Random variability in congenital hypothyroidism from thyroid dysgenesis over 16 years in Québec

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.     

Accuracy of ultrasonography to establish the diagnosis and aetiology of permanent primary congenital hypothyroidism

OBJECTIVE: To compare ultrasonography and 99mTc thyroid scintigraphy for the aetiologic diagnosis of permanent congenital hypothyroidism (CH). STUDY DESIGN: Eighty-eight consecutive patients with CH were recruited at an endocrinology outpatient clinic and submitted to high-frequency ultrasonography and to 99mTc scintigraphy. RESULTS: Seventy-six patients were diagnosed with permanent CH and 12 with transitory CH. The agreement between ultrasound and scintigraphy was very high (kappa coefficient = 0.866; P < 0.001) for the entire group. In permanent CH patients, ultrasonography identified 67 cases of dysgenesis (absence of thyroid gland in the usual anatomical location in 66 and hemiagenesis in one), and this diagnosis was confirmed by scintigraphy (absence of functional thyroid tissue in 43 and ectopia in 24). In the other nine permanent CH patients, the thyroid was in the usual anatomical location on ultrasonography but scintigraphy did not identify functional tissue in one patient. In the 12 transitory CH patients, a normally shaped thyroid was detected by ultrasound in the usual location, whereas scintigraphy showed absence of functional tissue in two identical twins and scarce concentration of isotope in a third patient. CONCLUSION: Ultrasonography is an accurate method to establish the presence of dysgenesis and might be used as the first imaging tool in patients with CH, whereas scintigraphy should be used mainly to distinguish agenesis from ectopia. Further examination is required to differentiate permanent CH with a normally located and shaped gland from transitory hypothyroidism.     

Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors

Although a few familial forms of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD) have been reported, this disorder is usually considered to be sporadic. Recently, we reported that 2% of CH patients with TD have a positive familial history. The aim of this study was to describe the clinical characteristics of these familial cases and to compare them with sporadic cases. 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.     

Developmental defects of the thyroid gland: relationship with advanced maternal age

Objective: Developmental defects of the thyroid gland are the most frequent causes of permanent congenital hypothyroidism. This study aimed to investigate the epidemiological features of patients with thyroid dysgenesis (TD).Methods: Medical records of 234 patients with TD followed between the years 2008 and 2010 were evaluated retrospectively. Diagnosis was made by ultrasonography.Results: Of 234 patients, 120 (51.3%) were male and 114 (48.7%) were female. Male to female ratio was 1.08 and there were no significant differences in epidemiologic and clinical findings between girls and boys. One hundred eighty-three patients (78.2%) were diagnosed as hypoplasia, 35 (14.9%) as thyroid agenesis, 4 as ectopic thyroid gland and 12 as hemiagenesis. The mean maternal age of the group was 28.9±0.4 years (range 18 to 45 years), which is significantly higher than the recently reported mean maternal ages for Turkish women.Conclusions: Advanced maternal age was more prevalent in patients with TD. Our clinical and epidemiologic findings suggested no evidence of sexual dimorphism. Conflict of interest:None declared.     

Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology

Since the advent of biochemical screening for congenital hypothyroidism, the majority of monozygotic twins reported with thyroid dysgenesis have been discordant, and most were missed on neonatal screening, presumably due to fetal blood mixing. We hypothesized that there may be bias leading to preferential reporting of discordant twins and/or of false negative screening results. Therefore, we performed a systematic search for twins in two congenital hypothyroidism screening centers, Quebec and Brussels, that use a primary TSH approach. In Quebec, 10 pairs of twins were identified, all discordant for congenital hypothyroidism due to thyroid dysgenesis (4 monozygotic and 4 dizygotic pairs) and dyshormonogenesis (2 dizygotic pairs). The 6 pairs identified in the Brussels database were also all discordant for congenital hypothyroidism due to thyroid dysgenesis (1 monozygotic and 3 dizygotic pairs) and dyshormonogenesis (2 dizygotic pairs). The median increase in TSH between screening and diagnosis was 7-fold in the monozygotic twins vs. 2-fold in matched singletons (P = 0.02), suggesting fetal blood mixing between the twins. In summary, discordance for thyroid dysgenesis is the rule in monozygotic twins, and fetal blood mixing may result in delayed or missed diagnoses. We therefore conclude that 1) a second sample for congenital hypothyroidism screening at 14 d of age should be considered for all same-sex twins; and 2) thyroid dysgenesis generally results from epigenetic phenomena, early somatic mutations, or postzygotic stochastic events.     

