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Endocrine Care |
Pediatric Endocrinology Unit and INSERM U457 (J.L., D.M., M.P., P.C.), and Radiology Department (C.G.), Hôpital Robert Debré, 75019 Paris, France; and INSERM U521 (C.B.-P.), Institut Gustave Roussy, 94807 Villejuif, France
Address all correspondence and requests for reprints to: Juliane Léger, M.D., Pediatric Endocrinology Unit and INSERM U 457, Hôpital Robert Debré, 48 Bd Serurier, 75019 Paris, France. E-mail: juliane.leger{at}rdb.ap-hop-paris.fr
Abstract
Congenital hypothyroidism (CH) is most frequently caused by thyroid developmental abnormalities and it has recently been seen to have a familial component. The aim of this study was to investigate whether thyroid developmental abnormalities exist in first degree relatives of CH children with thyroid dysgenesis, an anomaly which, when present, is sometimes asymptomatic.
Thyroid ultrasonography and function were evaluated among first degree relatives (n = 241) of 84 isolated CH children with thyroid dysgenesis. The results were compared with those of an unselected control population (n = 217).
In 19 individuals (7.9% of cases) belonging to 18 families (21.4%), 21 cases of thyroid developmental abnormalities were detected, whereas only 2 subjects (0.9%) were affected in controls (P < 0.001). These 21 thyroid developmental abnormalities included thyroglossal duct cysts (n = 14), additional thyroid tissue with presence of a pyramidal lobe (n = 3), thyroid hemiagenesis (n = 3), and ectopic thyroid tissue (n = 1). All of these subjects showed normal thyroid function and belonged to nuclear families of CH children with athyreosis (n = 8), ectopic thyroid tissue (n = 9), or hemiagenesis (n = 1).
A segregation analysis led to the conclusion that thyroid developmental abnormalities are compatible with an autosomal dominant mode of inheritance with a low penetrance estimated at 21% for asymptomatic thyroid developmental abnormalities and a probability of less than 7% of developing CH for a carrier of the susceptibility allele.
In conclusion, these observations support the hypothesis of a common genetic component of the disorder with heterogeneous phenotypes.
CONGENITAL HYPOTHYROIDISM (CH) secondary to developmental anomalies of the thyroid gland accounts for 85% of CH cases, with an incidence of 1 in 5000 live births (1). Its manifestations include ectopic thyroid tissue, athyreosis, or hypoplasia of the thyroid gland. The pathogenesis of the disease is unknown. We have recently reported that 2% of cases are familial, a proportion significantly higher than would be expected by chance (2). This familial component suggests that, at least in a minority of cases, genetic factors might be involved. Moreover, because in certain families the affected members of the same family have either athyreosis, ectopic or eutopic thyroid gland, it seems possible that a common underlying mechanism exists for both etiological groups (3).
Other variations involving the thyroid anatomy such as thyroid hemiagenesis, ectopic lingual thyroid, cysts of the thyroglossal duct, and additional thyroid tissue have occasionally been described in asymptomatic patients (1). The prevalence of these latter forms of thyroid dysgenesis among asymptomatic euthyroid subjects is unknown.
We hypothesized that thyroid developmental anomalies (TDA) might also be present in families of patients with CH due to thyroid dysgenesis. Because these anomalies might be totally asymptomatic, they had to be researched by systematic screening, but it was considered that their presence would furnish another argument for a genetic participation in thyroid dysgenesis. Therefore, the aim of this prospective study was to investigate whether an increased incidence of thyroid tract abnormalities could be shown by ultrasonography among first degree relatives of children with CH caused by thyroid dysgenesis, and if so, which genetic model would best fit the data.
Subjects and Methods
Subjects
The study population consisted of first degree relatives of 84 children with CH (23 males, 61 females) who were diagnosed by TSH newborn screening and referred for treatment and follow-up at the Robert Debré Hospital (Paris, France). In all children, elevated TSH levels at screening were confirmed by measurements of serum TSH and FT4 concentrations. Etiological diagnosis with regard to thyroid gland embryogenesis was made on the basis of radioiodine scanning (n = 82), and cases were classified as athyreosis (n = 25), ectopic gland (n = 56), or hemiagenetic gland (n = 1). In case of apparent athyreosis, the absence of any thyroid tissue in the normal location was confirmed by ultrasonography that was performed in 23 of the 25 athyreosis subjects. In two cases, thyroid dysgenesis was diagnosed by ultrasonography showing an absence of thyroid gland in the normal location.
