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Random Variability in Congenital Hypothyroidism from Thyroid Dysgenesis over 16 Years in Québec

Endocrinology Service and Research Center (J.D., G.V.V.), Sainte-Justine Hospital and Department of Pediatrics, University of Montreal, Montreal H3T 1C5, Canada; and Quebec Neonatal Screening Laboratory (N.B.), Centre Hospitalier de l’Université Laval, Québec City G1V 4G2, Canada

Address all correspondence and requests for reprints to: Guy Van Vliet, M.D., Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal H3T 1C5 Québec, Canada. E-mail: guy.van-vliet{at}recherche-ste-justine.qc.ca.

	Abstract

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Context: Research on the etiology of congenital hypothyroidism from thyroid dysgenesis (CHTD) (comprising mostly ectopy and agenesis) over the past decade has focused on genetic mechanisms. However, the possibility that environmental factors might be involved has been raised by studies showing a seasonal variability of the incidence of CHTD.

Objectives: The objective of this study was to assess the variability in incidence of CHTD in the province of Québec, Canada.

Design, Setting, Patients, and Main Outcome Measure: The Québec provincial newborn screening database was analyzed from January 1990 to December 2005. Only cases of permanent congenital hypothyroidism with thyroid ectopy or agenesis on scintigraphy were analyzed.

Results: During the study period, 1,303,341 children were screened, and 424 cases of permanent congenital hypothyroidism were diagnosed, giving an overall incidence of 1:3074. Of these, 306 had CHTD (overall incidence 1:4259) from either ectopy (n = 231) or agenesis (n = 75). Over the 16 yr of the study, this incidence remained stable (P = 0.57), and no significant variability in monthly incidence was found (P = 0.87).

Conclusions: The incidence of CHTD did not vary over the observation period, and its monthly variation was random. Therefore, environmental factors do not appear to play a significant role in the etiology of CHTD.

	Introduction

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CONGENITAL PRIMARY hypothyroidism (CH) occurs in one of 3000–4000 live births in iodine-sufficient regions throughout the world (1). In the vast majority of cases, the disease is due to defects in thyroid differentiation, migration, or growth resulting in athyreosis, ectopy, or in situ hypoplastic glands, respectively. The specific defect is best established through scintigraphy (2). Most single gene disorders identified over the past 10 yr have been in patients with in situ glands (3, 4, 5, 6), while the vast majority of cases with ectopy or athyreosis remain unexplained (7). In this group, which we define hereafter as congenital hypothyroidism from thyroid dysgenesis (CHTD), most cases appear to be nonfamilial, and the high discordance rate in monozygotic twins argues against a significant contribution of mendelian and environmental factors in the pathogenesis (8). However, the possible contribution of environmental factors was suggested by two recent studies from Japan that reported seasonal variability of CHTD (9, 10). These two reports prompted us to analyze our screening database to evaluate temporal trends in CHTD incidence in the Province of Québec, Canada.

	Materials and Methods

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Definitions and classification

Since November 1987, the CH newborn screening program in Québec has been based on the measurement of TSH on eluates of dry blood collected on filter paper at 2–3 d of life as the primary screening test. The details of the screening methodology have been reported elsewhere (11). More than 90% of the cases of CH identified by the screening laboratory are referred to one of the four university pediatric endocrinology clinics. The screening laboratory subsequently requests from the clinician to send a form specifying: 1) if CH was confirmed by plasma thyroid function tests; and 2) if so, whether the etiology based on scintigraphy with sodium pertechnetate was ectopy, agenesis, in situ thyroid gland, or goiter. Because genetic causes explain the majority of the latter two categories (3, 4, 5, 6), seasonal variability was studied only in the ectopy/agenesis (CHTD) group. The study started in January 1990, at which time all participating centers started obtaining the thyroid scintigraphy in the newborn period, before starting treatment. Over the study period, CH screening results were obtained in more than 99% of children born in Québec, so we used the number of tests as a proxy for the number of births.

Statistical analyses

The monthly number of CHTD cases was standardized over the number of tests for each month analyzed (n = 192 months, 16 yr) to obtain the standardized monthly incidence, which was expressed as number of CHTD cases per 10⁴ tests performed. Next, the pooled results for each month over the 16 yr were considered. The Shapiro-Wilk normality test, the Kruskal-Wallis test, Bartlett’s test of homogeneity of variances, and the Poisson regressions were performed as appropriate using the free statistical software R (12). Dunn’s posttest and post hoc ANOVA were obtained using the statistical software GraphPrism (GraphPad Software Inc., San Diego, CA). A P value < 0.05 was considered statistically significant.

	Results

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Database characterization and standardization

The Quebec Newborn Screening Database was analyzed to compare the monthly incidence of CHTD from January 1990 to December 2005. Over the 192 consecutive months, 1,303,341 individuals were tested, 424 cases of permanent CH were diagnosed (overall incidence 1:3074), of which 306 had CHTD (overall incidence 1:4259). A total of 217 (70%) were female and, as previously reported (13), this female predominance was more pronounced in ectopy (Table 1). The number of tests performed in May was significantly higher than in February, November, and December (P < 0.05 for comparison of the medians). This seasonal variability in the number of tests is a direct consequence of seasonal variation of birth rate, a well-documented phenomenon that is strongly influenced by sociodemographic factors (14). Because the number of tests per month showed a significant seasonal variability, we standardized the monthly number of CHTD cases over the number of tests performed per month.

No significant differences were observed when comparing the yearly incidences of CHTD (Poisson regression, P = 0.58; data not shown) or when comparing the monthly incidence each year with the Kruskal-Wallis test (P = 0.50; Fig. 1A).

