A novel mutation (M310L) in the thyroid hormone receptor beta causing resistance to thyroid hormone in a Brazilian kindred and a neonate.

Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone (T3) caused by mutations in the thyroid hormone receptor beta (TRbeta). The index patient of the family reported here, a 17-year-old woman, came to medical attention because of a diffuse goiter, short stature, and learning disabilities. Biochemical tests revealed an elevated free T4 of 5.2 ng/dl (0.8-2.1), a T3 of 270 ng/dl (80-220), and a nonsuppressed TSH of 1.79 mU/l (0.4-4). Administration of exogenous T4 or T3 did not result in the usual TSH suppression, prompting the clinical diagnosis of RTH. Her father and one of her brothers also had clinical and biochemical findings consistent with RTH. Direct sequence analysis of the TRbeta gene revealed a heterozygous transition 928A>G in exon 9 resulting in substitution of methionine 310 by leucine (M310L). This novel receptor mutant has a reduced affinity for T3 ( approximately 10% of normal) and dominant negative properties that are similar in comparison to other RTH mutations. The index patient had a normal pregnancy and delivery. At birth, the female neonate had no goiter, a significantly elevated T4, and increased TSH. The diagnosis of RTH was confirmed by sequencing the TRbeta gene. She was underweight at birth and her length was between the 5th and 10th percentile. At 26 months, her height remained at the 10th percentile but her bone age was 18 months, suggesting mild hypothyroidism at the level of the bone. In contrast, increased heart rate and restlessness are consistent with hyperthyroidism in other tissues, such as the heart and possibly the brain.