All participants were identified as being the parents (n = 168) or the siblings (n = 90; 45 males and 45 females) of the 84 affected CH subjects. The participation rate was 92% among the parents (n = 155; chronological age, 38.8 ± 8.9 yr) and 96% among the siblings (n = 86; chronological age, 10.4 ± 6.3 yr); a total of 241 individuals participated.
The control population in which asymptomatic TDA was assessed by thyroid ultrasonography consisted of 217 (91 male, 126 female) unselected adults (n = 89; chronological age, 34.5 ± 8.9 yr) and children (n = 128; chronological age, 8.6 ± 5.3 yr), subjects for whom no previous thyroid disorder had been reported. The cohort was recruited through personal contacts of the collaborators of the radiology department.
Methods
Thyroid ultrasonography was performed and interpreted by the same experienced radiologist (C.G.), using the same equipment with a 5–12 MHz linear transducer (ATL, HDI 5000, Philips ultrasound, Bothell, WA). The subjects were examined in the supine position with hyperextended neck. Images were obtained in the transverse and longitudinal planes. The sonogram was evaluated for the following features: presence or absence of the thyroid gland at normal location, presence or absence of the isthmus and each lateral thyroid lobe and their shape, and any additional thyroid tissue. The anterior cervical area was systematically studied for the persistence of part of the thyroglossal duct from the foramen caecum to the normal anatomic position of the thyroid gland and even lower above the sternal manubrium. Any cyst lying along the thyroglossal duct in the base of the tongue besides the hyoid bone was considered to be a thyroglossal cyst even without histopathological proof (4). Each thyroglossal duct cyst was assessed for size, shape, border, and echogenicity. The site was characterized in the relationship to the hyoid bone and the midline. The cystic component of the lesion was always assessed by a posterior enhancement of the echo.
The presence of a pyramidal lobe, which represents the persistence of the caudal portion of the thyroglossal duct, was also assessed. It usually lies in the midline attached to the thyroid gland but can arise from either lobe (more commonly from the left lobe).
When ectopic or additional thyroid tissue was found by ultrasound, radioiodine thyroid scanning (radioactive iodide, 123I) was performed to identify functional thyroid tissue.
Serum TSH and FT4 concentrations were measured in all 241 first degree relatives of CH children. This was carried out by competitive immunoassay based on enhanced luminescence (Bayer Corp., Paris, France).
The study protocol was reviewed and approved by the faculty ethics committee, and written consent was obtained from the parents and adult subjects.
Segregation analysis
Ultrasonography data regarding the presence of TDA were compared for familial and control individuals using the 
2 test.
To determine the most likely mode of inheritance, segregation analysis was performed using the maximum likelihood method as proposed by Morton (5). The model is characterized by a proportion x of sporadic cases (not inherited) and a proportion 1-x of genetically inherited cases with a segregation frequency p. The segregation frequency is the probability of a child being affected in families in which the anomaly segregates. The contribution of each sibship to the likelihood depends on these parameters and also on the probability 
that an affected child is ascertained.
In families with an affected or obligate carrier parent, cases are necessarily genetic cases, and the likelihood of such sibships depends on and p. In families without an affected or carrier parent, the cases are genetic if there is more than one affected child (multiplex sibships). If there is only one affected child (simplex sibships), this isolated case may be either a true sporadic case or a chance isolated case. Therefore, the likelihood of such sibships depends on x, p, and .
In the present analysis, being affected is defined as having any form of the disease, either major forms with CH or asymptomatic forms discovered by ultrasonography. Because only the former cases may be probands and because there is never more than one proband per sibship, the selection was considered as unique, and was arbitrarily set at a low value of 0.01 (5).
The likelihood for the whole sample is computed iteratively, using a priori p and x values, until the maximum likelihood is reached, providing the estimates of p and x.
