Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

75B. Hypothyroidism in Infants and Children: Congenital Hypothyroidism

Guy van Vliet

A relationship between an absent or defective thyroid gland and mental retardation was recognized long ago, but the most striking description of the clinical picture of “cretinism,” as it was then called, was made by Sir William Osler in 1897, who then wrote,  No type of human transformation is more distressing to look at than an aggravated case of cretinism. The stunted stature, the semi-bestial aspect, the blubber lips, retroussě nose sunken at the root, the wide open mouth, the lolling tongue, the small eyes half-closed with swollen lids, the stolid, expressionless face, the squat figure, the muddy dry skin, combine to make the picture of what has been termed the ‘pariah of nature’” (1).

A century ago, thyroid extract was found to normalize the physical appearance of patients with congenital hypothyroidism. However, the mental deficiency was irreversible, because treatment was started after the most critical period of sensitivity of the brain to thyroid hormone deficiency. Mental deficiency from congenital hypothyroidism was only eradicated when widespread mass biochemical screening of neonates was implemented in the 1980s (see section Neonatal Screening in this chapter). During the same period, progress toward the elimination of iodine deficiency, the most important extrinsic factor causing congenital hypothyroidism, has been made in many countries (see section Iodine Deficiency in Chapter 11 and Chapter 49).

CLASSIFICATION OF CONGENITAL HYPOTHYROIDISM

Like acquired hypothyroidism, congenital hypothyroidism can be classified as primary (thyroidal), if the defect occurs at the level of the thyroid gland; peripheral, if the defect is in thyroid-hormone sensitive peripheral tissues; and central, if the defect involves the hypothalamus or pituitary gland (Table 75B.1). Central hypothyroidism may be further divided into secondary (pituitary causes) and tertiary (hypothalamic causes). Hypothyroidism can also be classified according to whether it is transient or permanent. Permanent primary congenital hypothyroidism is by far the most common form of congenital hypothyroidism, and is, in fact, the most common congenitalendocrine disorder; it is found in approximately 1 in 3,500 newborn infants.

TABLE 75B.1. CLASSIFICATION OF CONGENITAL HYPOTHYROIDISM

 

Permanent hypothyroidism

   Central (hypothalamic, pituitary) hypothyroidism

      Pituitary stalk interruption syndrome or other developmental defects

      Inactivating mutations:

  TRH receptor

         Transcription factors (HESX-1, LHX-3, LHX-4, PIT-1, PROP-1)

  β-subunit of TSH

   Primary (thyroidal) hypothyroidism

      Thyroid dysgenesis: ectopy, agenesis, hypoplasia, hemiagenesis

Thyroid dyshormonogenesis

      Resistance to TSH from:

   Inactivating mutations of the TSH receptor

         Other mechanisms (e.g., pseudohypoparathyroidism)

 Peripheral hypothyroidism

   Resistance to thyroid hormone

Transient hypothyroidism (all are of the primary type)

   Severe iodine deficiency

    Acute iodine load (usually on a background of borderline iodine deficiency)

    Maternal antithyroid drug therapy

    Transplacental transfer of TSH receptor-blocking antibodies

   Heterozygous mutations inactivating THOX2

 

TRH, thyrotropin-releasing hormone; TSH, thyrotropin.

In 80% to 90% of infants, permanent primary congenital hypothyroidism is caused by thyroid dysgenesis, which includes multiple abnormalities in thyroid gland development. Among them, the most common is ectopic thyroid tissue (~60% of cases). The ectopic thyroid tissue is usually located above where the normal thyroid should be, as a result of an arrest in downward migration of the median thyroid anlagen during embryonic development; this ectopic tissue contains the only thyroid follicular cells in the affected infants (see Chapter 2). Approximately 20% of infants have complete absence of thyroid tissue (thyroid agenesis or athyreosis); this may result from a defect in the differentiation of thyroid follicular cells or from their disappearance during prenatal life. Less common are thyroid hypoplasia (< 5% of cases), which is characterized by small thyroid lobes in the normal position, and thyroid hemiagenesis (< 1% of cases), in which one lobe (usually the left), is missing. Ten percent to 20% of cases of permanent primary congenital hypothyroidism are due to defects in thyroid hormone biosynthesis (thyroid dyshormonogenesis), which, because of the trophic actions of thyrotropin (TSH), eventually lead to thyroid enlargement (see Chapter 48). However, thyroid enlargement is often not detected clinically at birth.

Permanent central hypothyroidism, resulting from defects at the level of the hypothalamus or pituitary, occurs in less than 1 in 50,000 births. In addition to these permanent conditions, transient alterations in thyroid function are occasionally encountered.