A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (CH)

Context  The guidelines of the National Academy of Clinical Biochemistry advocated the use of low bloodspot TSH (b-TSH) threshold for newborn screening of congenital hypothyroidism (CH). The impact generated by the application of this indication is largely unknown.
Objective  To determine the impact on CH epidemiology and classification generated by the introduction of low b-TSH cutoff.
Design  Retrospective study of 629,042 newborns screened with b-TSH cutoffs of 12 (years 1999–2002) or 10 mU/l (2003–2005).
Measurements  Congenital hypothyroidism incidence and classification. Results were compared with those virtually obtained with the previous cutoff (20 mU/l). Clinical re-evaluation after L-T4 withdrawal of a representative group of 140 CH children at 3–5 years.
Results  Low b-TSH cutoffs allowed the detection of 435 newborns with confirmed CH (incidence 1:1446). Forty-five percent of CH infants, including 12/141 dysgenesis, would have been missed using the 20 mU/l cutoff. In contrast to current classification, 32% CH newborns had thyroid dysgenesis and 68% had a gland in situ (GIS). Premature birth was present in 20% of cases being associated with a 3–5 fold increased risk of GIS CH. Re-evaluation at 3–5 years showed a permanent thyroid dysfunction in 78% of 59 CH toddlers with GIS.
Conclusions  The use of low b-TSH cutoff allowed the detection of an unsuspected number of children with neonatal hypothyroidism, evolving in mild permanent thyroid dysfunction later in life. The incidence of CH in this Italian population appears to be double than previously thought with a clear-cut prevalence of functional defects over dysgenetic ones.     

Congenital hypothyroidism

Congenital hypothyroidism is the principle cause of preventable mental retardation, with a prevalence of 1 in 3,500 neonates. The disorder may be permanent or transitory. Permanent congenital hypothyroidism is caused principally by thyroid dysgenesis. In industrialized countries, mass screening allows the disorder to be diagnosed at birth. The severity is variable but is generally more pronounced in females. The majority of studies point to a genetic origin for the disease and no consistent evidence has been found to suggest a major role for environmental factors. The genetic factors have already been identified and involve several elements (mutations in the TTF-1, TTF-2, PAX8 and TSH receptor genes). The etiological diagnosis is based on scintigraphy, ultrasound and the level of circulating thyroglobulin. At present, treatment is administered at an adapted dose during the first two weeks of life and should allow the child to reach its full intellectual potential. However, minor anomalies have been reported in some treated children, suggesting that this treatment cannot compensate for a certain degree of foetal hypothyroidism.     

A negative iodine balance is found in healthy neonates compared with neonates with thyroid agenesis

We studied the effects of the presence or absence of the thyroid gland on the iodine metabolism and excretion in term Dutch newborns by performing a retrospective study of the urinary iodine excretion in 193 term newborns with abnormal congenital hypothyroidism screening results. Thirty-six euthyroid newborns with decreased thyroxine-binding globulin levels were compared with 157 hypothyroid patients, 54 due to thyroid agenesis and 103 due to thyroid dysgenesis. A significant difference in the urinary iodine excretion was observed between the agenesis group (mean: 28 micrograms/24 h) and the euthyroid newborns (mean: 46 micrograms/24 h, P=0.001). In conclusion, healthy, euthyroid, term newborns excreted more iodine in their urine than newborns with thyroid agenesis. These results strongly indicated the existence of a temporarily negative iodine balance: the excretion of iodine prevailed over the intake and the newborn's thyroidal iodine, stored during pregnancy, could be used for thyroxine synthesis in the postnatal period. Since healthy term neonates were able to maintain adequate plasma free thyroxine concentrations under normal TSH stimulation, the prenatally acquired iodine stores could be considered sufficiently high to compensate for the transient postnatal losses.     

A familial case of congenital hypothyroidism caused by a homozygous mutation of the thyrotropin receptor gene.

Most of the time congenital hypothyroidism appears as a sporadic disease. In addition to the rare defects in hormonosynthesis associated with goiters, the causes of congenital hypothyroidism include agenesis and ectopy of the thyroid gland. The study of some familial cases has allowed the identification of a few genes responsible for congenital hypothyroidism. We report here a familial case of congenital hypothyroidism, transmitted as a recessive trait, and caused by a homozygous mutation in the thyrotropin receptor (TSH-R). The initial diagnosis of thyroid agenesis, based on the absence of tracer uptake on scintiscan, was incorrect, because ultrasound examination identified severely hypoplastic thyroid tissue in the cervical region.     

Serum thyroglobulin determinations in the differential diagnosis of congenital hypothyroidism

The value of serum thyroglobulin (Tg) determination in the differential diagnosis of congenital hypothyroidism was assessed by serum Tg measurements in 14 patients with proven congenital hypothyroidism, in 3 subjects with transient perinatal hypothyroidism, in 3 newborns with congenital thyroxine binding globulin (TBG) deficiency and in 34 normal controls. Serum Tg was undetectable in all 6 cases with thyroid agenesis, normal or moderately elevated in the 4 cases with ectopic thyroid, markedly increased in the 4 cases with dyshormonogenic goiter and normal in the 3 cases with transient hypothyroidism and in the 3 with TBG deficiency. The present data indicate that serum Tg measurements may be useful in the differentiation of athyreotic hypothyroidism from other conditions of congenital hypothyroidism.     