Results
Among the 241 first degree relatives of the 84 CH patients, 19 individuals (7.9% of cases) had asymptomatic TDA. As shown in Fig. 1
, they belonged to 18 families (21.4%) of the 84 families investigated. One family had two affected members with asymptomatic TDA. This proportion of affected individuals in the nuclear families of CH patients was significantly higher than that seen in the control population, in which only two subjects (0.9%) were found to be affected (P < 0.001).
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In the control population, thyroglossal duct cyst was found in two female subjects aged 26 and 32 yr. The cysts were oval with a diameter of 5 mm and well defined borders, hypoechoic and located in the midline at a suprahyoid level.
Description of family data
Among the 19 subjects with asymptomatic TDA, 21 anomalies were detected with 2 subjects showing 2 different asymptomatic TDA (Fig. 1
). These 21 anomalies included thyroglossal duct cysts (n = 14), additional thyroid tissue with presence of a pyramidal lobe (n = 3), thyroid hemiagenesis (n = 3), and ectopic thyroid tissue (n = 1).
Thyroglossal duct cyst was found in 14 subjects (7 males, 7 females) who were the sibs (n = 6) or the parents (n = 8) of 13 CH children with ectopic thyroid tissue (n = 5), athyreosis (n = 7), or hemiagenesis (n = 1). As shown in Fig. 2, they were seen in a suprahyoid location at the base of the tongue in 11 cases. In three cases, the cyst was located at a position inferior to the hyoid between the hyoid bone and the thyroid cartilage. All cysts were located in the midline except in two patients for whom the location was slightly shifted to the left (at 0.5 cm of the midline in a suprahyoid level and at 1 cm of the midline inferior to the hyoid, respectively). Thyroglossal duct cysts ranged in maximum diameter from 3–18 mm with a mean of 7.0 ± 4.2 mm. They were oval or round (n = 11) in shape or lobulated (n = 3). All revealed well defined borders, and lesions were hypoechoic (n = 9) or anechoic (n = 5). The thyroid gland was normally located in all patients.
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).
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).
Cervical ectopic thyroid gland was found in a 6-yr-old sister of one CH child with athyreosis. Physical examination of this healthy child clinically and biologically euthyroid showed a 2-cm right-sided neck mass situated anteriorly to the thyroid cartilage. It was soft and moved up with swallowing. Ultrasonography demonstrated no evidence of thyroid tissue in the normal location and the presence of ectopic thyroid tissue in the thyro-hyoid region between the hyoid bone and the empty thyroid area that was confirmed by radioiodine thyroid scanning and concordant with the clinical finding (Fig. 4).
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Sex ratio
The male to female ratio for asymptomatic TDA was 0.90 (9 males, 10 females), demonstrating an equal proportion of boys and girls. This differs from the sex ratio seen in CH patients in whom there is a well known female preponderance. Indeed, in the 18 families observed here with both asymptomatic TDA and CH patients, there was a male to female ratio of 0.50 in the CH patients (6 males, 12 females). However, the difference is not significant.
Segregation analysis
Among the families of the CH children, there were 8 families with asymptomatic affected siblings (1 family with 2 cases) and 10 families with asymptomatic affected parents demonstrating both horizontal and vertical transmission. Analysis of the distribution among asymptomatic affected individuals showed a similar proportion of affected parents [10 of the 155 individuals evaluated (6.5%)] and siblings [9 of the 86 individuals evaluated (10.5%)], which favors a dominant mode of inheritance of an allele conferring susceptibility to both TDA and CH, asymptomatic TDA being a minor manifestation and CH a major manifestation of the same allele.
Among the 84 families, only 60 had other children than the proband and could thus be taken into account for segregation analysis. There were no families with two cases of CH. There were 10 families with a parent affected by a minor case (8 families) or an obligate carrier parent (2 families in which mothers of probands were sisters). Among these 10 families, there were no minor cases among the 19 probands’ siblings. The remaining 50 families had no affected or carrier parents and 8 of them were multiplex, with a total of 9 affected children showing a minor anomaly among 67 probands’ siblings. The proportions of affected siblings are not statistically different between the two types of families, and surprisingly are even reversed with respect to expected existence of sporadic cases (not inherited). Indeed, considering that a certain number of sporadic cases might be present, the families without an affected or carrier parent are a mixture of sporadic and genetic cases, whereas families with an affected or carrier parent are all genetic. Therefore, the proportion of affected siblings would be expected to be greater in the latter than in the former cases. This is not what is observed, and this makes the estimation of x converge to the value of 0. The estimate of p is found to be 0.105 (SE 0.033). In addition, these data allow a prediction of the occurrence risk after an isolated case of 10.5% for asymptomatic TDA.