ETIOLOGY AND PATHOGENESIS

Permanent Congenital Hypothyroidism

Thyroid dysgenesis was until recently considered a sporadic entity, although there had been some reports of familial occurrence. A systematic evaluation of the heritability of thyroid dysgenesis in France revealed that 48 of 2,472 infants with thyroid dysgenesis (2) had an affected relative; this figure is 15-fold higher than predicted by chance alone (2). Pedigree analysis was most compatible with dominant inheritance with variable penetrance, although there was genetic heterogeneity and possible multigenic inheritance in some pedigrees (2,3). In another study by the same group, subclinical abnormalities of thyroid development (mostly persistence of thyroglossal duct remnants) were identified by ultrasonography in 8% of euthyroid first-degree relatives of children with thyroid dysgenesis, as compared with only 0.8% in a control population (4). On the other hand, a recent systematic survey of monozygotic twins revealed that discordance for thyroid dysgenesis was the rule, being observed in 12 of 13 reported twin pairs (92%) (5). Also incompatible with simple mendelian inheritance is the observation that thyroid dysgenesis (especially thyroid ectopy) has a marked female predominance (6).

Consistent with these epidemiologic findings, germ line mutations in genes known to be involved in thyroid development (, and) have been identified in only about 50 patients with thyroid dysgenesis, among about 500 who were screened (see Chapter 2). Thus, alternative hypotheses have to be formulated to explain most cases of thyroid dysgenesis. These include epigenetic modifications, somatic mutations occurring early in embryogenesis in the parent thyroid follicular cell, or stochastic developmental events. The lines of evidence in favor of mendelian and nonmendelian mechanisms of thyroid dysgenesis are summarized in Table 75B.2 and are discussed in detail elsewhere (7,8).TTF-1, TTF-2, PAX-8TSH receptor

TABLE 75B.2. PROPOSED MECHANISMS OF THYROID DYSGENESIS AND SUPPORTING FINDINGS

 

Mendelian Inheritance

Non-Mendelian Inheritance

 

Findings

2% of infants with thyroid dysgenesis have an affected relative (15-fold higher than chance)

Marked preponderance of females with ectopy (3 females for 1 male)

Subclinical abnormalities of thyroid development in 8% of first- degree relatives of infants with thyroid dysgenesis (vs. 0.8 % in a control population)

92% discordance among monozygotic twin pairs

Mechanisms

Autosomal dominant with variable penetrance Genetic heterogeneity Multigenic

Epigenetic Early somatic mutations Stochastic events
 


Thyroid dyshormonogenesis results from a defect in any one of the steps involved in the biosynthesis of thyroid hormone, from the transport of iodine to the synthesis of thyroglobulin (see Chapter 48). These defects are inherited as autosomal-recessive traits, and they therefore occur at higher frequency in consanguineous families.

Given the different mechanisms underlying congenital hypothyroidism caused by thyroid dysgenesis and by dyshormonogenesis, it is essential that these two forms be distinguished when comparing prevalence figures between ethnic groups. Thus, evidence suggesting that congenital hypothyroidism is less prevalent among blacks should be viewed with caution because the etiology was not determined (9).

Although the prevalence of dyshormonogenesis is higher in inbred populations, the prevalence of thyroid ectopy does not seem to vary substantially around the world. The lack of consistent regional, and also seasonal, variation in the frequency of thyroid dysgenesis argues against an important role of environmental factors (10).

Congenital central hypothyroidism almost always occurs in conjunction with other pituitary hormone deficiencies, and it is usually caused by structural abnormalities of the pituitary or hypothalamus or functional abnormalities in hypothalamic or pituitary development (Table 75B.1). Isolated central hypothyroidism caused by mutations of the gene for the β-subunit of TSH is rare. These mutations result in the production of a TSH molecule with little biologic or immunologic activity, and affected infants usually have severe hypothyroidism (11,12). Other rare causes are inactivating mutations in the thyrotropin-releasing hormone receptor (13) and in pituitary transcription factors (14). TSH screening misses infants with these rare disorders.

Transient Congenital Hypothyroidism

Transient primary congenital hypothyroidism has been well described in areas where the iodine intake of the population is either severely or moderately deficient (see section Iodine Deficiency in Chapter 11 and Chapter 49). In the latter areas, it usually occurs in premature newborns and is associated with an acute iodine overload, most often from use of iodine-containing antiseptic agents in the infant or mother. Cessation of the use of these antiseptic agents in newborn nurseries has led to the almost complete disappearance of this form of transient primary hypothyroidism (15). It is rare in areas of iodine sufficiency such as North America.

