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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 3 1212-1216
Copyright © 2003 by The Endocrine Society

Additional Phenotypic Abnormalities with Presence of Cysts within the Empty Thyroid Area in Patients with Congenital Hypothyroidism with Thyroid Dysgenesis

Daniella Marinovic, Catherine Garel, Paul Czernichow and Juliane Léger

Pediatric Endocrinology Unit and Institut National de la Santé et de la Recherche Médicale, U-457 (D.M., P.C., J.L.), and Radiology Department (C.G.), Hôpital Robert Debré, 75019 Paris, France

Address all correspondence and requests for reprints to: Juliane Léger, M.D., Pediatric Endocrinology Unit and INSERM, U-457, Hôpital Robert Debré, 48 boulevard Serurier, 75019 Paris, France. E-mail: juliane.leger{at}rdb.ap-hop-paris.fr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Congenital hypothyroidism (CH) is most frequently caused by thyroid developmental abnormalities, and it has recently been shown to have a familial component with members affected by either CH or asymptomatic thyroid developmental abnormalities. The pathogenesis of the disease is unknown, but it seems possible that a common genetic mechanism underlies these heterogeneous phenotypic expressions. Associations among these anomalies in the same individuals have occasionally been described. The aim of this study was to investigate whether cysts of the thyroglossal duct could be shown by ultrasonography in patients with CH caused by thyroid dysgenesis.

Children with CH (n = 57) who were diagnosed by newborn TSH screening were prospectively evaluated by ultrasonography at the age of 10.5 ± 4.5 yr. The etiology of CH (ectopic thyroid tissue, n = 42; athyreosis, n = 15) was established before treatment initiation on the basis of thyroid radioiodine scanning and the absence of any thyroid tissue in the normal location confirmed by ultrasonography. Cysts were found in 39 patients (68% of cases) with either ectopic thyroid tissue (n = 29) or athyreosis (n = 10). All cysts were located in the empty thyroid area in the left (57%) or right (43%) side and were mostly closer to the midline. Patients had either a single cyst (n = 16 patients) or multiple cysts (n = 23 patients). The cysts were bilateral in 17 of the 39 patients. Most of them were vertically oval or round, with a size ranging in diameter from 2–21 mm (mean, 3.5 ± 2).

In conclusion, the presence of cysts within the empty thyroid area in 68% of patients with CH due to thyroid dysgenesis is a novel observation that is part of the developmental anomaly of this disease. Several explanations can be put forward to explain the presence of these cysts. They might be due to the persistence of the ultimobranchial bodies as a cystic structure or part of the thyroid-forming material, which may migrate along the normal pathway of the usual course of the thyroglossal duct, giving rise to cell residues within the empty thyroid area.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONGENITAL HYPOTHYROIDISM (CH) caused by developmental anomalies of the thyroid gland (ectopic thyroid tissue or athyreosis) account for 85% of CH cases, with an incidence of 1 in 5000 live births. The pathogenesis of the disease is unknown, and genetic factors might be involved (1). Indeed, we have recently reported a familial component of the disease (2% of cases), with families having at least two affected members with CH with athyreosis, ectopic thyroid tissue, or both (2). Moreover, we have also shown that among first degree relatives of a CH population with thyroid dysgenesis, there is an elevated rate of asymptomatic thyroid developmental anomalies even in euthyroid subjects (8% of cases) when they are systematically screened by ultrasound. These thyroid developmental anomalies include cysts of the thyroglossal duct, thyroid hemiagenesis, additional thyroid tissue with the presence of a pyramidal lobe, and ectopic thyroid tissue (3). These observations support the hypothesis that all thyroid developmental defects (whether they lead to CH or not) have a common genetic basis. The association of several thyroid developmental defects in the same individual has occasionally been described (4, 5, 6).

