Disorders of the Thyroid Gland in Infancy, Childhood and Adolescence

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Thyroid hormone is essential for the growth and maturation of many target tissues, including the brain and skeleton. As a result, abnormalities of thyroid gland function in infancy and childhood result not only in the metabolic consequences of thyroid dysfunction seen in adult patients, but in unique effects on the growth and /or maturation of these thyroid hormone-dependent tissues as well. In most instances, there are critical windows of time for thyroid hormone-dependent development and so the specific clinical consequence of thyroid dysfunction depends on the age of the infant or child. For example, newborn infants with congenital hypothyroidism frequently have hyperbilirubinemia, and delayed skeletal maturation, reflecting immaturity of liver and bone, respectively, and they are at risk of permanent mental retardation if thyroid hormone therapy is delayed or inadequate; their size at birth, however, is normal. In contrast, hypothyroidism that develops after the age of three years (when most thyroid hormone-dependent brain development is complete) is characterized predominantly by a deceleration in linear growth and skeletal maturation but there is no permanent effect on cognitive development. In general, infants with severe defects in thyroid gland development or inborn errors of thyroid hormonogenesis present in infancy whereas babies with less severe defects or acquired abnormalities, particularly autoimmune thyroid disease, present later in childhood and adolescence. In the newborn infant , thyroid function is influenced not only by the neonate ’ s own thyroid gland but by the transplacental passage from the mother of factors that affect the fetal thyroid gland.

In the last several decades, there have been exciting advances in our understanding of fetal and neonatal thyroid physiology, and screening for congenital hypothyroidism has enabled the virtual eradication of the devastating effects of mental retardation due to sporadic congenital hypothyroidism in most developed countries of the world. In addition, advances in molecular biology have led to new insights regarding the early events in thyroid gland embryogenesis and mechanisms of thyroid action in the brain. At the same time, the molecular basis for many of the inborn errors of thyroid hormonogenesis and thyroid hormone action is being unraveled. However, new questions and new challenges arise. In particular, the survival of increasingly small and premature fetuses has resulted in a growing number of neonates with abnormalities in thyroid function and a continuing controversy as to which of these infants require therapy. This chapter will focus on current concepts regarding the ontogenesis of thyroid function in the fetus and will review the major disorders of thyroid gland function in infants and children.

Ontogenesis of thyroid function in the fetus and infant

The ontogeny of mature thyroid function involves the organogenesis and maturation of the hypothalamus, pituitary, and thyroid glands as well as the maturation of thyroid hormone metabolism and thyroid hormone action. The placenta also plays a key role in the transfer of hormones and factors other than T4 that impact on thyroid function. In the first half of pregnancy, maternal T4 provides an important source of hormone for the developing fetus. Much of our knowledge derives from work in animal models, particularly sheep and rat. In interpreting these data, it is important to remember potential limitations in these models because of differences both in the structure of the placenta and timing of maturation. For example, the rat thyroid gland is much less mature at birth than its human counterpart and significant maturation of the thyroid gland and of the hypothalamic-pituitary-thyroid axis in this species occurs in the first 2 or 3 weeks after birth in the absence of placental or maternal influence, as compared with the third trimester in human infants.

Thyroid gland embryogenesis

Thyroid gland development is extensively reviewed in an earlier chapter and is shown diagrammatically in Figure 1. In brief, the thyroid gland is derived from the fusion of a medial outpouching from the floor of the primitive pharynx, the precursor of the thyroxine (T4)-producing follicular cells, and bilateral evaginations of the fourth pharyngeal pouch, which gives rise to the parafollicular, or calcitonin (C) secreting cells. Commitment towards a thyroid-specific phenotype as well as the growth and descent of the thyroid anlage into the neck results from the coordinate action of a number of transcription factors, including thyroid transcription factor 1 ( TTF1 , now called NKX2. (1) ), TTF2 (now called FOXE1 ) and PAX8 ( 1, 2) . Because these transcription factors are also expressed in a limited number of other cell types, it appears to be the specific combination of transcription factors and possibly non-DNA binding cofactors acting coordinately that determine the phenotype of the cell.

Other transcription factors and growth factors that play a role in early thyroid gland organogenesis include HHEX1 , HOXA3 , (3) and members of the fibroblast growth factor family, e.g., FGF10 , but the initial inductive signal is unknown. A role of the neighboring heart primordium in the specification of the thyroid anlage has been postulated. Studies of cadherin expression suggest that the caudal translocation of the thyroid anlage may also arise indirectly, as a result of the growth and expansion of adjacent tissues, including the major blood vessels (4) . In late organogenesis, the sonic hedgehog ( SHH ) gene and its downstream target TBX1 appear to play an important role in the symmetric bilobation of the thyroid (5) ; SHH also suppresses the ectopic expression of thyroid follicular cells (6) .