In iodine-sufficient areas, the most common cause of transient primary hypothyroidism is maternal therapy with an antithyroid drug. These drugs are cleared rapidly from the infant's circulation, and therefore the hypothyroidism is short-lived; most affected infants have normal serum TSH and free thyroxine (T4) concentrations at recall. Transplacental transfer of maternal antibodies that block the action of TSH is a rare cause of transient primary hypothyroidism in newborn infants, causing only about 1% to 2% of cases (16); these infants may still have hypothyroidism at the time of recall because the antibodies are cleared relatively slowly. These antibodies do not interfere with the formation, migration, and growth of the thyroid gland, and therefore do not cause permanent primary congenital hypothyroidism. Transient primary congenital hypothyroidism from a heterozygous mutation in , the gene encoding one of the enzymes involved in the generation of HTHOX22O2 needed for iodine oxidation and organification in the thyroid (17), has recently been described. Its frequency remains to be determined.

CLINICAL PRESENTATION

Few infants with congenital hypothyroidism have an abnormal appearance or behavior at birth or even at recall when the diagnosis is confirmed and treatment started. On the other hand, the few newborn infants with clinical manifestations of hypothyroidism would probably benefit from diagnosis in the first days after birth and from treatment begun even earlier than can be achieved by screening programs (18). Thus, it is important to recognize the clinical manifestations of hypothyroidism in newborn infants. These include unexplained postmaturity, macrosomia, an open posterior fontanel, jaundice, and delayed skeletal maturation (19). A few infants have a goiter, but it is rarely of sufficient size to impede delivery or cause airway obstruction. Other symptoms and signs include poor feeding, hypothermia, lethargy, constipation, prolonged jaundice, abdominal distention, umbilical hernia, dry and mottledskin, macroglossia, a hoarse cry, and a myxedematous appearance (Fig. 75B.1).

 

FIGURE 75B.1. Photographs of infants with congenital hypothyroidism.  4-month-old infant with many signs of hypothyroidism, including puffy eyelids, macroglossia, and umbilical hernia. Treatment from this age onward results in disappearance of the physical stigmata of hypothyroidism, but irreversible brain damage has already occurred.  14-day-old twin brothers, one of whom has severe congenital hypothyroidism due to thyroid agenesis. Note that they are clinically indistinguishable. Thanks to early treatment through biochemical screening, the intellectual development of the hypothyroid twin should be comparable with that of the euthyroid twin.Left:Right:

A clinical suspicion of hypothyroidism in a newborn or very young infant should always lead to the immediate measurement of serum TSH and free T4, even if the screening blood sample has already been collected. Also, the possibility of human or technical error in the screening process, of central hypothyroidism [in areas using a TSH-first screening approach (see section Neonatal Screening in this chapter)], or of falsely normal (false-negative) results should be kept in mind.

Among infants referred for an abnormal screening result, a family history should be obtained, with focus on consanguinity and on the existence of even distant relatives with congenital hypothyroidism (Table 75B.3). A family history of thyroid disorders with onset in later life is usually irrelevant, but a maternal history of thyroid disease, treatment for thyroid disease, or exposure to iodine-rich compounds such as radiographic contrast agents is relevant. An examination of the infant seeking the above-listed physical signs should be conducted. A goiter may be seen or palpated when the infant's neck is hyperextended. The only extrathyroid malformations consistently associated with thyroid dysgenesis are defects in heart septation (2,6,20); these are usually mild and not noted at the first visit.

TABLE 75B.3. DIAGNOSTIC EVALUATION OF A NEWBORN INFANT SUSPECTED TO HAVE CONGENITAL HYPOTHYROIDISM

 

Family history: especially sibling with congenital hypothyroidism or maternal thyroid disease

Infant history: length of gestation, birth weight, constipation, poor feeding

Physical examination: jaundice, open fontanels, goiter (neck hyperextended)

Obtain blood for measurements of serum TSH and free T4

 Anteroposterior x-ray of the knee

99mTcO4 (or 123I) scintigraphy of cervical, lingual and mediastinal area (not required if goiter on clinical examination):

   If thyroid ectopy: permanent congenital hypothyroidism confirmed

    If 99mTcO4(or 123I) uptake uindetectable, measure serum thyroglobulin:

Serum thyroglobulin undetectable: thyroid agenesis confirmed

Serum thyroglobulin detectable: thyroid tissue present

   Transplacental transfer of TSH receptor-blocking antibodies (transient hypothyroidism)

   Mutations in the TSH receptor or  (permanent hypothyroidism)PAX-8

    If low uptake by a small or normal thyroid of normal shape:

Iodine overload, TSH receptor–blocking antibodies (transient hypothyroidism)

Mutations in the TSH receptor or  (permanent hypothyroidism)PAX-8

 

T4, thyroxine; TSH, thyrotropin.

