Electronic Letters to:

Endocrine Care: A. S. Paul van Trotsenburg, Thomas Vulsma, Susanne L. Rutgers van Rozenburg-Marres, Anneloes L. van Baar, Jeannette C. D. Ridder, Hugo S. A. Heymans, Jan G. P. Tijssen, and Jan J. M. de Vijlder 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 [Abstract] [Full text] [PDF]

eLetters: Submit a response to this article

Electronic letters published:

Response to Letter to the Editor

A. S. Paul van Trotsenburg, Thomas Vulsma   (15 September 2005)

Letter to the Editor

Jose C. Florez   (15 September 2005)

Response to Letter to the Editor 15 September 2005
A. S. Paul van Trotsenburg University of Amsterdam, Thomas Vulsma Send letter to journal: Re: Response to Letter to the Editor a.s.vantrotsenburg{at}amc.uva.nl A. S. Paul van Trotsenburg, et al.	With regard to Dr. Florez’s first question we would like to remind that the main reason for designing our trial the way we did [i.e. randomizing the Down syndrome (DS) neonates to T4 or placebo irrespective of their baseline TSH or FT4] (1) was our previous finding of lowered T4 concentrations in all DS neonates (2). Based on the definite group character of this finding we hypothesized that (a) all DS children have a thyroid (regulation) disorder, (b) this results in a mildly hypothyroid state at least during the first weeks to months of life, and (c) this might be harmful to early development and growth. And that is exactly what we found in our trial. In a recently submitted manuscript we have further substantiated hypotheses (a) and (b) by showing that the TSH concentration frequency distributions of the placebo treated children are clearly shifted to higher values during the entire study period. Of course, one DS neonate may have benefited more from the two-years T4 treatment than the other, and the children who benefited least may have been the ones with plasma TSH concentrations persistently within the age- specific general population reference interval. However, like in previous studies TSH concentrations fluctuated over time (from “normal” to elevated, and vice versa) (3, 4), and in only a few (10 to 15%) of the placebo treated children all TSH measurements were within the reference range. This obviously hampers Dr. Florez’s proposed analyses. With regard to the last question, we would like to recall that neonatal congenital hypothyroidism screening programs (i.e. carried out in the first days of life) were instituted to prevent brain damage due to postnatal thyroid hormone deficiency. From our answer to question one it may be clear that all DS neonates may be at risk for brain damage due to (mild) hypothyroidism, but that even a few consecutive TSH measurements may be insufficient for identifying the children with the highest risk. However, with frequent screening in time most DS children will have at least one TSH concentration above the general population reference interval. If only then T4 treatment is started the “time-window of opportunity” to prevent brain damage may have passed. 1. van Trotsenburg ASP, Vulsma T, Rutgers van Rozenburg-Marres SL, van Baar AL, Ridder JCD, Heymans HSA, Tijssen JGP, de Vijlder JJM 2005 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 90:3304-3311 2. van Trotsenburg ASP, Vulsma T, van Santen HM, Cheung W, de Vijlder JJM 2003 Lower Neonatal Screening Thyroxine Concentrations in Down Syndrome Newborns. J Clin Endocrinol Metab 88:1512-1515 3. Crino A, Ciampalini P, DiGilio MC, Obregon MG, Giannotti A, Borrelli P 1993 Abnormal thyrotropin secretion in Down’s syndrome. In: Castells S, Wisniewski KE, eds. Growth hormone treatment in Down’s syndrome. New York: John Wiley and Sons; 101–109 4. Rubello D, Pozzan GB, Casara D, Girelli ME, Boccato S, Rigon F, Baccichetti C, Piccolo M, Betterle C, Busnardo B 1995 Natural course of subclinical hypothyroidism in Down’s syndrome: prospective study results and therapeutic considerations. J Endocrinol Invest 18:35–40
Letter to the Editor 15 September 2005
Jose C. Florez, MD Massachusetts General Hospital Send letter to journal: Re: Letter to the Editor jcflorez{at}partners.org Jose C. Florez	Van Trotsenburg et al. (1) address an important issue: whether thyroxine replacement to neonates with Down syndrome (DS) improves development and growth. The hypothesis is based on previous findings documenting a high incidence of hypothyroidism in this patient group, which often goes undetected. However, several key questions remain unanswered: First, does thyroxine replacement help all neonates with DS, or only those who are hypothyroid? The observed differences might have been due to the treatment of underlying occult hypothyroidism, rather than to thyroxine supplementation in all children in the intervention arm. That is, since the incidence of hypothyroidism is so high in this population, a large group of children in the intervention arm may have benefited from having their hypothyroidism addressed, whereas a similarly large group of children in the placebo arm developed hypothyroidism and went untreated. In order to distinguish between the two possibilities, it would be interesting to restrict the analysis to children in the placebo arm whose TSH measurements remained normal during the course of the study, compared to those who received thyroxine. If there are no statistically significant differences (and power is adequate), one might conclude that the treatment only benefited children who developed hypothyroidism. Second, should we change the “normal range” of TSH measurements for this patient population? It is quite possible that the definition of hypothyroidism needs to be adjusted in DS, revising the upper limits of normal TSH downwards so that more children are captured and treated. Another subgroup analysis of the present study might help: if the children whose TSH measurements were in the upper 50th percentile of the “normal” range performed better when randomized to thyroxine, one might conclude that this upper 50th percentile defines a heretofore unrecognized hypothyroid state. And third, what is the appropriate interval for screening? This study shows that children with DS benefit from having their thyroid status addressed. Regardless of whether all children or only some children should be treated, we should heighten our awareness and attempt to capture conventional hypothyroidism in all cases. A detailed analysis of the individual data obtained in the placebo arm of this study may shed light on the number of times hypothyroidism would have been missed with increasing screening interval lengths. At a minimum, an evidence-based screening protocol which maximizes the opportunity to capture this easily treatable condition in children with DS would in itself be a most valuable contribution. 1. van Trotsenburg ASP, Vulsma T, Rutgers van Rozenburg-Marres SL, van Baar AL, Ridder JCD, Heymans HSA, Tijssen JGP, de Vijlder JJM 2005 The effect of thyroxine treatment started in the neonatal period on development and growth of two years old Down syndrome children: a randomized clinical trial. J Clin Endocrinol Metab 90:3304-3311