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A Search for the Possible Molecular Mechanisms of Thyroid Dysgenesis: Sex Ratios and Associated Malformations

Departments of Pediatrics, University of Montreal (G.V.V.), McGill University (C.R.), University of Sherbrooke (N.G.), and Laval University (R.L.), Montreal, Quebec, H3T 1C5 Canada

Address all correspondence and requests for reprints to: Guy Van Vliet, M.D., Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5. E-mail: gvanvliet{at}justine.umontreal.ca

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Permanent primary congenital hypothyroidism (CH) can be caused by abnormal thyroid differentiation (athyreosis), migration (ectopy), or function (leading to goiter). Goiters follow an autosomal recessive pattern of inheritance, whereas ectopy and athyreosis are considered as a single sporadic entity with a female preponderance. On the other hand, a high prevalence of extrathyroidal malformations has been reported in CH, but without linking specific defects to specific types of CH. On the basis of TSH screening, 273 newborns were referred to an academic pediatric endocrinology clinic in the province of Quebec between 1988 and 1997. Of 230 patients with permanent primary CH who had scintigraphy at diagnosis, 141 had ectopy (104 girls), 36 had athyreosis (21 girls), 42 had goiter (18 girls), 10 (3 girls) had a normal scan, and 1 girl had hemiagenesis. Only in the ectopies was the proportion of girls significantly higher than 0.5 (P < 0.001). Isolated cardiac malformations were observed in 7 patients (3.0%), a prevalence 5-fold higher than that in the general population; this was largely due to atrial and ventricular septal defects, which were only observed in ectopy and athyreosis. Our data suggest that the molecular mechanisms that lead to complete absence of thyroid differentiation or defective thyroid migration 1) may be similar, but are modulated by the genetic makeup of the embryo and/or the hormonal milieu of the fetus; and 2) may also be involved in septation of the embryonic heart.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE MAJOR causes of permanent primary congenital hypothyroidism (CH) are 1) incomplete or aberrant migration of the anlage, resulting in an ectopic gland without lateral lobes; 2) defective thyroid differentiation or growth, resulting in athyreosis; or 3) hormone biosynthetic defects, leading to goiter. The first two entities are grouped under the term thyroid dysgenesis, which is sporadic with a female predominance; the third entity, dyshormonogenesis, is autosomal recessive (1, 2).

Whether abnormalities in embryonic thyroid development or function are associated with other congenital malformations remains unclear. Recent studies have reported a higher prevalence of extrathyroidal abnormalities in permanent CH (3, 4) or in transient CH (5), whereas one study did not distinguish permanent and transient CH (6). Furthermore, in these studies, a large percentage of patients had not had a thyroid scintigraphy, a prerequisite for etiological diagnosis of primary CH (7).

The aims of the present study were 1) to confirm our suggestion of a different sex ratio in children with athyreosis or with ectopic glands (8) on a larger number of patients, and 2) to establish whether there was an increased prevalence of extrathyroidal abnormalities in our CH population and whether specific malformations were associated with one of the etiological categories. A precise description of these associations could shed light on molecular mechanisms interfering with thyroid differentiation and migration in humans. The roles of several genes involved in thyroid development and growth, which are also expressed in extrathyroidal tissues (tshr, pax-8, ttf-1, and ttf-2) has been suggested by the observation of natural mutations in mice (9) or by knockout experiments (10, 11, 12). However, extensive search for germline mutations in the homologous genes in humans with thyroid dysgenesis has only identified a few cases (8, 13, 14, 15, 16).

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
All patients referred to the pediatric endocrinology clinic of an academic center in the province of Quebec from January 1, 1988 to December 31, 1997 were studied. The screening and evaluation procedure has been previously described (17); if the TSH level, measured on dried blood spots collected on filter paper after 24 h of life, is more than 30 mIU/L, the neonate is immediately referred for evaluation and treatment; if the TSH concentration is 15–30 mIU/L, another sample is requested, and the child is referred if TSH is still more than 15 mIU/L.

