean birth weight in patients with activating TSHR mutations was lower than in patients with inactivating TSHR mutations (2338 g vs. 3470 g, P = 0.004). CONCLUSIONS Premature delivery and low birth weight are consistent features of NAH due to activating TSHR germline mutations. This suggests a possible role for the fetal thyroid axis in the regulation of the timing of delivery and possibly fetal growth.