During caudal migration the pharyngeal region of the thyroid anlage contracts to form a narrow stalk, known as the thyroglossal duct, which subsequently atrophies. Usually no lumen is left in the tract of its descent but, occasionally, an ectopic thyroid and/or persistent thyroglossal duct or cyst form if thyroid descent is abnormal.


Figure 15- 1. Approximate timing of thyroid gland maturation in the human fetus.

In the human, embryogenesis is largely complete by 10 to 12 weeks gestation At this stage, tiny follicle precursors can be seen, iodine binding can be identified and thyroglobulin (Tg) detected in follicular spaces (7, 8) . Thyroid hormones are detectable in fetal serum by gestational age 11 to 12 weeks with both thyroxine (T4) and triiodothyronine (T3) being measurable. However, as discussed in further detail below, it is likely that a fraction of the hormones detectable at this early stage is contributed by the mother through transplacental transfer. Thyroid hormones continue to increase gradually over the entire period of gestation as does serum thyroxine-binding globulin (TBG ) (9 , 10) . TBG is present at levels of 100 nmol/L (5 mg/L) at gestational age 12 weeks and progressively increases up to the time of birth, reaching concentrations of 500 nmol/L (25 mg/L). The serum TBG concentrations are higher in the infant then in adult humans as a consequence of placental estrogen effects on the fetal liver. In addition to the increase in total T4 there is also a progressive increase of the free T4 concentration indicating a maturation of the hypothalamic- pituitary- thyroid axis. The increased total T4 / thyrotropin ( TSH) and free T4 /TSH ratios also indicate an increased ability of the thyroid gland to respond to TSH due to upregulation of the TSH receptor (11) . Whereas the TBG and total T4 levels rise throughout gestation, the concentrations of free T4, and TSH rise until 31 to 34 weeks, declining thereafter to term (12) .

Tg can be identified in the fetal thyroid as early as the 5th week, and is certainly present in follicular spaces by 10 to11 weeks, but maturation of Tg secretion takes much longer and it is not known when circulating Tg first appears in the fetal serum (not shown). By the time of gestational age 27 to 28 weeks, however, Tg levels average approximately 100 mg/L, much higher than in the adult and they remain approximately stable until the time of birth (13 , 14) . Iodide concentrating capacity can be detected in the thyroid of the 10 to 11 week fetus, but maturation of the Wolff-Chaikoff effect (reduction of iodide trapping in response to excess iodide) does not appear until 36 to 40 weeks gestation. Thus the premature fetus is more sensitive than the full term neonate to the thyroid-suppressive effects of iodine exposure.

The hypothalamic-pituitary axis

TSH is detectable at levels of 3 to 4 mU/L at gestational age 12 weeks and increases moderately over the last two trimesters to levels of 6 to 8 mU/L (8 , 9) .The maturation of the negative feedback control of thyroid hormone synthesis is observed by approximately mid-gestation (Figure 1) , with elevated serum TSH concentrations being observed in hypothyroid infants as early as 28 weeks (8) . When TSH-Releasing Hormone (TRH) is given to mothers, a rise in TSH in the fetal circulation has been noted as early as 25 weeks gestation (15) . It is of interest that the fetal TSH increment after TRH is greater than is the paired-maternal response, a consequence either of enhanced TSH release or impaired TSH degradation, perhaps due to immaturity of the hepatic glycoprotein metabolic clearance system. Similarly TSH is reduced in the cord serum of infants with neonatal thyrotoxicosis due to the transplacental passage of thyroid-stimulating antibodies from mothers with Graves disease as early as the end of the 2nd trimester.

Serum levels of TRH are higher in the fetal circulation than in maternal blood, the result both of extrahypothalamic TRH production (placenta and pancreas) and the decreased TRH degrading-activity in fetal serum. The physiological significance of these increased levels of TRH in the fetal circulation is not known.

Maturation of peripheral thyroid hormone metabolism

As discussed in an earlier chapter , there are three iodothyronine deiodinases involved in the activation and inactivation of thyroid hormone (Figure 2). All three are coordinately regulated during gestation and function to closely regulate the supply of T3 to developing tissues while at the same time protecting the fetus against the effects of excess thyroid hormone. The physiological rationale for the maintenance of reduced circulating T3 concentrations throughout fetal life is still unknown, but it has been suggested that its function may be to avoid tissue thermogenesis and potentiate the anabolic state of the rapidly growing fetus while at the same time permitting highly regulated, tissue- specific maturation in an orderly, temporal sequence.