After history and physical examination, the concentrations of free T₄ (FT₄), T₃, TSH, and antithyroperoxidase antibodies were measured in plasma from the infant and from the mother. A ^99mpertechnetate scintigraphy of the head, neck, and mediastinum was performed before starting treatment; according to its results, the children were divided into five groups: 1) ectopy, 2) athyreosis, 3) goiter, 4) normal scan, and 5) hemiagenesis.

The presence of congenital malformations, either at the initial evaluation or during a follow-up visit, was ascertained from chart review when all children were more than 8 months of age. Because up to 2.75% of live newborns have isolated atrial and/or ventricular septal defects that close spontaneously (18), only those that were documented after 28 days of age were considered significant.

The proportion of girls, with 95% confidence intervals, was calculated in the major etiological categories and compared to a theoretical proportion of 0.5 (which is expected in autosomal recessive conditions) using the z statistic (19).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients

Two hundred and seventy-three infants with CH, representing about 90% of CH patients identified by the Quebec Network of Genetic Medicine, were referred during the study period. There were 37 children with transient primary CH on the basis of spontaneous normalization of TSH between screening and diagnosis and/or no rise in TSH after stopping T₄ treatment. In all of those who had a scan (n = 26), this showed a thyroid of normal position and shape in 20; most were born to mothers who were being treated with antithyroid drugs or who had antithyroperoxidase antibodies. In 5 boys and 1 girl with transient CH from transplacental transfer of TSH receptor-blocking antibodies (demonstrated in 2, suspected in 4), there was absolutely no uptake on scan during the neonatal period (20). Two preterm newborns died before a scintigraphy could be performed and before the transient or permanent nature of their CH could be determined.

Thus, there were 234 children with permanent primary CH; of these, 6 had not had a scintigraphy: 1 preterm infant was considered too unstable for scintigraphy, 3 fullterm infants in whom the reason for not performing the scintigraphy was not specified, and 2 patients with evidence of dyshormonogenesis (1 girl whose older sister has a congenital goiter and another, born to consanguineous parents, who had respiratory distress after a term birth and a goiter on physical and ultrasound examinations; these 2 patients are included in the goiter group in Table 1).

Etiological diagnosis and sex ratio in permanent primary CH (Table 1)

In keeping with most (7), but not all (3, 16, 21, 22), series, patients with ectopies represent 61.3% of all cases of permanent primary CH, with athyreosis and goiter representing 15.6% and 18.3%, respectively. This is the first series in which the female predominance is significant (P < 0.001) for ectopy and not for athyreosis.

As in other series (21), scintigraphy fails to demonstrate an anatomical or functional defect in about 5% of patients. Lastly, our survey identified one girl with definite primary CH [screening: TSH, 170 mIU/L; total T₄, 54 nmol/L (normal, >85); diagnosis: TSH, 151 mIU/L (normal, 0.1–5.0); free T₄, 3.2 pmol/L (normal, 9–27)] and left thyroid hemiagenesis.

Extrathyroidal abnormalities in permanent primary CH (Table 2)

Among the children with permanent primary CH, 12 (5.2%) had associated extrathyroidal congenital abnormalities. These are described in Table 2.

Most striking was the finding that atrial and ventricular septal defects were found only in patients with ectopy or athyreosis. All three children with ventricular septal defects had ectopic thyroid and a single orifice in the muscular portion of the septum.

Other/complex syndromes

Among the five children with other/complex syndromes, there were two girls with ectopic thyroid, born to nonconsanguineous parents and with a negative family history. Patient 1 had septo-optic dysplasia with blindness, which has been associated with pituitary insufficiency (23), but not with primary CH. This patient had an appropriate elevation of TSH in the face of low T₄ (screening: TSH, 80 mIU/L; total T₄, 51 nmol/L; diagnosis: TSH, 91.2 mIU/L; FT₄, 8.7 pmol/L); linear growth at age 6 years proceeded regularly along the 75th percentile under T₄ substitution alone, indicating adequate GH secretion. A search for a mutation in HESX1 (24) is underway. Patient 2 had a combination of a cardiac and a urological malformation. Patients with PAX-8 mutations and an association of thyroid dysgenesis and unilateral renal agenesis have been reported (16), but our patient also had stenosis of the pulmonary valve, and PAX-8 is not known to be expressed in the heart (11). Patient 3 and her euthyroid mother had neurofibromatosis.

