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Original Studies |
Pediatric Endocrinology Unit and INSERM, U-457, Hôpital Robert Debré (M.C., M.P., P.C., J.L.), 75019 Paris, France; INSERM, U-393, Hôpital Necker Enfants-Malades (S.L.), Paris, France; and INSERM, U-521, Institut Gustave Roussy (C.B.-P.), 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 boulevard Serurier, 75019 Paris, France. E-mail: juliane.leger{at}rdb.ap-hop-paris.fr
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Abstract |
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We used the French national population-based registry of the first 19-yr screening program, which included 14,416,428 screened neonates with a 100% recovery rate. Familial history of CH with TD was investigated by means of a questionnaire sent to the pediatricians (n = 592) who provided ongoing clinical care for the 4049 CH patients detected during this period, including 2863 CH cases due to TD. Information was obtained from 73% of these pediatricians who were following up 2472 CH patients with TD (86%).
In all, 67 patients with a positive family history of CH with TD were referred, belonging to 32 multiplex families (i.e. including at least 2 affected members). Families were identified with ectopic gland (n = 12), athyreosis (n = 7), or both (n = 13). Comparison of familial with isolated cases showed a similar etiological diagnosis distribution of CH (40% vs. 33% for athyreosis and 60% vs. 67% for ectopic thyroid gland, respectively), whereas a significantly lower predominance of females was found in familial than in isolated cases (1.4 vs. 2.7; P < 0.03). Extrathyroidal congenital malformations were found with a similarly higher incidence in familial and isolated CH populations compared with the general population (respectively, 9% and 8.2% vs. 2.5%).
In conclusion, although familial cases represent a minority of cases of congenital hypothyroidism caused by thyroid dysgenesis, they were observed in a significantly higher proportion (>15-fold) than would be expected from chance alone. This familial clustering, including athyreosis and ectopic thyroid gland, strongly suggests that genetic factors could be involved in thyroid dysgenesis with a common underlying mechanism for both etiological groups. Moreover, the high proportion of extrathyroidal congenital malformations in a population affected by CH due to TD suggests that the potential genetic factors involved in thyroid gland organogenesis are also involved in the development of other organs.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The pathogenesis of thyroid dysgenesis is as yet unknown, and the disease is usually regarded as sporadic with a female predominance (2). Possible roles of autoimmune (3, 4, 5) or unidentified environmental factors (6) have been suggested, but not confirmed. Epidemiological studies have shown a lower incidence of the disease in African American infants (7) and a higher prevalence of extrathyroidal congenital anomalies among infants with CH compared with the general population (8, 9, 10, 11, 12). These arguments are in favor of a possible genetic component.
Furthermore, some familial cases of CH caused by thyroid dysgenesis have been reported with either athyreosis (13, 14, 15, 16, 17) or ectopic gland in affected members (18, 19, 20, 21, 22). We recently reported a significant important proportion of familial cases of congenital hypothyroidism due to thyroid dysgenesis (2%), affirming the existence of a strong familial component in CH due to TD (23). Recent data from knockout mice have demonstrated the roles of several genes in thyroid organogenesis [thyroid-specific transcription factors (TTF-1 and TTF-2), Pax 8, and TSH receptor], and their impairment has been occasionally reported in CH cases (24, 25, 26, 27, 28, 29, 30). Taken together, these observations indicate that genetic factors contribute to the development of thyroid dysgenesis.
The aim of this study was to describe the clinical characteristics of familial forms of CH with TD and to compare them with those of sporadic cases based on a population screened from the beginning of the neonatal systematic screening program in France.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sex distribution was ascertained in all screened cases. Existence of associated extrathyroidal congenital malformations was only determined during the last 6 yr of the screening program, thus concerning 1345 CH patients, as this information base has only been included in the standardized birth registration form since 1994. Among these 1345 subjects, after exclusion of normally sited gland (n = 348 cases) and nonclassified forms (n = 97 cases), 901 patients (67%) were found to have thyroid dysgenesis.
Familial cases of congenital hypothyroidism due to TD
Familial history of CH caused by thyroid dysgenesis was investigated by means of a questionnaire sent to all pediatricians (n = 592) who provided ongoing clinical care for the CH patients detected by the French screening network. Seventy-three percent of the pediatricians (n = 435) responded. They were responsible for 2472 CH patients with TD, thus representing 86% of the total number of CH due to TD cases diagnosed from the start of the systematic screening program. Of these cases, 817 showed athyreosis, and 1655 showed ectopic thyroid tissue.