View larger version (19K): [in this window] [in a new window]   FIG. 1. A, Monthly incidence of CHTD in each consecutive year (Kruskal-Wallis test, P = 0.5; n = 12 for each year). B, Monthly incidence of CHTD. Comparison of the medians over 16 consecutive years (Kruskal-Wallis test, P = 0.87; n = 16 for each month). The boxes include the 25th to 75th percentile (IQR), and the whiskers include the 10th to 90th percentile. The horizontal lines in the box indicate the medians. All observations greater than the 90th percentile are shown as open circles. Apr, April; Aug, August; Dec, December; Feb, February; Jan, January; Jul, July; Jun, June; Mar, March; Nov, November; Oct, October; Sep, September.

The monthly incidences were not normally distributed (Shapiro-Wilk normality test, P < 0.001, n = 192; and P < 0.05, n = 16 for the months of September, November, and December). Therefore: 1) monthly incidences are presented as medians and interquartile ranges (IQRs) in Table 1; and 2) we used the nonparametric Kruskal-Wallis test to compare the medians. No significant differences were observed when comparing the monthly incidences of CHTD (P = 0.87; Fig. 1B). The one-way ANOVA test has been robust to nonnormality when the variances are homogeneous (15). Here, the variances of monthly incidences were homogeneous as assessed by a nonsignificant Bartlett’s test. Therefore, we have reanalyzed our data with the classical one-way ANOVA test, which also showed no significant differences between the monthly incidences of CHTD (P = 0.93). This allowed us to calculate post hoc a statistical power of 99% for the one-way ANOVA of the monthly incidences. Finally, even multiple Poisson regressions did not reveal any significant differences between monthly incidences (all P values > 0.8).

	Discussion

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Although considerable progress has been made over the past decade in our understanding of single gene disorders affecting the thyroid axis (16), the etiology of defects in thyroid development represent one of the remaining enigmas in the pathophysiology of thyroid disease (17). Therefore, all possible etiological factors have to be considered, including either environmental chemicals, which may be suggested by temporal trends, or viral infections, which may be suggested by seasonal variation (9).

Two recent reports showed seasonality in the incidence of CH in two different prefectures in Japan (9, 10). The possibility that some seasonal factors in association with a distinct genetic background might contribute to some degree to the pathogenesis of CH is an attractive hypothesis. However, the collection and interpretation of the data need to be scrutinized. First, Miyai et al. (9) and Nakamizo et al. (10) analyzed all cases of CH without mentioning the diagnostic categories, and neither study used scintigraphy to establish the etiology of CH. Second, Miyai et al. (9) reported a relatively high incidence of CHTD (1: 2850) and a rather weak female predominance (1.2:1). Third, neither study considered the wide variability of incidence within a month over the years. Finally, although the reports came from the same country, the months with reported peak incidences were different.

Virtanen et al. (18) also showed a seasonal variability in the incidence of CHTD in Finland. However, as discussed by Reijneveld and Verkerk (19), the number of cases analyzed in the Finnish study was too small, and the estimated power of their study was less than 20%. Moreover, seasonal variability was also observed for the incidence of dyshormonogenesis, which is rather surprising considering the genetic etiology underlying this diagnosis (18).

On the other hand, our previous finding that monozygotic twins are generally discordant for CHTD (8) speak against a significant contribution of environmental factors. The random nature of the yearly and monthly variations in incidence found in the present study [and the lack of seasonal variation in a previous study from The Netherlands (19)] confirms that environmental factors are unlikely to play a role in CHTD pathogenesis.

The discrepancy between our results and those of the two recent studies from Japan underlines the need for a clear description of diagnostic and ascertainment criteria.

In conclusion, only random variability was observed in the monthly and yearly incidences of CHTD over 16 consecutive years in the Province of Quebec. We report the largest number of CHTD cases ascertained by thyroid scintigraphy, and the time period analyzed here is the longest observation documented so far. Therefore, our results strongly argue against a significant environmental influence on thyroid gland differentiation and migration during embryogenesis.

Having excluded environmental factors as a cause of CHTD, we propose a two-hit model for thyroid dysgenesis, which would be compatible with the usual discordance of monozygotic twins and the evidence for some genetic predisposition. In this model, a combination of a germline mutation with a somatic mutation or epimutation in threshold-sensitive developmental genes would be required for abnormal differentiation or migration of the thyroid anlage (20).

	Acknowledgments

 
We thank the physicians who have contributed to the Québec congenital hypothyroidism screening database over the study period, Drs. Claude Laberge and Yves Giguère (Quebec Neonatal Screening Laboratory) for their support, Mr. Lubomir Alexandrov for statistical advice, and Dr. Scott Grosse (Centers for Disease Control and Prevention, Atlanta, GA) for helpful discussions.

	Footnotes

 
This work was supported by the Swiss Foundation of Medical-Biological Scholarships (PASMA-112979), a research grant of the Endocrine Fellows Foundation (U.S.), and a fellowship grant of the Departments of Pediatrics of the University of Montreal (to J.D.). Research in pediatric thyroid diseases at Sainte-Justine Hospital is supported by generous donations from Mr. John H. McCall McBain (to G.V.V).

Disclosure Summary: The authors have nothing to declare.

First Published Online May 15, 2007

Abbreviations: CH, Congenital primary hypothyroidism; CHTD, congenital hypothyroidism from thyroid dysgenesis; IQR, interquartile range.

Received March 8, 2007.

Accepted May 3, 2007.

	References

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