Except when it is due to mutations of the β-subunit of TSH, congenital central hypothyroidism is clinically and biochemically mild and associated with other pituitary hormone deficiencies, the clinical expression of which leads to the diagnosis. Thus, the infant may have hypoglycemia caused by corticotropin (ACTH) or growth hormone deficiency, or micropenis and cryptorchidism caused by gonadotropin deficiency. The presence of midline malformations such as cleft lip or palate or optic nerve hypoplasia may also suggest the presence of these pituitary deficiencies.

DIAGNOSTIC EVALUATION

Serum TSH and free T4 should be measured in all newborn infants recalled because of abnormal screening results, and also in any infant suspected clinically to have hypothyroidism immediately after birth (Table 75B.3). The biochemical severity of the hypothyroidism tends to be less in infants with thyroid ectopy or hypoplasia than in those with thyroid agenesis, and it is highly variable in infants with thyroid dyshormonogenesis. However, the overlap in values among infants with these different disorders is substantial; therefore, the cause of congenital hypothyroidism cannot be predicted reliably based on serum TSH and free T4 concentrations.

The onset of hypothyroidism can be estimated from an anteroposterior x-ray of the knee. The absence of both the femoral and tibial epiphyseal centers in a term newborn infant suggests severe hypothyroidism, and these radiologic findings have consistently been found to be a reliable predictor of greater risk for developmental delay, even with early treatment (21,22). Unless a goiter is seen or palpated, scintigraphy should be performed to distinguish between the different types of thyroid dysgenesis. Detection of thyroid ectopy immediately establishes the permanent nature of the disorder (Table 75B.3) and allows estimation of the risk for recurrence in future pregnancies.

For scintigraphy, pertechnetate (99mTcO4) is preferred; it provides satisfactory images, is available daily in most nuclear medicine services, and the imaging can be completed in 15 to 30 minutes (Fig. 75B.2). 99mTcO4 is also taken up by the salivary glands: it is therefore essential to feed the baby between the injection of the tracer and scanning, so that any uptake in the lingual area can be ascribed to thyroid tissue. Iodine 123 is satisfactory, but it usually must be specially ordered, and the test itself takes longer, because the imaging is done 4 to 6 or even 24 hours after 123I administration. Difficulties in arranging for immediate imaging should never delay treatment, and it can be done during the first 3 to 4 days of treatment. Indeed, it is safer to start treatment in all infants referred for positive screening results immediately after the blood sample for measurement of serum TSH and free T4 is obtained.

 

FIGURE 75B.2. Radionuclide images of the head and neck in infants with congenital hypothyroidism.  Ectopic thyroid tissue in the lingual region. Athyreosis. Radioactivity is seen in the salivary glands, large vessels, and heart because the image was made at a high sensitivity in an effort to identify thyroid tissue.  Normally located thyroid lobes. These images were made 30 minutes after intravenous administration of A:B:C:99mTcO4-pertechnetate.

If scintigraphy cannot be done before or soon after treatment is started, it is done when the child is 3 years old. At that time, T4 therapy can be safely discontinued for 1 month. If the diagnosis of hypothyroidism is confirmed by measurements of serum TSH and free T4, its cause can be determined by scintigraphy. Infants with dyshormonogenesis are not studied routinely to determine the specific biosynthetic defect, for example, with a perchlorate discharge test, because a precise diagnosis of the defect has no impact on genetic counseling or treatment.

Thyroid ultrasonography is noninvasive, and no radioactivity is given, but it is less sensitive than scintigraphy in identifying small amounts of ectopic thyroid tissue (23), even when color Doppler ultrasonography is used (24). In infants in whom no thyroid tissue is detected by scintigraphy, serum thyroglobulin should be measured; only about 50% of these infants have complete thyroid agenesis as defined by an undetectable serum thyroglobulin concentration (25). The remainder have some thyroid tissue, however small in volume. Some of these infants have thyroid tissue that is not functioning (but should be detectable by ultrasonography) because of transplacentally transferred maternal TSH receptor-blocking antibodies (Table 75B.3).