Details concerning etiological diagnosis (chemical, ultrasound, and scintiscan) of CH, associated malformations (if any), and family pedigree were requested. In 81% of the cases, scintigraphic and ultrasonographic recordings were then reread by a single radiologist to assess the quality of etiological diagnosis. In cases of apparent athyreosis, the absence of any thyroid tissue in the normal location was confirmed in doubtful cases by a recent ultrasound scan.
The study was approved by the faculty ethics committee, and participants (or their parents in the cases of children) provided informed consent.
Statistical analysis
The number of isolated (nonfamilial) cases was assessed from the
CH-screened population covered by the participating pediatricians,
familial cases excluded. As the number of relatives could only be
assessed in familial cases and not in isolated (nonfamilial) cases, it
was not possible to estimate the frequency of CH due to TD among
relatives of all screened cases. However, we could compare the observed
proportion of familial cases with the expected proportion (Pe) of cases
due to chance alone if the disease was only sporadic, restricting the
family to first degree relatives. Assuming an average number of 3 first
degree relatives (2 parents and 1 sibling) per family, we can calculate
the expected proportion (Pe) of cases with at least one affected first
degree relative (I being the incidence of CH by TD in the general
population, i.e. 1/5035): Pe = 1 - (1 -
I)3. The expected number (Ne) of familial cases
was derived from the total number (N) of CH due to TD and the expected
proportion (Pe) of familial cases: Ne = N x Pe. The observed
number was compared with the expected number of cases with a positive
familial history among first degree relatives using a Poisson
distribution. Etiological diagnosis, sex distribution, and associated
extrathyroidal congenital malformations were compared in familial and
isolated cases of CH with TD using the 
2
test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The participating pediatricians referred a total of 67 patients with a positive family history of CH due to TD belonging to 32 multiplex families (i.e. with at least two affected members).
As shown in Fig. 1
, most familial cases
were seen in families with 2 affected members (n = 30). Two
families had 3 or 4 affected members. Among first degree relatives
(n = 23), both horizontal and vertical transmissions were
observed; there were 13 families with affected siblings, and 10
families with affected parents and offspring (Fig. 1A). The affected
members in the other 9 families had more distant relationships,
i.e. first cousins in 6 families, second cousins in 1
family, and more distantly relationships in 2 families (Fig. 1B).
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Among the 67 patients affected by CH due to TD identified in these 32
families, 38 subjects had ectopic thyroid gland (57%), and 29 subjects
had athyreosis (43%). Etiological diagnosis was ascertained by
scintigraphy in all patients, and ultrasound examination of the thyroid
area was assessed in 21 of the 29 subjects (72%) with athyreosis to
confirm the absence of thyroid tissue. Families were identified with
ectopic gland (n = 12 families), athyreosis (n = 7), or both
(n = 13). Moreover, in the latter group, 2 families presented CH
members with a normally sited and sized gland (these CH patients were
not included among the 67 CH patients with TD; Fig. 1A
).
Comparative analysis of etiological diagnosis and sex distribution in familial vs. isolated cases of CH due to TD born during the period 1980–1998
Of the 67 familial cases, 48 patients were born after the start of the French generalized screening program, and 19 were born before the start of the program. Thus, the number of isolated cases of CH due to TD screened since the start of the systematic program and covered by the participating pediatricians was 2424 (i.e. Ni = 2472 - 48).
Etiological diagnosis distribution
Among the 2424 isolated CH cases, 798 had athyreosis (33%), and 1626 had ectopic thyroid gland (67%). Among the 48 CH familial cases born after the start of the screening program, 29 subjects had ectopic thyroid gland (60%), and 19 subjects had athyreosis (40%). An analysis of the etiological diagnosis distribution showed that similar proportions of patients were affected by athyreosis and ectopic thyroid gland for the familial case and the isolated case groups.
Sex distribution
The sex distribution was ascertained in the 48 familial cases and in the 2424 isolated CH cases. The female/male ratio was significantly lower in familial compared with isolated cases (1.4 vs. 2.7; P < 0.03). According to the etiological diagnosis of thyroid dysgenesis, a slightly lower proportion (non significant) of females was observed in familial cases compared with isolated cases of CH with ectopic thyroid gland (1.9 vs. 2.8), whereas in CH with athyreosis the female/male ratio was significantly reduced in familial compared with isolated cases (0.9 vs. 2.7; P < 0.02). In familial cases of CH caused by athyreosis, equal proportions of girls and boys were seen.
