Longitudinal study of thyroid function in Down's syndrome in the first two decades

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Gibson PA, Newton RW, Selby K, Price DA, Leyland K, Addison GM. Arch Dis Child 2005;90:574-8

Context The association between thyroid dysfunction and Down's syndrome is well recognized, but the natural history of this dysfunction is not known. Existing data and recommendations may lead many pediatricians to check thyroid function in those with Down's syndrome on an annual basis.

Objective To define the properties of thyroid function tests carried out late in the first decade of life and to what extent they predict subsequent abnormality in the second decade.

Design Longitudinal cohort study.

Setting Manchester, England.

Participants 122 children with Down's syndrome age 6 to 14 years.

Interventions Thyroid function tests were obtained at baseline and then repeated 4 to 6 years later in 103 adolescents (85% of the group of 122) when they were age 10 to 20 years (median, 14.4 years).

Main Outcome Measures Properties of the test, expressed as likelihood ratios.

Results At the first test there were 98 (80%) euthyroid children; 83 were retested, and 4 (5%) had isolated raised elevated thyroid stimulating hormone (IR-TSH). At the first test, 24 had IR-TSH; 20 were retested, and 14 (70%) had become normal. Seventeen with IR-TSH on initial testing had a thyrotrophin-releasing hormone test within 3 months; TSH had become normal in 8 (47%) of these children. There was no association between reported clinical symptoms and IR-TSH, but there were clear symptoms in 1 of the 2 children with definite hypothyroidism. The likelihood ratio for a positive result on second testing when raised TSH and positive antibody status on first testing are combined is 20.

Conclusions These findings suggest that initial testing results could be used as a basis to select a subgroup for further testing at 5-year intervals unless new symptoms emerge in the interim. It also suggests that yearly screening (as recommended by the American Academy of Pediatrics) is probably not justified in the first 20 years of life.

Comment The prevalence of overt congenital hypothyroidism from thyroid dysgenesis or dyshormonogenesis is not increased in patients with Down syndrome. However, a population-based study in the Netherlands showed that the whole distributions of thyrotropin (TSH) and thyroxine (T₄) measured on neonatal blood spots are slightly shifted to the right and left, respectively, in newborns with Down syndrome compared with normal newborns.¹ Based on this observation, the same investigators undertook a double-blinded randomized controlled trial of thyroxine versus placebo from the neonatal period in almost 200 newborns with Down syndrome, regardless of their TSH or T₄ values. Recently published results of this trial suggest that the T₄-treated children had significantly greater gains in length and weight and also, most importantly, a 0.7-month less delay in motor development score at 2 years of age.² This major study requires extension at later ages and ideally should be replicated, but these findings may have a major impact on the care of newborns with Down syndrome.

In older patients with Down syndrome, TSH and T₄ are probably skewed as well, although this has not been studied as rigorously in this group as in neonates. In addition, there is a propensity to develop acquired thyroid dysfunction from autoimmunity, and thus yearly screening is recommended by the American Academy of Pediatrics. This study by Gibson and colleagues from the United Kingdom challenges this recommendation. At the first screening, the most commonly observed abnormality was isolated hyperthyrotropinemia, found in 20% of patients; however, only 1 of those patients was found to be hypothyroid at the second screening. Hypothyroidism was also present at the second screening in 2 patients who were euthyroid at the first screeening. Isolated hyperthyrotropinemia was not associated with reported clinical symptoms. The presence of thyroid autoantibodies at the first screening was not significantly associated with hypothyroidism at the second screening.

In conclusion, both biochemical screening for and treatment of thyroid dysfunction in newborns, infants, and children with Down syndrome require further study. In the meantime, monitoring of height and weight should enable detection of overt hypothyroidism and, until the results of the Dutch study are extended and replicated, clinicians should refrain from treating on the basis of isolated elevations of TSH, at least after age 2 to 3 years, when there is no evidence that this has a negative impact on brain development.

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References 

1. van Trotsenburg AS, Vulsma T, Van Santen HM, Cheung W, de Vijlder JJ. Lower neonatal screening thyroxine concentrations in Down syndrome newborns. J Clin Endocrinol Metab. 2003;88:1512–1515
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2. van Trotsenburg AS, Vulsma T, Rozenburg-Marres SL, van Baar AL, Ridder JC, Heymans HS, et al. The effect of thyroxine treatment started in the neonatal period on development and growth of two-year-old Down syndrome children: a randomized clinical trial. J Clin Endocrinol Metab. 2005;90:3304–3311
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