Given the low yield of the searches for germline mutations discussed above, molecular genetic analyses are only performed on a research basis, and could probably be restricted to patients with positive family histories or suggestive phenotypes. Thus, unexplained respiratory distress, hypotonia, and choreoathetosis suggest a  mutation (26,27), and cleft palate and kinky hair a  mutation (28,29). In infants with isolated thyroid hypoplasia or apparent agenesis, a family history suggesting dominant inheritance points to a  mutation (30,31,32,33), whereas one suggesting recessive inheritance points to a  mutation (34).TTF-1TTF-2PAX-8TSH receptor

TREATMENT AND OUTCOME

As stated above, treatment should be started at recall regardless of whether imaging is done and without waiting for the results of the confirmatory serum tests. Every day of delay may result in loss of IQ; the loss is greater soon after birth than later (35). Therefore, it is safer to start treatment in all newborns, even those with marginal screening values; it can be stopped in the very few newborns who have normal serum TSH and T
4 concentrations at the time of the diagnostic evaluation.

The treatment of choice is T4. The tablets should be crushed and given in water with a spoon or even given whole before feeding, but should never be added to a bottle of milk or formula that the infant may then not empty. Soy formulas tend to decrease the absorption of T4, but are rarely used now. T4 in solution for oral administration is available in some countries, but is not as stable as the tablet form. Compared with infants with thyroid ectopy, infants with thyroid agenesis usually need higher doses of T4, whereas those with thyroid dyshormonogenesis need lower doses (36,37).

During chronic oral therapy, a missed dose can be given later that day, or two doses can be given the next day. However, mental retardation was attributed to more infrequent (i.e., weekly) dosing in one infant (38), and regular daily treatment is therefore recommended. The dose should be repeated if an infant or child vomits within an hour after taking T4. If needed, which is rare, T4 can be given as a daily intravenous injection; the dose should be about 75% of the oral dose. The addition of triiodothyronine (T3) has no benefit (39).

In the first decade after screening was implemented, treatment was typically started at a mean age of 20 to 35 days and with doses of T4 of 5 to 6 µg/kg/day. It was quickly noted that serum TSH concentrations remained high for weeks or even months with these doses. The persistent elevation was attributed to resistance to the negative feedback action of thyroid hormone on TSH secretion, rather than to inadequate treatment (40). Also, developmental problems and even premature fusion of the fontanels had been reported in infants with congenital thyrotoxicosis (41) and in infants treated with a total of 200 to 500 µg of T4 for several months (42), so that iatrogenic thyrotoxicosis was considered to be as deleterious for the brain as hypothyroidism. It is now clear that only a minority of infants have resistance of TSH secretion to T4 and that this resistance is transient (43).

More importantly, studies of outcome in infants and children treated with these doses of T4 revealed that bone maturation remained delayed until 3 years of age (44), and that those with more severe congenital hypothyroidism (defined on the basis of retarded bone maturation or a very low serum T4 concentration at diagnosis) had a clinically important loss of 6 to 22 IQ points (45,46,47). There seemed to be a threshold effect of severity of congenital hypothyroidism on IQ, superimposed on the well-known influence of socioeconomic status of the parents on the results of psychometric testing of their children (48). Some interpreted these findings as suggesting that irreparable brain damage would always occur before treatment could be started in infants with severe congenital hypothyroidism. However, before delivery, the brain of hypothyroid fetuses is protected to some extent by transplacental passage of maternal T4 (49) and by local up-regulation of type 2 deiodinase (see Chapter 7). Indeed, newer studies suggest that normal intellectual potential can be reached in infants who are treated early and vigorously, as discussed below.

Since about 1990, most term newborn infants have been treated with T4 in doses of 10 to 15 µg/kg/day (in practice, 50 µg/day for a term infant of normal weight) (50). The efficacy of these doses was confirmed in a study in which 47 infants weighing 3 to 4 kg were randomly assigned to treatment with 37.5 µg/day, 62.5 µg/day for 3 days then 37.5 µg/day, and 50 µg/day: only in the group treated with 50 µg/day was the mean serum TSH concentration normal within 2 weeks (51). There is no randomized study of different initial doses of T4 on intellectual development, but observational studies strongly suggest that both initiation of treatment within 2 weeks after birth and a high initial dose are required for children with severe congenital hypothyroidism to develop normally (52,53,54).