The seleno-enzyme type 1 iodothyronine deiodinase (D1), an important activating enzyme in adult life, is low throughout gestation. In addition to catalyzing T4 to T3 conversion, D1 catalyzes the inactivation of the sulfated conjugates of T4. As a consequence, circulating T3 concentrations in the fetus are quite low whereas the serum levels of the biologically inactive isomer reverse T3 and of T3 sulfate (not pictured) are increased10. Unlike D1, both the Type 2 deiodinase (D2), an activating enzyme and D3, an inactivating enzyme are present in fetal brain as early as 7 weeks ’ gestation (16) . D2 converts T4 to T3 while D3 converts T4 to reverse T3 (Figure 3). D2 and D3 are the major isoforms present in the fetus and are especially important in defining the level of T3 in the brain and pituitary. The highest concentration of D2 is in brain, pituitary, placenta and brown adipose tissue. D3 is present in many fetal tissues, most prominently the brain, uteroplacental unit, skin, and gastrointestinal tract (17) . This is consistent with the key role of D3 in protecting fetal tissues against high maternal T4 concentrations present either in the placenta or in amniotic fluid.


Figure 15-2. Molecular structure of the major thyroid hormones and the action of the monoiodothyronine deiodinase enzymes. The type l (D1) and ll (D2) deiodinases are activating deiodinases because they deiodinate the outer (phenol) ring to form metabolically active T3. The type lll deiodinase (D3) is an inactivating deiodinase because it deiodinates the inner (tyrosyl) ring to form inactive reverse (r) T3. D1 can also function as an inactivating deiodinase. Thyroid hormone is also metabolized by other mechanisms, including sulfation, glucuronidation.

In the presence of hypothyroidism, D2 activity increases while D3 decreases These coordinate activities have been found to be critically important in defending the rat fetus against the effects of fetal hypothyroidism as long as maternal T4 levels are maintained at normal concentrations (18, 19). Despite the low levels of circulating T3, brain T3 levels are 60-80% those of the adult by fetal age 20-26 weeks (20) . Thus, whereas the physiological interrelationships between the various deiodinases in the fetus and placenta seem designed to maintain circulating T3 concentrations at a reduced level, specific mechanisms have evolved for maintaining brain T3 concentrations so that normal development can proceed.

Role of the Placenta

Contributions of the maternal thyroid to fetal thyroid economy.

In the human infant under normal circumstances, the placenta has only limited permeability to thyroid hormone and the fetal hypothalamic-pituitary- thyroid system develops relatively independent of maternal influence. The relative impermeability of the human placenta to thyroid hormone is due to the presence of D3 which serves to inactivate most of the thyroid hormone presented from the maternal or fetal circulation. The iodide released in this way can then be used for fetal thyroid hormone synthesis.

Interest in the potential role of maternal T4 in the fetal thyroid economy was reawakened with the recognition that in infants with the congenital absence of thyroid peroxidase, the cord serum concentration of T4 is nonetheless between 25 and 50% of normal (21) . Since these infants are completely unable to synthesize T4, the measured hormone must be maternal in origin. Similar results are obtained in retrospective studies of cord serum in infants with sporadic congenital athyreosis. This maternal T4 disappears rapidly from the newborn circulation with a half-life of approximately 3 to 4 days.

There is also evidence that maternal-fetal T4 transfer occurs in the first half of pregnancy, when fetal thyroid hormone levels are low (19, 22) . Low concentrations of T4, presumably of maternal origin, have been detected in human embryonic coelomic fluid as early as 6 weeks gestation and in fetal brain as early 10 weeks gestation prior to the onset of fetal thyroid function. Furthermore, both D2 and D3 activity as well as thyroid hormone receptor (TR) isoforms are present in low concentrations in human fetal brain from the mid first trimester, indicating that the machinery to convert T4 to T3 and to respond to T3 is present.

It seems likely that when fetal thyroid function is normal, the net flux of T4 from mother to fetus is relatively limited. However, when the fetus is hypothyroxinemic, there is significant bulk transfer of T4 to the fetal circulation. This can occur both at the level of the placental maternal capillary interface and via uptake of thyroid hormone from the amniotic fluid through the immature epidermis. T4 uptake by the fetus can also occur via fetal ingestion of amniotic fluid. While the T4 concentrations in amniotic fluid appear modest, the fraction of T4 free in amniotic fluid is approximately ten-fold higher than that of serum and thus the free T4 concentration in amniotic fluid is approximately equal to that in fetal serum at 20 weeks gestation. It has been shown on numerous occasions in both animals and humans that amniotic fluid iodothyronine concentrations reflect those in the maternal circulation (23) .

