Prenatal diagnosis of thyroid hormone resistance

A 29-yr-old woman with pituitary resistance to thyroid hormones (PRTH) was found to harbor a novel point mutation (T337A) on exon 9 of the thyroid hor mone receptor beta (TR beta) gene. She presented with symptoms and signs of hyperthyroidism and was successfully treated with 3,5,3'-triiodothyraaceti c acid (TRIAC) until the onset of pregnancy. This therapy was then disconti nued in order to prevent TRIAC, a compound that crosses the placental barri er, from exerting adverse effects on normal fetal development. However, as the patient showed a recurrence of thyrotoxic features after TRIAC withdraw al, we sought to verify, by means of genetic analysis and hormone measureme nts, whether the fetus was also affected by RTH, in order to rapidly reinst itute TRIAC therapy, which could potentially be beneficial to both he mothe r and fetus. At 17 weeks gestation, fetal DNA was extracted from chorionic villi and was used as a template for PCR and restriction analysis together with direct sequencing of the TR beta gene. The results indicated that the fetus was also heterozygous for the T337A mutation. Accordingly, TRIAC trea tment at a dose of 2.1 mg/day was restarted at 20 weeks gestation. The moth er rapidly became euthyroid, and the fetus grew normally up to 24 weeks ges tation. At 29 weeks gestation mild growth retardation and fetal goiter were observed, prompting cordocentesis. Circulating fetal TSH was very high (28 7 mU/L) with a markedly reduced TSH bioactivity (B/I: 1.1 +/- 0.4 vs 12.7 /-: 1.2), while fetal FT4 concentrations were normal (8.7 pmol/L; normal Va lues in age-matched fetuses: 5-22 pmol/L). Fetal FT3 levels were raised (7. 1 pmo/L; normal values in age-matched fetuses: <4 pmol/L), as a consequence of 100% cross-reactivity of TRIAC in the FT3 assay method. To reduce the e xtremely high circulating TSH levels and fetal goiter, the dose of TRIAC wa s increased to 3.5 mg/day. To monitor the possible intrauterine hypothyroid ism, another cordocentesis was performed at 33 weeks gestation, showing tha t TSH levels were reduced by 50% (from 287 to 144 mU/L). Furthermore, a sim ultaneous ultrasound examination revealed a clear reduction in fetal goiter . After this latter cordocentesis, acute complications occured, prompting d elivery by cesarean section. The female neonate was critically ill, with mu ltiple-organ failure and respiratory distress syndrome. In addition, a smal l goiter and biochemical features of hypothyroidism were noted transiently and probably related to the prematurity of the infant. At present, the baby is clinically euthyroid, without goiter, and only exhibits biochemical fea tures of RTH. In summary, although further fetal studies in cases of RTH ar e necessary to determine whether elevated TSH levels with a markedly reduce d bioactivity are a common finding, our data suggest transient biochemical hypothyroidism in RTH during fetal development. Furthermore, we advocate pr enatal diagnosis of RTH and adequate treatment of the disease in case of ma ternal hyperthyroidism, to avoid fetal thyrotrope hyperplasia, reduce fetal goiter, and maintain maternal euthyroidism during pregnancy.