Congenital hypothyroidism with gland in situ: diagnostic re-evaluation

In the past, most congenital hypothyroidism (CH) children with thyroid gland in situ were considered to be affected by hormonogenesis defect. Nowadays, the improved sensitivity of neonatal screening, novel insights into the pathogenic mechanisms and the advances of genetic analyses have reopened the discussion about the etiology of CH with thyroid in situ. We report the etiological re-evaluation of 31 children with thyroid in situ, who had been identified by the CH screening program. The purposes of this re-evaluation were: a) to investigate the definitive diagnosis and pathogenetic mechanism of CH with thyroid in situ in eligible children suspected of dyshormonogenetic defect and b) to verify the adequacy of the treatment schedules. Thirty out of 31 children were affected with permanent hypothyroidism and only one child was euthyroid at re-evaluation (transient CH). Thyroid hormone organification defects were present in less than half of the CH patients with thyroid in situ (13/30); a higher prevalence of partial defects of iodine organification than severe or complete forms was found. An inactivating TSH-receptor gene mutation was found in only one patient without iodine organification defect. Some questions remain unanswered concerning the adequacy of the schedules of treatment, particularly about the proper treatment of mild and borderline forms of CH.     

PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations

Thyroid dysgenesis (TD) is responsible for most cases of congenital hypothyroidism, a condition that affects about one in 4000 newborns. Mutations in PAX8, TITF1, or FOXE1 may account for congenital hypothyroidism in patients with either isolated TD or TD with associated malformations involving kidney, lung, forebrain, and palate. Pax8, titf1, and foxe1 are expressed in the mouse thyroid bud as soon as it differentiates on the pharyngeal floor. Because the spatio-temporal expression of these genes is unknown in humans, we decided to study them at different stages of human embryonic and fetal development. PAX8 and TITF1 were first expressed in the median thyroid primordium. Interestingly, PAX8 was also expressed in the thyroglossal duct and the ultimobranchial bodies. Human FOXE1 expression was detected later than in the mouse. PAX8 was also expressed in the developing central nervous system and kidney, including the ureteric bud and the main collecting ducts. TITF1 was expressed in the ventral forebrain and lung. FOXE1 expression was detected in the oropharyngeal epithelium and thymus. In conclusion, the expression patterns described here show some differences from those reported in the mouse. They explain the malformations associated with TD in patients carrying PAX8, TITF1, and FOXE1 gene mutations.     

Morphogenesis of the thyroid gland

Congenital hypothyroidism is mainly due to structural defects of the thyroid gland, collectively known as thyroid dysgenesis. The two most prevalent forms of this condition are abnormal localization of differentiated thyroid tissue (thyroid ectopia) and total absence of the gland (athyreosis). The clinical picture of thyroid dysgenesis suggests that impaired specification, proliferation and survival of thyroid precursor cells and loss of concerted movement of these cells in a distinct spatiotemporal pattern are major causes of malformation. In normal development the thyroid primordium is first distinguished as a thickening of the anterior foregut endoderm at the base of the prospective tongue. Subsequently, this group of progenitors detaches from the endoderm, moves caudally and ultimately differentiates into hormone-producing units, the thyroid follicles, at a distant location from the site of specification. In higher vertebrates later stages of thyroid morphogenesis are characterized by shape remodeling into a bilobed organ and the integration of a second type of progenitors derived from the caudal-most pharyngeal pouches that will differentiate into C-cells. The present knowledge of thyroid developmental dynamics has emerged from embryonic studies mainly in chicken, mouse and more recently also in zebrafish. This review will highlight the key morphogenetic steps of thyroid organogenesis and pinpoint which crucial regulatory mechanisms are yet to be uncovered. Considering the co-incidence of thyroid dysgenesis and congenital heart malformations the possible interactions between thyroid and cardiovascular development will also be discussed.     

Further studies on episodic occurrence of congenital dysgenetic hypothyroidism in Osaka, Japan

A total of 1,228,551 newborn babies, who were almost all of babies born in Osaka for 14 years (168 months), were screened for congenital primary hypothyroidism by an identical mass-screening program using the thyrotropin method, and 429 patients with hypothyroidism due to thyroid dysgenesis (dysgenetic hypothyroidism) were found. The occurrence of the patients in every month was not random but episodic and the incidence was higher in the late autumn (from October to December). These observations support a hypothesis that some environmental factors may cause this disorder overtime and the possibility of relation with intrauterine viral infection was discussed.