The aim of this study was to investigate whether cysts of the thyroglossal duct could be shown by ultrasonography among patients with CH caused by thyroid dysgenesis. The precise phenotypic characterization of such patients will provide information to better understand the mechanisms of thyroid developmental anomalies.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
All children (n = 57; aged at least 2.5 yr) diagnosed with CH due to thyroid dysgenesis by newborn TSH screening and followed by one of us (J.L.) were included. The mean chronological age at the time of the study was 10.5 ± 4.5 yr (range, 2.7–21.5 yr). The diagnosis of CH was made during the neonatal period at the age of 17 ± 8 d by clinical evaluation and measurements of serum TSH, free T4 (FT4), and free T3 (FT3). The etiological diagnosis was established before treatment initiation based on thyroid radioiodine scanning (123I), and patients were classified as having ectopic thyroid tissue (n = 42; 36 females and 6 males) or athyreosis (n = 15; 10 females and 5 males). In cases of apparent athyreosis, the absence of any thyroid tissue in the normal location was confirmed by ultrasonography. The characteristics of the patients at diagnosis and at the time of the study are shown in Table 1Go. At the time of diagnosis, therapy was started with 8.2 ± 1.4 µg/kg·d L-T4, and the dose was modified thereafter according to clinical evaluation and serum TSH and FT4 levels, which were measured two or three times a year from the age of 6 months onward. The L-T4 dose was adjusted to maintain serum FT4 concentrations in the upper half of the normal range for age and TSH levels suppressed in the normal range. During follow-up (data not shown) and at the time of the study (Table 1Go), no significant differences were noted for either serum thyroid hormone levels or L-T4 dosage among the patients with ectopic thyroid tissue or athyreosis. Quality of treatment was assessed by the number of serum TSH values 10 mIU/liter or greater during follow-up from the age of 6 months onward. On that basis, patients were classified into three groups (group A, no evaluation with serum TSH value >=10 mIU/liter; group B, one or two TSH values >=10 mIU/liter; group C, at least three evaluations with TSH values >=10 mIU/liter; none of the patients had more than five TSH values >=10 mIU/liter).


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  		Table 1. Characteristics of 57 children with CH due to thyroid dysgenesis at diagnosis and at the time of the study with respect to etiological diagnosis: ectopic thyroid tissue (n = 42) and athyreosis (n = 15)

 
Four patients (one with athyreosis and three with ectopic thyroid tissue) had other congenital malformations (cardiac, n = 1; bilateral chondroma of the external auditory canal, n = 2) or chronic disease (neurological, n = 1). Fifteen patients showed a familial form of thyroid developmental anomalies with either familial cases of CH (n = 3, including one family with two cases) or with asymptomatic thyroid developmental anomalies (n = 12) among their first degree relatives in whom thyroglossal duct cyst (n = 9), thyroid hemiagenesis (n = 2), or additional thyroid tissue with presence of a pyramidal lobe (n = 1) were detected by systematic ultrasonography (3).

At the time of the study and in addition to the ultrasonography determination, patients were evaluated as usual for clinical status, L-T4 replacement dosage, and thyroid hormone levels.

Thyroid ultrasonography was performed and interpreted by the same experienced radiologist (C.G.), who was not aware of the etiological diagnosis and who used the same equipment with a 5- to 12-MHz linear transducer (ATL, HDI 5000, Philips Ultrasound, Bothell, WA). The subjects were examined in the supine position with the neck hyperextended. Images were obtained in the transverse and longitudinal planes. The anterior cervical area was systematically studied for absence of thyroid tissue in the normal location (empty thyroid area) and for detecting cysts along the normal pathway of the thyroglossal duct from the foramen cecum to the empty thyroid area and even lower above the sternal manubrium. Any cyst lying in this area was assessed for size and shape. The location of the cyst was also defined in relation to the hyoid bone and the midline. A structure was considered to be a cyst (>=2 mm) if it was hypo- or anechoic compared with the neck muscles, with a posterior enhancement of the echo and without any vascularization inside using a Doppler examination (which ruled out the presence of lymph nodes).