Although the parents of patient 4 had no known consanguinity, they both originated from the Saguenay-Lac Saint-Jean area of Quebec [a region known for an increased prevalence of some specific recessive diseases (25)]. This patient had some of the features of Bamforth syndrome (26, 27), such as cleft lip and palate and athyreosis; however, she did not have choanal atresia, kinky hair, or bifid epiglottis, and she had other malformations that are not part of the syndrome (dextrocardia and imperforate anus). Because TTF-2 mutations have been described in the Bamforth syndrome (14), the coding region of TTF-2 was sequenced, with normal results.

Patient 5 had congenital rubella syndrome with intrauterine growth retardation, including microcephaly, cataracts, deafness, and pulmonary valve stenosis. On day 34, her blood spot TSH was 16 mIU/L, and total T₄ was 125 nmol/L; on day 67, these were 36 and 112, respectively; on day 87, plasma TSH was 42 mIU/L, free T₄ was 15 pmol/L, and a thyroid scintigraphy was normal. Increases in TSH under T₄ substitution at 2 and 3 yr of age indicated permanent CH. Acquired hypothyroidism has been reported in patients with the congenital rubella syndrome (28), but not in CH.

Extrathyroidal abnormalities in transient primary CH

Among the 37 infants with transient primary CH, 5 had congenital malformations. Three were siblings with CH due to transplacental transfer of TSH receptor-blocking antibodies. The 3 older siblings (including 1 born before this survey) were reported in 1995; all had an extrathyroidal abnormality, possibly related to an immune mechanism (29). A fourth sibling, a boy born in 1996, had transient CH and pyloric stenosis like 1 of his older brothers. In 1 girl born at 34 weeks with gastroschisis, blood spot TSH was 26 mIU/L on day 3 of life, 2 days after abdominal surgery involving exposure of the peritoneal cavity to iodine-containing disinfectants; however, this cause of transient CH has only been described in areas of lower iodine intake than Quebec (30). Lastly, 1 girl possibly had VACTERL syndrome (31).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present report has two major strengths: 1) in 97% of subjects with permanent primary CH, ^99mpertechnetate scintigraphy was performed at diagnosis to establish the etiology of CH; and 2) it included 90% of children diagnosed with CH in Quebec during that period, thus avoiding referral bias. In other series, the percentage of patients who had scintigraphy either was not reported (4, 5) or was performed in a much smaller proportion of patients (6, 32, 33). In addition, the proportion of athyreosis and goiter was higher in some populations than in ours, perhaps suggesting a different genetic background and rate of consanguinity (3, 16, 21, 22). Furthermore, the large studies from Israel (3) and the U.S. (4) are based on a screening strategy using T₄ as the primary test. In the present study, blood spot T₄ was normal in 45% of infants with an ectopic thyroid and in only 5% of those with apparent athyreosis, confirming that the proportion of patients with specific etiologies may differ substantially depending on the screening technique (34). Lastly, the quality of the scintigraphic technique is crucial (7).

Our results regarding the sex ratio of the main etiological groups confirm our earlier suggestion (8) that a significant female predominance is found for ectopy, but not for athyreosis. In athyreosis, as in goiter, the proportion of girls is not significantly different from 0.5, compatible with autosomal recessive mechanisms. Although germline inactivating mutations in the TSH receptor gene (TSHR) can present as autosomal recessive apparent athyreosis (8, 35), groups of apparently athyreotic patients without a family history have not been screened for TSHR mutations.

However, not all apparently athyreotic CH patients have TSHR mutations (8), and other molecular mechanisms must also be involved. Indeed, congenital athyreosis is itself heterogeneous; it includes the patients with apparent athyreosis just discussed (who have a markedly hypoplastic and hypofunctional gland that does not take up ^99mpertechnetate) and patients with true athyreosis. The latter could result either from an initial lack of differentiation of cells from the pharyngeal floor into thyrocytes or from later disappearance of thyrocytes after partial or complete migration. On the other hand, the TSHR is not involved in thyroid migration (8), and TSHR is therefore not a candidate gene for ectopy. TTF-1, TTF-2, and PAX-8 are candidate genes for ectopy, but dominant PAX-8 mutations have only been described in a few pedigrees (15).