Extrathyroidal congenital malformations in isolated and familial cases
Extrathyroidal congenital malformations were ascertained in 901
patients affected by CH due to TD screened during the last 6-yr period.
After exclusion of familial cases (n = 14) and CH patients for
whom the information was missing (n = 206), 56 of 681 isolated CH
patients were found to have extrathyroidal congenital malformations
(8.2%). A similar proportion of associated malformations was
observed in both etiological groups, i.e. the 18 patients
with athyreosis and the 38 patients with ectopic thyroid tissue (Table 1). Details of associated malformations
were noted in 36 isolated CH cases (64%). A significant proportion of
cardiac congenital malformations (n = 16; 28%) and facial
abnormalities (n = 9; 16%) were observed. The other abnormalities
affected various organs, such as genito-urological, neural, and
digestive systems. Of the 67 CH patients with familial history, 6
showed associated congenital malformations (9%). Bilateral chondroma
of the external auditory canal was observed in 3 children with CH due
to ectopic gland, belonging to 2 different families. Cleft palate was
found in 2 affected brothers with athyreosis, and uterus agenesis was
seen in 1 girl with athyreosis, belonging to a family with 2 affected
members; the other had ectopic thyroid gland. As shown in Table 1,
similar proportions of extrathyroidal associated congenital
malformations were found in familial and isolated CH cases due to TD
(respectively, 9% vs. 8.2%), with a similar distribution
in each etiological group.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As all relatives of all CH-affected patients could not be assessed, it was not possible to perform a segregation analysis to determine the most likely mode of inheritance. However, according to the hypothesis of genetic homogeneity (only one mode of transmission in all affected families) and considering the frequency of the disease, the high proportion of transmissions from parent to offspring makes a dominant mode more likely than a recessive one. Under the latter hypothesis of dominant inheritance, the penetrance of the trait would necessarily be incomplete, because a high proportion of families display several affected siblings with no affected parent or affected distant relatives, and autosomic transmission could be supported by father to son transmission (n = 2). Thus, in the most significant pedigrees, the transmission pattern could be compatible with an autosomal dominant mode of inheritance with incomplete penetrance. However, these transmission patterns could also result from genetic heterogeneity.
Comparative analysis of familial and isolated cases of CH due to TD shows a similar distribution of etiological diagnosis. In the families investigated here, CH was linked with athyreosis, ectopic thyroid gland, or (reported here for the first time) both athyreosis and ectopic thyroid gland. It is generally accepted that thyroid scintigraphy provides the most accurate means of determining the cause of CH. Using thyroid scintigraphy, isotope uptake can identify ectopic functional thyroid tissue with little chance of misdiagnosis. However, the absence of any detectable thyroid tissue could be due to true athyreosis, but could also be related to apparent athyreosis in patients with severe TSH resistance due to complete loss of TSH receptor function. In these cases, there may be no iodine uptake even when the ultrasonography shows a hypoplastic thyroid gland (28). It is also possible that extremely small ectopic thyroid glands are not visible even with excellent thyroid scintigraphy. It thus remains possible that a certain degree of misclassification might exist, and to make an accurate diagnosis of athyreosis, it is important to obtain a good thyroid scan and ultrasonography definition. Undetectable serum thyroglobulin levels in CH patients may provide an additional clue in athyreosis cases (33, 34). However, in this study, patients with familial history were already undergoing treatment with L-T4; therefore, serum thyroglobulin measurement was of no use. All patients underwent thyroid radioisotopic scanning, and the ultrasonography recordings from familial cases with athyreosis were analyzed by a single pediatric radiologist in most cases (72%). This led us to reclassify and exclude two affected patients belonging to the same family who presented apparent athyreosis on scintigraphy and showed eutopic hypoplastic thyroid gland on ultrasound scan. Furthermore, eutopic thyroid gland with hypothyroidism was observed in our study in two families in which at least two other members were affected by either athyreosis or ectopic gland. Moreover, thyroid hemiagenesis and lingual thyroid gland, most often reported in euthyroid subjects, has been previously reported in families whose affected members showed CH caused by ectopic thyroid gland (21, 35). In this study we excluded families with at least two members affected with these latter forms of TD because the prevalence of lingual thyroid or hemiagenesis among asymptomatic euthyroid patients was unknown (36). Taken together, these observations support the hypothesis that a common underlying mechanism might lie behind the defects in embryogenetic migration, differentiation, or growth of the thyroid gland during organogenesis, leading to ectopic, athyreosis, or eutopic thyroid gland.