Serum TSH and FT4 concentrations were measured by competitive immunoassay based on enhanced luminescence (Bayer Corp., Paris, France).

Informed consent was obtained from the parents and patients.

Statistical analysis

Results were expressed as the mean ± SD. Mann-Whitney U and {chi}2 tests were performed for comparisons between groups. Repeated measures ANOVAs were performed to determine the patterns of thyroid hormone levels and L-T4 dose among etiological groups.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Among 57 patients treated for CH due to thyroid dysgenesis, 39 (68% of cases) had 1 or several cysts within the empty thyroid area. These cysts were not detected anywhere else along the path of normal migration of the median thyroid anlage. In all patients, the empty thyroid area contained two structures on both sides of the trachea, each measuring, on the average, 5 x 5 mm, isoechoic compared with the sc fat and presenting with a marked hyperechogenicity compared with the muscles (Fig. 1Go). None of the patients classified as having athyreosis at diagnosis showed any thyroid tissue by ultrasonography.



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  		Figure 1. Cervical ultrasonography of a child with a normal thyroid gland (A) and of children treated since the neonatal period for CH due to thyroid dysgenesis (B–D). A, Normal thyroid gland in a 7-yr-old child (transverse slice). The thyroid gland is hyperechoic compared with the superficial cervical muscles. It is hypoechoic compared with the sc fat. The vessels (carotid artery and jugular vein) are clearly depicted, externally to the thyroid gland. B, Empty thyroid area in a 9-yr-old girl treated for CH due to ectopic thyroid tissue (transverse slice). No thyroid tissue can be detected within the thyroid area. The thyroid area contains small hyperechogenic masses located on both sides of the trachea, which have the same echogenicity as the sc fat and are hyperechoic compared with superficial cervical muscles. These structures are approximately 5 mm wide and have the same size as the thyroid gland of a neonate. The trachea appears huge compared with the thyroid area. C, Cyst in the thyroid area in a 15-yr-old girl treated for CH due to athyreosis (transverse slice). The cyst is located in the right part of the empty thyroid area at the medium part of the hyperechoic structure. It is round and anechoic, with a posterior enhancement of the echoes and a vertical diameter of 15 mm. D, Cysts in the empty thyroid area in a 9-yr-old boy treated for CH with ectopic thyroid tissue (longitudinal slice). The cysts are vertically oriented as a string of beads. 1, Trachea; 2, empty thyroid area; 3, carotid artery; 4, superficial cervical muscles; 5, esophagus; 6, jugular vein; 7, thyroid gland; *, cyst.

 
The cysts were either single (n = 16 patients; Fig. 1CGo) or multiple (n = 23 patients) with 2 (n = 12), 3 (n = 5), 4 (n = 4), or 5 cysts (n = 2). They were located in the thyroid area on the left (57%) or right (43%) sides and were generally closer to the midline as their locations were mostly at the internal (15%) and medium (68%) parts of each lateral hyperechogenic structure on both sides of the trachea, with 17% of them externally located. The cysts were bilateral in 17 of the 39 patients (44%). Their sizes ranged in maximum diameter from 2–21 mm with a mean of 3.5 ± 2 mm. Among these 81 cysts, most of them were oval with a vertical axis (n = 53; 65% of the cysts). The others were round (n = 27), and 1 cyst was multilobulated. Some of the multiple cysts were disposed as a string of beads (in 15 patients, including 37 cysts with a mean vertical diameter of 10.3 ± 5 mm; Fig. 1DGo). All of them consisted of an anechoic, well circumscribed cyst.

As shown in Table 2Go, the patients with or without cysts in the thyroid area did not differ significantly with respect to sex ratio, etiological diagnosis (ectopic thyroid tissue vs. athyreosis), quality of treatment either at the time of the study or during follow-up from the age of 6 months onward (as evaluated by the number of episodes of insufficiently suppressed serum TSH levels), family history, and age at the time of the study (chronological age, 9.9 ± 4.6 and 11.7 ± 4.1 yr in patients with and without cysts, respectively).