Among infants in whom treatment is started, there is considerable variation in the frequency at which the infants are seen and the biochemical targets of treatment. Reference intervals for serum free T4 and TSH are higher in infants than in older children and adults (55), but normative data for the first months of life are scarce, and the different commercially available serum free T4 assays are variably influenced by changes in serum thyroid hormone–binding proteins (56). Based on the rule of thumb that four times the half-life of T4 should elapse before steady state is achieved, it seems unnecessary to measure serum free T4 before infants are treated for 2 or 3 weeks. In terms of what the target serum free T4 value should be when the first follow-up sample is obtained, the study mentioned above (51) suggests that it should be about 5 ng/dL (65 p) after treatment for 2 weeks if the serum TSH concentration is to be normal at that time.M

With respect to chronic T4 therapy, the required dose declines from 10 to 15 µg/kg/day in very young infants to about 4 to 5 µg/kg/day at age 5 years; this decrease is due to the progressive decrease in the turnover rate of T4 with age (see Chapter 74). Conversely, the rate of weight gain decreases quickly in early infancy, so that a starting dose of 50 µg/day may not need to be changed for many months. Low serum TSH concentrations indicate subclinical thyrotoxicosis, but in rapidly growing infants the same dose of T4 may soon be appropriate. Overt thyrotoxicosis is rare, perhaps because serum T3concentrations remain in the normal range even in infants with high serum free T4 concentrations (50), but its presence should lead to a decrease in dose of T4. The finding of a high serum TSH concentration should lead to inquiry about compliance, and if satisfactory the dose of T4 should be increased to maintain serum TSH and free T4 concentrations in the normal range for age, normal serum TSH values being more important than normal serum free T4 values.

Although the frequency of follow-up visits varies considerably between clinics, there is no evidence that infants and children who are seen more often and have more dosage adjustments have a better developmental outcome. Based on the rapid growth rates of infants, it seems reasonable to reassess thyroid function at intervals of 3 months in the first year and of 6 months from age 1 to 3 years. After 3 years, because there is no irreversible effect of undertreatment on brain function, yearly assessments are probably sufficient. Poor compliance with treatment is associated with poorer developmental outcome (18,54). Therefore, a suspicion of poor compliance may justify more frequent visits.

If treatment is adequate, the mean height and weight are similar to those of normal children, but the mean head circumference of infants with congenital hypothyroidism is about 1 standard deviation above the mean of normal infants. This increase is likely related to differential maturation of the cranial base and of the skull and has no impact on the size of the brain or cerebral ventricles (52). However, it may sometimes be so marked in an individual infant as to lead to unnecessary imaging. Bone maturation at 3 years should be normal; in infants with delayed bone maturation at diagnosis, complete catch-up should occur. In the remainder, bone maturation is not advanced, confirming that the treatment regimen has not induced overt thyrotoxicosis (41,42).

Sensorineural hearing loss is a known consequence of congenital hypothyroidism, but does not seem to occur in children treated within 2 weeks after birth (57,58). As regards intellectual development, it appears that with the early high-dose regimen described above, the developmental gap between children with severe and those with moderate congenital hypothyroidism (or normal children) that was noted in children treated during the first decade of screening has now largely disappeared. In addition to cognitive performance, mean behavioral indexes up to school age are within normal limits, and there is no specific cognitive or behavioral trait that can be ascribed to congenital hypothyroidism or its treatment in any individual child (59). Thus, even among infants with severe congenital hypothyroidism, those who are treated vigorously and continuously from before 2 weeks of age should have growth, development, and behavior that proceed within normal limits.

Because of the recent studies on the genetic component of thyroid dysgenesis (2), the genetic counseling given to these families has changed. They should be told that the risk for congenital hypothyroidism is probably about 2% for subsequent siblings and for the offspring of the affected child. Because of the importance of euthyroidism in pregnant women from the beginning of gestation for the brain development of their offspring (60,61), girls with congenital hypothyroidism should be advised to have measurements of serum TSH and free T4 when they contemplate pregnancy as well as throughout their pregnancies, because they may need a higher dose of T4 during that time (see Chapter 80).

REFERENCES

1. Brown RS, Demmer LA. The etiology of thyroid dysgenesis—still an enigma after all these years.  2002;87:4069.J Clin Endocrinol Metab

2. Castanet M, Polak M, Bonaiti-Pellie C, et al. Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors.  2001;86:2009.J Clin Endocrinol Metab

3. Castanet M. Měcanismes molěculaires impliquěs dans les anomalies du děveloppement de la glande thyroïde. Universitě Reně Descartes-Paris V, 2002.

4. Leger J, Marinovic D, Garel C, et al. Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism.  2002;87:575.J Clin Endocrinol Metab

5. Perry R, Heinrichs C, Bourdoux P, et al. Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology.  2002;87:4072.J Clin Endocrinol Metab

6. Devos H, Rodd C, Gagne N, et al. A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations.  1999;84: 2502.J Clin Endocrinol Metab

7. Van Vliet G. Development of the thyroid gland: lessons from congenitally hypothyroid mice and men.  2003;63: 445.Clin Genet

8. Van Vliet G. Molecular mechanisms of normal and abnormal thyroid gland development. In: Pescovitz OH, Eugster EE, eds.  Philadelphia: Lippincott Williams & Wilkins, 2004: 479.Pediatric endocrinology: mechanisms, manifestations, and management.

