Congenital hypothyroidism: an evolving common clinical conundrum

Newborn screening for congenital hypothyroidism, initiated in 1975 (1), has led to the recognition and treatment of affected infants before the onset of clinical signs and symptoms of hypothyroidism. Widespread screening has in large part reduced, if not eliminated, the adverse neurological and developmental effects of congenital hypothyroidism. Compared with the prescreening period, the worldwide reported incidence has more than doubled and is now estimated to be between 1:2000 and 1:4000 newborns. Although there is general agreement that treatment should begin as early as possible and with daily oral doses of T4 between 10 and 15 g/kg (2), there is a remarkable lack of uniformity in the diagnoses assigned and in the reporting and follow-up of infants identified and treated with hormone replacement therapy. A report by Mengreli et al. in the current issue of JCEM (3) using a primary TSH screening method (at 3–5 d of age) reports a significant increase in the incidence of congenital hypothyroidism diagnosed when the neonatal TSH threshold limit was decreased from 20 to 10 mU/liter. With this change, 28% more infants were placed on replacement thyroid hormone (3). Not unexpectedly, this also resulted in a 10-fold rise in the recall rate of screened infants. At 3 yr of age, 151 of the 200 children identified as having congenital hypothyroidism were reevaluated. What was most remarkable is that 88.7% of the 151 reevaluated children were deemed to have permanent hypothyroidism. Thirty-one (20%) of the reevaluated children were premature infants, with 23 of these children having permanent hypothyroidism. One third of the babies with permanent hypothyroidism had screening TSH levels between 10 and 20 mU/liter and would therefore have been missed had the cutoff level remained at 20 mU/ liter, and half of the premature babies with persistent congenital hypothyroidism had screening TSH levels of less than 20 mU/liter. Structural abnormalities of the thyroid gland were detected in 20% of the infants with screening TSH levels of less than 20 mU/liter. The diagnosis of permanent hypothyroidism was based on a serum TSH concentration of greater than the upper limit of normal for the assay (5 mU/liter) after discontinuation of therapy for at least 3 wk, the presence of a sibling with an increased serum TSH, or an abnormal thyroid gland on either imaging or functional tests. Imaging tests consisted of ultrasound and radioisotope screening and perchlorate discharge. Of note, the initial screening was obtained at 3–5 d of age, which is somewhat later than the age at which screening tests are obtained in the United States. By applying the TSH threshold of 10 mU/liter, the prevalence of permanent congenital hypothyroidism was 1:1,749, whereas that of transient congenital hypothyroidism was 1:14,154. These findings are consistent with those of Corbetta et al. (4), who reported an increase in the incidence of congenital hypothyroidism from 1:2654 to 1:1446 cases with a reduction in TSH cutoff from greater than 20 mU/liter to greater than 10–12 mU/liter. The increase was largely, but not exclusively, in those with eutopic thyroid glands. When reevaluated at 3 yr of age, 78% of these cases were thought to have permanent hypothyroidism. TSH levels greater than 10 mU/liter with low or normal free T4 were seen in 34% of the cases, and mild permanent thyroid dysfunction with TSH levels between 5 and 9.9 mU/liter with normal free T4 was seen in 44% of the cases. In the