The female preponderance over males for isolated CH was similar for patients with athyreosis or an ectopic thyroid gland. Our results in this large series of 2424 patients are different from those reported in a Quebec population in which the sex ratio was equal in 36 isolated athyreosis patients (8). However, in our study a significantly lower proportion of girls was observed in familial cases of CH due to TD compared with isolated cases. Why a female predominance exists in isolated CH cases remains unclear, but our results suggest the possible involvement of sex-modified etiological factors in familial cases, perhaps more so in cases of athyreosis.
That genetic factors may be involved in the pathogenesis of the disease is supported by recent studies showing that defects of at least three thyroid-specific transcription factors (TTF-1, TTF-2, and Pax 8) may be responsible for CH caused by TD. TTF-1 gene inactivation in mice has led to the total absence of thyroid gland and severe defects of the lung and forebrain, indicating a critical role for this factor in early events of organogenesis (25). TTF-2 gene inactivation revealed that this factor is required for the downward migration of the thyroid gland as well as for palate enclosure. TTF-2 knockout mice showed either athyreosis or ectopic gland associated with cleft palate (27). This observation supported the hypothesis that ectopic thyroid gland and athyreosis have a common underlying mechanism. Pax 8 knockout mice demonstrated a smaller thyroid gland than control animals, with complete absence of follicular structures (30). Despite several research programs throughout the world, only a few cases of CH in humans have been associated with defects in these genes, and the actual proportion is still unknown (26, 29, 37, 38, 39, 40). The familial clustering described in our series suggests the potential involvement of genetic factors, potentially including other genes, that are as yet unknown.
The significantly higher incidence of extrathyroidal congenital malformations in the CH population than in the general population constitutes a further argument supporting the involvement of genetic factors (8, 9, 10, 11, 12). The results from this large series of CH patients is in agreement with this finding, showing an incidence of 8.2% of additional congenital malformations compared with 2.5% in the general French population (41). As suggested in some previous studies, this higher proportion is similar in isolated CH cases due to ectopic thyroid gland and in cases with athyreosis (8, 10, 11). Cardiac and facial malformations were the most frequent extrathyroidal malformations observed in our study population. These associated malformations were from embryological or anatomical areas adjacent to the embryonic thyroid gland, suggesting that one or several factors may have simultaneously affected several adjacent organs during development.
A similarly higher percentage of associated malformations was seen in the 67 familial cases of CH due to TD (9%). However, these malformations were somewhat different from those previously described, including uterus agenesis associated with athyreosis and bilateral chondroma of the external auditory canal in 2 families with members showing ectopic thyroid gland (malformations described here for the first time). As previously reported in 2 affected members of 1 family showing athyreosis and homozygous TTF-2 gene mutation (26), cleft palate was also seen in our study in 2 brothers with athyreosis. Moreover, cleft palate was associated with either athyreosis (n = 1) or ectopic thyroid gland (n = 1) in isolated CH cases (8, 10, 12), supporting the hypothesis that the TTF-2 gene is involved in both development of thyroid gland and palate enclosure in humans.
In conclusion, this study demonstrates that although familial cases represent a minority of cases of congenital hypothyroidism caused by thyroid dysgenesis, they are unexpectedly observed in a significantly higher proportion than would be expected from chance alone, thus suggesting a familial component. Families identified with both athyreosis and ectopic thyroid gland suggest a common underlying mechanism for both etiological groups. Comparison of familial and isolated cases of CH due to TD shows a similar distribution of etiological diagnosis, but a significantly smaller predominance of females in familial than in isolated cases. Moreover, a higher incidence of extrathyroidal congenital malformations was found among both familial and isolated cases than in the general population. Although common unidentified environmental factors cannot be totally ruled out, these reports suggest the potential existence of genetic factors involved in thyroid dysgenesis that might be controlled by sex-modified factors and be implicated in the development of several organs. Further genetic studies must be performed to confirm this hypothesis.
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Acknowledgments |
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Footnotes |
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Received September 9, 2000.
Revised October 25, 2000.
Revised December 4, 2000.
Accepted February 7, 2001.
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,
Affected CH individuals by TD due to either ectopic thyroid gland (E)
or athyreosis (A). 
and 
, CH patients with normally sited
thyroid. 
and 
, Nonaffected patients.