9. Brown AL, Fernhoff PM, Milner J, et al. Racial differences in the incidence of congenital hypothyroidism.  1981;99:934.J Pediatr

10. Toublanc JE. Comparison of epidemiological data on congenital hypothyroidism in Europe with those of other parts in the world.  1992;38:230.Horm Res

11. Brumm H, Pfeufer A, Biebermann H, et al. Congenital central hypothyroidism due to homozygous thyrotropin beta 313 delta T mutation is caused by a founder effect.  2002;87:4811.J Clin Endocrinol Metab

12. Deladoey J, Vuissoz JM, Domene HM, et al. Congenital secondary hypothyroidism due to a mutation C105Vfs114X thyrotropin-beta mutation: genetic study of five unrelated families from Switzerland and Argentina.  2003;13:553.Thyroid

13. Collu R, Tang J, Castagne J, et al. A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene.  1997;82:1561.J Clin Endocrinol Metab

14. Ward L, Chavez M, Huot C, et al. Severe congenital hypopituitarism with low prolactin levels and age-dependent anterior pituitary hypoplasia: a clue to a PIT-1 mutation.  1998; 132:1036.J Pediatr

15. Chanoine JP, Pardou A, Bourdoux P, et al. Withdrawal of iodinated disinfectants at delivery decreases the recall rate at neonatal screening for congenital hypothyroidism.  1988;63:1297.Arch Dis Child

16. Brown RS, Bellisario RL, Botero D, et al. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies.  1996;81:1147.J Clin Endocrinol Metab

17. Moreno JC, Bikker H, Kempers MJ, et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism.  2002;347:95.N Engl J Med

18. New England Congenital Hypothyroidism Collaborative. Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations.  1981;2:1095.Lancet

19. Van Vliet G, Larroque B, Bubuteishvili L, et al. Sex-specific impact of congenital hypothyroidism due to thyroid dysgenesis on skeletal maturation in term newborns.  2003;88:2009.J Clin Endocrinol Metab

20. Olivieri A, Stazi MA, Mastroiacovo P, et al. A population-based study on the frequency of additional congenital malformations in infants with congenital hypothyroidism: data from the Italian Registry for Congenital Hypothyroidism (1991–1998).  2002;87:557.J Clin Endocrinol Metab

21. Wolter R, Noel P, De Cock P, et al. Neuropsychological study in treated thyroid dysgenesis.  1979; 277:41.Acta Paediatr Scand Suppl

22. Wasniewska M, De Luca F, Cassio A, et al. In congenital hypothyroidism bone maturation at birth may be a predictive factor of psychomotor development during the first year of life irrespective of other variables related to treatment.  2003;149:1.Eur J Endocrinol

23. Perry RJ, Maclennan A, Maroo S, et al. Ultrasound findings versus isotope scanning in neonates with TSH elevation.  2002;58(suppl 2):64.Horm Res

24. Ohnishi H, Sato H, Noda H, et al. Color Doppler ultrasonography: diagnosis of ectopic thyroid gland in patients with congenital hypothyroidism caused by thyroid dysgenesis.  2003;88:5145.J Clin Endocrinol Metab

25. Djemli A, Fillion M, Belgoudi J, et al. Twenty years later: a reevaluation of the contributon of plasma thyroglobulin to the diagnosis of thyroid dysgenesis in infants with congenital hypothyroidism.  2004;37:818.Clin Biochem

26. Pohlenz J, Dumitrescu A, Zundel D, et al. Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.  2002;109:469.J Clin Invest

27. Krude H, Schutz B, Biebermann H, et al. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2–1 haploinsufficiency.  2002;109:475.J Clin Invest

28. Clifton-Bligh RJ, Wentworth JM, Heinz P, et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia.  1998;19:399.Nat Genet

29. Castanet M, Park SM, Smith A, et al. A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate.  2002;11:2051.Hum Mol Genet

30. Macchia PE, Lapi P, Krude H, et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis.  1998;19:83.Nat Genet

31. Vilain C, Rydlewski C, Duprez L, et al. Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8.  2001;86:234.J Clin Endocrinol Metab

32. Congdon T, Nguyen LQ, Nogueira CR, et al. A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child.  2001;86:3962.J Clin Endocrinol Metab

33. Komatsu M, Takahashi T, Takahashi I, et al. Thyroid dysgenesis caused by PAX8 mutation: the hypermutability with CpG dinucleotides at codon 31.  2001;139:597.J Pediatr