The estimation of the penetrance f (probability that a carrier individual be affected) may be easily obtained, because under a dominant mode of inheritance, the segregation frequency p is equal to f/2. Thus, the estimation of the penetrance is 0.21 (SE 0.066). Thus, the model with the best fit is the dominant inheritance of a susceptibility allele conferring a risk of 21% of asymptomatic TDA in carriers, and no sporadic cases. Because none of the probands were affected with CH, it is not possible to estimate the risk of CH associated with the susceptibility allele, but we can compute the upper limit of the 95% confidence interval. There were 86 siblings, half of whom would be carriers of the susceptibility allele. Using an exact computation of risks with a binomial distribution, we obtained an upper limit of the 95% confidence interval of 0.07. This means, that if the risk of CH was equal to or greater than 0.07, the probability that no affected siblings would be observed would be less than 5%. We can conclude that the risk of CH associated with a carrier status of susceptibility allele is less than 7 per 100.
Discussion
We recently reported that 2% of CH patients with thyroid dysgenesis have a positive familial history among their first degree (72% of the families) or more distant relatives, indicating that the disease has a familial component and there probably exist major genetic factors contributing to the risk of CH (2). The present study demonstrates that among first degree relatives of a CH population with thyroid dysgenesis, there is an elevated rate of asymptomatic TDAs when they are systematically screened for by ultrasound. Our estimates of prevalence of families with both minor forms of TDA and major form with CH (21.4% of our investigated families) are much higher than the proportion of families with at least two affected CH members. It should also be pointed out that even this high proportion may be underestimated because we decided to only evaluate first degree relatives by systematic screening excluding more distant relatives who cannot be examined extensively.
Among asymptomatic affected members, various forms of thyroid dysgenesis without CH have been found that can all be considered to be due to inappropriate development of the thyroid gland. The thyroid gland primordium first appears in the late fourth week in the midline of the floor of the primitive pharynx at a point that is later known as the foramen caecum on the developing tongue. The thyroid primordium descends through the anterior midline of the neck to reach its final position below the thyroid cartilage by the seventh week of embryonic life. During this descent, the developing thyroid gland retains an attachment to the pharynx by a narrow epithelial stalk known as the thyroglossal duct. This duct usually becomes obliterated by the eighth to 10th week of gestation. Normally, the only remnant of the thyroglossal duct is the foramen caecum itself. Occasionally, cell residues may remain, giving rise to a thyroglossal cyst or a pyramidal lobe at the distal portion of the duct that remains attached to the thyroid gland, usually to the left lobe. Other variations represent an arrest in the usual descent of part or all of the thyroid tissue along the normal pathway, and this ectopic thyroid development can result in a lingual, suprahyoid, or infrahyoid location. Finally, developmental failure of all or part of the gland resulting in agenesis or hemiagenesis that may be unilateral or isthmic at a normal location may occur (1, 6). Associations among these anomalies have occasionally been described, such as hemiagenesis accompanying an ectopic gland (7) or a thyroglossal duct cyst (8), or ectopic thyroid with thyroglossal duct cyst (9). Furthermore, familial cases have been reported with asymptomatic forms without CH such as familial thyroglossal duct cysts (10, 11, 12), major forms with CH (2) or both, such as hemiagenesis and either ectopic thyroid tissue or athyreosis in affected members of the same family (13, 14, 15).
