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 tis sue responsiveness to thyroid hormone (T3) caused by mutations in the thyro id hormone receptor beta (TR beta). The index patient of the family reporte d here, a 17-year-old woman, came to medical attention because of a diffuse goiter, short stature, and learning disabilities. Biochemical tests reveal ed 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 (0.3-4). Administration of exogenous T 4 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 TR beta gene revealed a heterozygous transition 928A>G in exon 9 resulting in substitution of methionine 310 by leucine (M310L). This novel receptor m utant has a reduced affinity for T3 (similar to 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 femal e neonate had no goiter, a significantly elevated T4, and increased TSH. Th e diagnosis of RTH was confirmed by sequencing the TR beta gene. She was un derweight 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 w as 18 months, suggesting mild hypothyroidism at the level of the bone. In c ontrast, increased heart rate and restlessness are consistent with hyperthy roidism in other tissues, such as the heart and possibly the brain. (C) 200 0 Academic Press.