34. Abramowicz MJ, Duprez L, Parma J, et al. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland.  1997;99:3018.J Clin Invest

35. Fisher DA. The importance of early management in optimizing IQ in infants with congenital hypothyroidism.  2000;136:273.J Pediatr

36. Germak JA, Foley TP Jr. Longitudinal assessment of L-thyroxine therapy for congenital hypothyroidism.  1990;117:211.J Pediatr

37. Hanukoglu A, Perlman K, Shamis I, et al. Relationship of etiology to treatment in congenital hypothyroidism.  2001;86:186.J Clin Endocrinol Metab

38. Rivkees SA, Hardin DS. Cretinism after weekly dosing with levothyroxine for treatment of congenital hypothyroidism.  1994;125:147.J Pediatr

39. Cassio A, Cacciari E, Cicognani A, et al. Treatment for congenital hypothyroidism: thyroxine alone or thyroxine plus triiodothyronine?  2003;111:1055.Pediatrics

40. Sack J, Shafrir Y, Urbach D, et al. Thyroid-stimulating hormone, prolactin, and growth hormone response to thyrotropin-releasing hormone in treated children with congenital hypothyroidism.  1985;19:1037.Pediatr Res

41. Daneman D, Howard NJ. Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years.  1980;97:257.J Pediatr

42. Penfold JL, Simpson DA. Premature craniosynostosis—a complication of thyroid replacement therapy.  1975;86:360.J Pediatr

43. Fisher DA, Schoen EJ, La Franchi S, et al. The hypothalamic-pituitary-thyroid negative feedback control axis in children with treated congenital hypothyroidism.  2000;85:2722.J Clin Endocrinol Metab

44. Van Vliet G, Barboni Th, Klees M, et al. Treatment strategy and long term follow up of congenital hypothyroidism. In: Delange F, Fisher DA, Glinoer D, eds.  New York: Plenum, 1989:245.Research in congenital hypothyroidism.

45. Glorieux J, Dussault J, Van Vliet G. Intellectual development at age 12 years of children with congenital hypothyroidism diagnosed by neonatal screening.  1992;121:581.J Pediatr

46. Derksen-Lubsen G, Verkerk PH. Neuropsychologic development in early treated congenital hypothyroidism: analysis of literature data.  1996;39:561.Pediatr Res

47. Oerbeck B, Sundet K, Kase BF, et al. Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults.  2003;112:923.Pediatrics

48. Tillotson SL, Fuggle PW, Smith I, et al. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect.  1994;309:440.BMJ

49. Vulsma T, Gons MH, de Vijlder JJ. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect of thyroid agenesis.  1989;321:13.N Engl J Med

50. Fisher DA, Foley BL. Early treatment of congenital hypothyroidism.  1989;83:785.Pediatrics

51. Selva KA, Mandel SH, Rien L, et al. Initial treatment dose of L-thyroxine in congenital hypothyroidism.  2002;141: 786.J Pediatr

52. Dubuis JM, Glorieux J, Richer F, et al. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment.  1996;81:222.J Clin Endocrinol Metab

53. Bongers-Schokking JJ, Koot HM, Wiersma D, et al. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism.  2000;136:292.J Pediatr

54. Leger J, Larroque B, Norton J. Influence of severity of congenital hypothyroidism and adequacy of treatment on school achievement in young adolescents: a population-based cohort study.  2001;90:1249.Acta Paediatr

55. Zurakowski D, Di Canzio J, Majzoub JA. Pediatric reference intervals for serum thyroxine, triiodothyronine, thyrotropin, and free thyroxine.  1999;45:1087.Clin Chem

56. Bongers-Schokking JJ, de Muinck Keizer-Schrama SM, Docter R. Pitfalls in serum free thyroxine measurements in infants with and without congenital hypothyroidism.  1999;51 (suppl 2):17.Horm Res

57. Francois M, Bonfils P, Leger J, et al. Role of congenital hypothyroidism in hearing loss in children.  1994;124: 444.J Pediatr

58. Rovet J, Walker W, Bliss B, et al. Long-term sequelae of hearing impairment in congenital hypothyroidism.  1996;128: 776.J Pediatr

59. Simoneau-Roy J, Marti S, Deal C, et al. Cognition and behavior at school entry in children with congenital hypothyroidism treated early with high-dose levothyroxine.  2004;144: 747.J Pediatr

60. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.  1999;341:549.N Engl J Med

61. Lavado-Autric R, Auso E, Garcia-Velasco JV, et al. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny.  2003;111:1073.