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  		Table 2. Relation between the presence of cyst within the empty thyroid area and variables including sex, etiological diagnosis, quality of treatment, and whether or not the patient belonged to a familial form of thyroid dysgenesis

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrates the presence of cysts within the empty thyroid area in 68% of patients with CH due to thyroid dysgenesis. These cysts were found in treated CH patients who had either ectopic thyroid tissue or athyreosis and were not related to the age of the patients, the quality of treatment, as evaluated by the number of episodes of insufficiently suppressed serum TSH levels, or the presence or absence of a family history of symptomatic or asymptomatic thyroid developmental anomalies.

The presence of cysts has occasionally been described in patients with thyroid dysgenesis. Anatomical study of three deceased children with CH due to athyreosis has shown small cysts (unilateral in one and bilateral in the other two cases) located on both sides of the trachea closed to the parathyroid glands (7, 8). The latter, originating from the third and fourth pharyngeal pouches, are known to be in the lateral periphery of the thyroid gland separated from it by the thyroid capsule. In adult autopsy series in cases in which thyroid tissue was totally lingual in location, cystic structures were also described in the neck near the upper parathyroid glands in five of seven cases (9). Finally, two patients with CH due to a Pax8 mutation have been recently reported with severe thyroid hypoplasia and cystic thyroid rudiments demonstrated by ultrasonography (10, 11).

Ultrasonography has been previously used as a noninvasive diagnostic imaging tool to determine the presence or absence of the thyroid gland in its normal location. It was not found to be reliable for detecting ectopic thyroid tissue and thus for differentiating ectopic tissue from athyreosis, and radionuclide scanning remains the best diagnostic modality for this purpose (12, 13, 14, 15, 16, 17, 18, 19). However, ultrasonography correctly establishes whether thyroid tissue is present in its normal location. In addition, it can determine that there is no thyroid tissue in the normal site and, as we found in our study, the thyroid area contains small hyperechogenic masses located laterally on both side of the trachea. They clearly differ from thyroid tissue because they are smaller than the normal thyroid lobes and, more importantly, have a marked hyperechogenicity (12, 17). Normal thyroid tissue is more echogenic than the muscles, but is less hyperechogenic than these structures and less echogenic compared with sc fat. Although the normal thyroid gland increases in size during childhood, in this study the volume of these structures was not related to the age at which the patients were investigated, and we can assume that the volume remains small and stable throughout childhood. Chanoine et al. (17) suggested that these structures could represent remnants of the ultimobranchial bodies, which are known to contain the calcitonin-secreting cells. To our knowledge, these previous studies did not show any cysts within the thyroid area. An explanation for that would be the higher sensitivity of our current equipment used for ultrasonography and that it was the aim of our study to systematically screen for cysts in this area.

These cysts within the normal thyroid area may result from the persistence of ultimobranchial bodies as a cystic structure. They might also be due to the persistence of the thyroglossal duct, with some cells of part of the thyroid forming material migrating along the normal pathway of the usual course of the thyroglossal duct within the thyroid area. Both hypotheses might also be valid and not mutually exclusive, as these cysts were found to contain cells staining for calcitonin and others staining for thyroglobulin (9). The contribution of the ultimobranchial body to both calcitonin and follicular cells of the thyroid gland has been hypothesized, but not confirmed in all studies (9, 20, 21).