An alternative explanation for the different sex ratios in ectopy and athyreosis can be formulated on the basis of our findings and on the results of knockout experiments. The ttf-2 knockout in mice results in athyreosis or ectopy in about 50% of homozygous animals, demonstrating that a single molecular event can lead to either phenotype depending on modifier genes or stochastic events; the sex ratio of these two phenotypic variants was not reported (12). We suggest that in humans, 1) ectopy results from molecular events that occur more often in female embryos; and 2) atrophy of ectopic cells occurs more readily in male fetuses; thus, a female predominance of ectopies but not of athyreosis is observed at birth.

Our small group of patients with permanent primary CH and normal thyroid on scan have not had a molecular diagnosis. Possible mechanisms include 1) germline inactivating mutations of TSHR (the majority of which lead to a mild phenotype (36)); 2) heterozygous deletions in the chromosomal region including the TTF-1 locus, although none of these patients had respiratory distress or developmental delay (37); and 3) dominant, non-TSHR-related TSH resistance (38); the fact these 11 patients include 2 pairs of siblings (and a cousin once remote of 1 of these pairs), whose mothers have unexplained, slight elevations of TSH suggest that this mechanism is relatively frequent.

Hemiagenesis is usually not listed among the causes of CH. Aside from the patient reported here, we have seen it in another girl with permanent primary CH (unpublished observation). Although most older patients remain euthyroid or have only slight transient TSH elevations after hemithyroidectomy (39), the amount of thyroid tissue required for normal function varies between individuals and was obviously insufficient in our two patients. Hemiagenesis has been reported to occur in euthyroid siblings of CH children with ectopies (40, 41) and in a euthyroid father and his CH son, both with a PAX-8 mutation (16). However, like ectopy, hemiagenesis is usually sporadic with a 3 to 1 female predominance (42).

As shown in Table 2, there was a higher than expected prevalence of major extrathyroidal abnormalities in children with permanent primary CH (12 of 230 or 5.2%, compared to 2.9% in the Quebec population) (43). Of note, isolated cardiac malformations were observed in 7 of 230 CH patients (3.0%) compared to 0.55% reported in the Quebec population (43); furthermore, this overall increase was largely due to persistent atrial and ventricular septal defects that occurred only in patients with ectopy or athyreosis. Genes that are expressed in both embryonic heart and thyroid include Nkx2.5, a transcription factor gene related to ttf-1 (44). Four dominant mutations in the homologous human gene have been described in 3 pedigrees with abnormal heart septation (45). Whether mutations in this or in related genes are involved in defective thyroid migration remains to be determined.

In summary, we describe the etiology based on thyroid scintigraphy in a large group of CH children. We found that there was a significant female predominance only in ectopy, not in athyreosis. This suggests that even though complete absence of initial thyroid differentiation or defective thyroid migration (possibly with later disappearance of the ectopic cells) can be caused by similar mechanisms, these are modulated by the genetic makeup of the embryo and/or the hormonal milieu of the fetus. On the other hand, we report that the excess of isolated cardiac malformations is largely due to septation defects, which were seen only in children with ectopy or athyreosis; this may orient future research to determining which molecular mechanisms are involved in those cases.

	Acknowledgments

 
We thank the personnel of the Screening Laboratory of the Quebec Network of Genetic Medicine (especially Ms. Nicole Bélanger), which continues to provide excellent service under the supervision of Dr. Jean H. Dussault. We thank Ms. Nicole Labbé for her help with the chart review, Drs. François Szötz and Khalil Khoury for their cooperation, and Dr. Louis Dallaire for helpful discussions. Dr. Gilbert Vassart is gratefully acknowledged for sequencing the TTF-2 coding sequence in one patient and for thoughtful comments.

	Footnotes

 
¹ Supported by the Blouin-MacBain Foundation.

Received January 27, 1999.

Revised March 4, 1999.

Accepted March 24, 1999.

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