The real incidence of these variations in the development of the thyroid gland is unknown, and simple clinical examination in euthyroid subjects is of course not reliable. Ultrasonography of the neck and radioisotope scanning are the only methods to describe these anomalies. Thyroid hemiagenesis and the presence of the pyramidal lobe are usually incidentally discovered in patients with other thyroid disorders when thyroid ultrasound or scintigraphy is performed (16, 17). Only one study has reported a prevalence of thyroid hemiagenesis of 0.2% through a systematic ultrasound investigation of normal children (18). A proportion of ectopic thyroid glands are also found incidentally in asymptomatic patients, which suggests that many are never diagnosed (19, 20). Thyroglossal duct cysts account for approximately 70% of congenital neck abnormalities (21) and were also the most frequent pathological finding in our study. They are usually diagnosed through an asymptomatic neck mass varying in size from 10–30 mm, acute infection, chronic inflammation, or hemorrhage. However, small lesions are not clinically apparent and may also not be diagnosed. The typical sonographic appearance has been described as an anechoic or hypoechoic well circumscribed cyst (4) but heterogeneous lesions have been described (22). Studies of anatomic variations of thyroid gland from people with no known thyroid disease are very scarce. The majority of them are from autopsy series (23, 24, 25, 26). For example, it has been shown in 200 consecutive necropsies on euthyroid Caucasian individuals that 10% of this population showed the presence of ectopic lingual thyroid tissue whose size varied from a few acini (which could not be detected by ultrasonography) to a nodule of 1 cm in diameter with males and females equally affected (23). The sex ratio was also found to be equilibrated in a larger series of symptomatic thyroglossal duct cysts (27, 28). To date, there is no published information on their incidences from diagnosis through systematic screening by ultrasonography, which can be an accurate alternative to evaluate macroscopic lesions.
In our control population, our estimate of prevalence of asymptomatic TDA by ultrasonography seems to indicate about 1% of affected subjects, which is significantly lower than the 7.9% affected first degree relatives of CH patients with various forms of thyroid dysgenesis belonging to 21.4% of the studied families. These observations constitute another major argument supporting the hypothesis that defects in embryogenesis, migration, differentiation, or growth of the thyroid gland during thyroid organogenesis leading to either major forms of TDA with CH or asymptomatic forms could have a common origin. Our results also indicate a higher proportion of asymptomatic TDA as compared with major forms of thyroid dysgenesis because we did not find any major forms through systematic ultrasound diagnosis among affected families, and the nonsporadic nature of thyroid dysgenesis certainly appears to be more likely. A major gene influence with polygenic and/or environmental effects can be evoked. The possible involvement of a sex-modified gene in cases of CH patients with thyroid dysgenesis should also be considered, bearing in mind the female preponderance in CH patients (3) that is not found in asymptomatic TDA populations including that in our study (23, 27, 28). Despite intensive research programs throughout the world, defects of some known genes implicated in the early events of thyroid organogenesis such thyroid transcription factor-1, thyroid transcription factor-2, Pax 8, TSH receptor genes, are only reported in a few cases of sporadic, familial or syndromic cases of CH due to thyroid dysgenesis (29, 30, 31, 32, 33, 34), and other genes unknown so far may be implicated.
Analyses of family data have shown that the transmission is compatible with an autosomal dominant mode of inheritance of the disorder. This unique sample of families including affected members with either asymptomatic or major forms of thyroid dysgenesis with CH also made a segregation analysis possible, demonstrating a low penetrance of the disease at 21% and an absence of sporadic cases. The great majority of affected individuals among carriers of the susceptibility allele would be affected by an asymptomatic form of TDA, the risk of CH being less than 7 per 100. Therefore, it is not surprising that only 2% of families of the total French sample were found to have a positive family history of CH (2), despite our conclusions that all cases of CH would be carriers of the susceptibility allele.
In conclusion, the present study demonstrates a high proportion of asymptomatic TDA among first degree relatives of patients with isolated non-syndromic CH due to thyroid dysgenesis, which supports the hypothesis of a common genetic component of the disorder with heterogeneous phenotypes. The segregation analysis is consistent with an autosomal dominant mode of inheritance with a low penetrance and an occurrence risk after an isolated case of 10.5% for asymptomatic TDA. In the future, identification of genes controlling the early events of the thyroid organogenesis in humans will provide an understanding of the disease, establish phenotype-genotype correlation, and lead to genetic counseling for this type of disorder.
Acknowledgments
We thank Michèle Noël (Laboratory Department, Hôpital Robert Debré, Paris, France) for thyroid hormones dosage.
Footnotes
Abbreviations: CH, Congenital hypothyroidism; TDA, thyroid developmental anomalies.
Received September 14, 2001.
Accepted November 12, 2001.
References
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|
|
|
 |
|
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|
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|
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|
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|
|
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 |
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|
|
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 |
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|
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|
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