The thyroid gland primordium develops as a midline endodermal invagination of the foramen cecum of the tongue and 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 8–10 wk gestation. At any point along the migratory path followed by the thyroid gland, epithelial cells can persist and fail to involute, causing the formation of a minor thyroid developmental anomaly such as a thyroglossal duct cyst or a pyramidal lobe, commonly attached to the left lobe of the thyroid gland (22). Thyroglossal duct cysts may have a suprahyoid, infrahyoid, or thyroid location. As in our study, it may be variable in size, well circumscribed, oval, round, or even bilobed (23, 24, 25). They are typically present as midline masses, but may be in a more lateral location, within 2 cm of the midline, with a tendency for the lesion to be more often to the left than to the right, which is in keeping with the location of the pyramidal lobe (23). In addition, as seen in some cases in our study, there may be more than one cyst present, located one above the other (26). Ectopic or maldescended thyroid tissue are not as uncommon, because lingual thyroid tissue has been demonstrated in 10% of autopsy subjects who had a thyroid gland in a normal location (27). More recently, nontumoral ectopic lingual thyroid has been reported in a patient treated for papillary cancer arising from an orthotopic thyroid in a normal location (28). Moreover, ectopic thyroid tissues can be present simultaneously at two sites (29).

Thyroid dysgenesis is a very heterogeneous condition. The mechanism of the disease is still unknown, but we have demonstrated by familial observations that a genetic component of the disorder might be hypothesized to explain the various forms of thyroid dysgenesis (3). Although thyroid radioisotope scanning and ultrasonography may fail to detect any thyroid tissue, serum thyroglobulin is not always undetectable in cases of so-called apparent athyreosis (15), suggesting that thyroid cell residues might be present, but cannot be detected by our current imaging modalities. Moreover, even when ectopic thyroid tissue is identified, this does not rule out the presence of thyroid cells in other locations (27, 28, 29). The ultimobranchial cells, which cannot be detected by ultrasonography in normal subjects, are usually located externally and posteriorly within the thyroid gland at the point of fusion between the median anlage and the ultimobranchial body, between the two parathyroid glands (30, 31). However, they can also be found throughout the thyroid lobes, but not in the isthmus (32). In our study the cysts were mostly found close to the midline, and this supports the hypothesis of the persistence of the distal end of the thyroglossal duct within the thyroid area. We should also be aware that the thyroid may harbor other tissues, as totally intrathyroid parathyroid as well as thymic tissue, which arise from the third pharyngeal pouch and are normally located inferior and ventral to the thyroid gland, have occasionally been identified in autopsied subjects (33).

Nevertheless, the thyroid gland develops from two distinct embryological origins: T4-producing follicular cells and parafollicular calcitonin-producing C cells derived from endodermal and neural crests, respectively. The latter constitute the minor component of the normal thyroid and are suggested to be less functional in cases of human congenital hypothyroidism with thyroid dysgenesis (17). Little is known about the molecular mechanisms that control the development of these different cell types. Mice lacking the thyroid transcription factor TTF1 lack both cell types. By contrast, newborn Pax8-/- mice show normal C cells, but no follicular cells can be detected (34). Furthermore, it has been shown in mice that the Eya 1 gene is required for normal fusion between ultimobranchial bodies and thyroid lobe (21).

In conclusion, 68% of children with thyroid dysgenesis had one or several cysts within the thyroid area. The exact nature of these cysts can only be established by histological examination, which would be unjustified in these patients. These findings could suggest cysts developing within the ultimobranchial bodies. However, because of their location close to the midline and along the distal part of the path of descent of the median anlage and because cysts are extremely rare in children with normal thyroid gland (35, 36), we suggest that they may also result from cystic degeneration of clusters of thyroid follicular cells that have completed their normal migration even if thyroid tissue has remained incompletely descended or the thyroid has disappeared entirely.


   Acknowledgments
 
We acknowledge the invaluable contribution of Prof. Guy Van Vliet (Sainte Justine Hospital, Montréal, Canada) in discussing and reviewing the manuscript.


   Footnotes
 
Abbreviations: CH, Congenital hypothyroidism; FT3, free T3; FT4, free T4.

Received September 23, 2002.

Accepted November 26, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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