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Detection of resistance to thyroid hormone by cord blood screening

Resistance to thyroid hormone (RTH) is a rare hereditary disorder characterized by elevated levels of thyroid hormone together with diminished central and peripheral tissue responsiveness to hormone action. This condition was first described by Refetoff et al. in 1967(1). In the following report, we described a Chinese family with RTH in which the index case was initially detected by routine neonatal cord blood screening. Thyroid stimulating hormone (TSH) was measured by an immunoradiometric assay (TSH RIABEAD 11, Abbot Laboratories) while total T4 was measured by Tetrabead125 radioimmunoassay (Abbott Laboratories). Sensitive thyroid stimulating hormone (STSH) was determined by a two-site chemiluminometric immunoassay (Magic Lite TSH, Ciba Corning), Serum-free triiodothyronine (FT,) was measured by Amerlex-M RIA method (Amersham, UK) and serum-free thyroxine (FT4) was determined by a two-step Gamma Coat RIA method (Clinical Assays, Baxter). This two-step FT4 assay does not produce abnormally high levels in patients with familial dysalbuminemic hyperthyroxinemia (2). A female Chinese baby was referred for assessment of thyroid status. The pregnancy and delivery were unremarkable. Birth weight was 2.5 kg. Routine cord blood screening showed that TSH and total T4 were both elevated at 30.6 mU/1 and 238 nmol/l, respectively. The upper cut-off points for TSH and total T4 are 14mIU/l and 200 nmol/l, respectively. Thyroid function tests were repeated at 1 week of age; total T4 has increased further to 418 nmol/l. On examination at 3 weeks of age, she remained well and her weight was 3.0 kg. Examination of the neck revealed no obvious goiter. Resting heart rate was elevated at 150 beats/min; otherwise, the physical examination was unremarkable. The thyroid function test was repeated at 6 weeks of age. STSH remained elevated at 9.9 mU/l. Serum FT3 was elevated at 21.6 pmol/l (normal range 3.3-8.2 pmol/l). Serum FT4 was also elevated; it was greater than 59.2pmol/l which is the upper measurable limit of the FT4 assay (normal range 7.0-21.8 pmol/l). She continued to have tachycardia at 6 weeks of age when anti-thyroid treatment was started, which included propanolol 2 mg every 8 h, propylthiouracil lOmg every 8 h and Lugol's iodine solution one drop every 8 h. Her clinical status remained unchanged and STSH increased further to 43.9mU/l after 1 week of anti-thyroid treatment. Anti-thyroid medications were then stopped. Blood from both parents and the patient was tested for the presence of thyroid autoantibodies this was negative. STSH and FT4 levels of the mother were normal at 1.4mU/1 and 18.5 pmol/l, respectively. For the father, STSH was 1.3mU/1 but FT4 and FT3 were elevated at 37.8 pmol/l and 11.7 pmol/l, respectively. He was clinically euthyroid and had a small goiter. At 4 months of age the patient was hospitalized to assess the pituitary sensitivity to thyroid hormone. Thyrotropin releasing hormone (TRH) tests were performed at baseline and after 2 weeks of supervised oral administration of L-triiodothyronine at a supraphysiologic dose of 20 pg/day. The results are summarized in Table 1. The STSH response was exaggerated at baseline and there was no significant suppression after 2 weeks of treatment. Computerized tomography of the head and pituitary was performed and was found to be normal. STSH levels decreased to within the normal range by 4 months of age while FT3 and FT4 remained elevated (Table 2). In our case report here, elevation of thyroid hormone was present at birth; therefore, screening for RTH by cord blood analysis is possible. Cord blood levels of thyroid hormone as well as TSH were elevated. A rapid increase in total T4 was evident in our case as total T4 increased from 238 to 418nmol/l by 1 week of age. A neonate, born to a mother with RTH, was found to have elevated TSH and T4 by blood-spot screening (3). This neonate was subsequently confirmed as having RTH. The molecular basis of RTH has been investigated extensively and in recent years has been confirmed as being due to mutations in the genes coding for thyroid hormone receptor (4). The consequences of not treating neonates with significant clinical hypothyroidism due to RTH have been documented to be similar to those of untreated primary hypothyroidism (5). Therefore, early diagnosis of patients with RTH is beneficial because appropriate thyroxine therapy can be started at an early age, when indicated.