Significance of Maternal T4

None of the neurological features of severe endemic cretinism (24) due to iodine deficiency are found in infants with sporadic congenital hypothyroidism whose mothers have normal thyroid function and who receive early and adequate postnatal treatment . Similarly, impaired hearing, when found is much milder and less frequent (25) . This would appear to provide unequivocal evidence that the neurological damage sustained by infants with endemic cretinism can be largely prevented by maternal T4. In addition to endemic cretinism, significant developmental delay despite early and adequate postnatal therapy has also been reported in other models of combined maternal-fetal hypothyroidism, such as materno-fetal POU1F1 deficiency (26) and TSH receptor blocking antibody-induced congenital hypothyroidism (27).

Maternal hypothyroidism alone has also been associated with an impairment in psychomotor development in the offspring, a result first noted by Man (28) . Unlike the severe developmental delay associated with untreated materno -fetal hypothyroidism , b oth the magnitude and critical window during pregnancy of the effect of isolated maternal hypothyroidism remain controversial . Haddow et al detected a 4 point IQ deficit in 7 to 9 year old children whose mothers were retrospectively found to have been hypothyroid at 17 weeks gestation , though the difference from normal was not statistically significant (29) . In support of this observation, Pop et al demonstrated that even babies born to women whose free T4 levels were in the lowest 10% of normal at 12 weeks gestation had a measurable impairment in psychomotor development at 2 years of age as compared with the rest of the population but this effect was not observed if maternal thyroid function was normal at 32 weeks (30) . These results were widely interpreted as supporting an important role of maternal thyr oid hormone early in pregnancy o n fetal brain development. At variance with the aforementioned studies, Liu et al , and more recently, Momotami et al failed to demonstrate any IQ deficit in babies born to hypothyroid mothers as long as the hypothyroidism was corrected by the end of the second trimester (31a, 31b) . Similar results were obtained by Downing et al in 3 children born after severe feto-maternal hypothyroidism due to TSH receptor blocking antibodies (31c) .Recently a large prospective randomized controlled trial failed to demonstrate any benefit of L-thyroxine treatment given to hypothyroid mothers from the 13 th week of gestation on the cognitive function of the offspring at 3 years of age (32) . Another large randomized control trial of early L-thyroxine therapy with cognitive evaluation at 5 years of age is currently underway.

The incidence of maternal hypothyroidism during pregnancy (3 per 1000 in iodine-sufficient populations (33) ) is almost ten times that of congenital hypothyroidism for which routine population screening is widespread. Because maternal hypothyroidism has been associated not only with potential adverse effects on fetal brain development but an increased risk of preterm delivery and of miscarriage as well (33b) some have argued that all pregnant women should be screened for hypothyroidism, a position that has been endorsed by some but not other professional societies

Placental permeability to maternal TRH, TSH, and to other factors

As noted, the placenta is freely permeable to TRH and to iodide (15) . The placenta is also permeable to certain drugs, hormones and to immunoglobulins (Igs) of the IgG class. Thus, the administration to the mother of excess iodide, drugs (especially propylthiouracil or methimazole), or the transplacental passage of TSH receptor antibodies from mothers with severe Graves disease or severe hypothyroidism due to chronic lymphocytic thyroiditis may have significant effects on fetal and neonatal thyroid function.

Maternal TSH does not cross the placenta. Similarly, Tg is undetectable in the serum of athyreotic infants, indicating the absence of any transplacental passage of this large protein.

Thyroid Function in the Neonate, the Infant, and During Childhood

The full-term neonate

Marked changes occur in thyroid physiology at the time of birth in the full term newborn. One of the most dramatic changes is an abrupt rise in the serum TSH which occurs within 30 minutes of delivery , reaching concentrations as high as 60 to 70 mU/L (8) . This causes a marked stimulation of the thyroid and an increase in the concentrations of both serum T4 and T3 (34) . These consist of an approximate 50% increase in the serum T4 and an increase of three- to four-fold in the concentration of serum T3 to adult levels at 1 to 4 days of life . Serum levels of T4, free T4 and TBG remain elevated over cord levels at 7 days of postnatal life (Figure 3), decreasing thereafter. The T3 concentration rises strikingly at Day 7, and continues to rise for the first 28 days. Opposite effects are noted in the reverse T3 levels and T3 sulfate (not pictured).

Studies in experimental animals suggest that the increase in TSH is a consequence of the relative hypothermia of the ambient extrauterine environment. However, while a significant portion of the marked increase in T3 from its low basal levels in cord serum can be explained by the abrupt increase in TSH, the simultaneous fall in reverse T3 and T3 sulfate are consistent with an increase in D1 activity occurring at the same time. D2 has been identified in human brown adipose tissue as well as brain and the acute increase in T3 in adipose tissue at birth is required for optimal uncoupling protein synthesis and thermogenesis ( 35, 36 ).

Premature infants

Thyroid function in the premature infant reflects, in part, the relative immaturity of the hypothalamic-pituitary-thyroid axis that is found in comparable gestational age infants in utero. Following delivery, there is a surge in T4 and TSH analogous to that observed in term infants, but the magnitude of the increase is less in premature neonates (8) In infants <31 weeks, the circulating T4 concentration may not increase and may even fall in the first 1 to 2 weeks of life (37)(Figure 4). This decrease in the T4 concentration is particularly significant in very premature infants, in whom the serum T4 may occasionally be undetectable. In most cases, the total T4 is more affected than the free T4 (38), a consequence of abnormal protein binding and/or the decreased TBG in these babies with immature liver function.


Figure 15-3. Postnatal changes in of T4, free T4, TBG, T3, rT3 and TSH according to gestational age. Note the increase in T4, free T4 and TBG in the full term infant in the first week of life. T3 also rises strikingly, while rT3 and TSH decline. The increase in T4 and free T4 is blunted in infants <35 weeks, and not seen at all in very premature infants in whom thyroid hormone levels may actually decline. (Redrawn from Williams et al10. See text for details.)

The causes of the decrease in T4 observed postnatally in premature infants are complex. In addition to the clearance of maternal T4 from the neonatal circulation, preterm babies have decreased thyroidal iodide stores (39) (a problem of particular significance in borderline iodine-deficient areas of the world), they are frequently sicker than their more mature counterparts, are less able to regulate iodide balance, and they may be treated by drugs that affect neonatal thyroid function (particularly dopamine and steroids). In addition, since the capacity of the immature thyroid to adapt to exogenous iodide is reduced, there is an increase in sensitivity to the thyroid-suppressive effects of excess iodide found in certain skin antiseptics and drugs to which these babies are frequently exposed (see below).

Despite the reduced total T4 observed in some preterm babies, the TSH concentration is not significantly elevated in most of these infants. In some babies, transient elevations in TSH are seen, the finding of a TSH concentration >40 mU/L being more frequent the greater the degree of prematurity. Frank et al found, for example, that the prevalence of a TSH concentration >40 mU/L in very low birth weight, (<1.5 kg), i.e., very premature, infants was 8-fold higher and in low birth weight, (1.5 kg-2.5 kg) neonates 2-fold higher than the prevalence in term babies (40). Whereas in some cases, an elevated TSH concentration may reflect true primary hypothyroidism, in other instances this increase in TSH may reflect the elevated TSH observed in adults who are recovering from severe illness. Such individuals may develop transient TSH elevations that are associated with still reduced serum T4 and T3 concentrations. These have been interpreted as reflecting a “ re-awakening ” of the illness-induced suppression of the hypothalamic pituitary axis. As the infant recovers from prematurity associated illnesses such as respiratory distress syndrome (RDS), a recovery of the illness-induced suppression of the hypothalamic- pituitary- thyroid axis would also occur.


Figure 15-4 . Cord blood levels of T4, free T4, TBG, T3, reverse T3 and TSH in the human infant. Note the low T3 and high reverse T3 concentrations as well as the discrepancy between the total T4 and free T4 levels in very premature babies, (Redrawn from Williams et al.10See text for details)

Somewhat surprisingly, given the relative immaturity of the thyroid gland, serum Tg concentrations are higher in the premature than in the full term infant (41), particularly in those who are sick with respiratory distress syndrome In view of the attenuated postnatal TSH rise in the latter babies, it is likely that impaired clearance and/or degradation of this glycoprotein from the circulation rather than increased secretion plays an important role.

Small-for-gestational-age (SGA) infants

SGA infants have significantly higher TSH and lower total and free T4 values than do

infants of normal weight (42). This can be related to the severity of the malnutrition in these infants, as well as to fetal hypoxemia and acidemia. Impaired placental perfusion and chronic starvation may also play a role. This pattern of reduced T4 and elevated TSH differs from the response to starvation in older individuals and healthy adults in whom TSH is reduced. The explanation for the relatively higher TSH in such infants is not known.

Infants and Children

Following the acute perturbations of the neonatal period there is a slow and progressive decrease in the concentrations of T4, free T4, T3 and TSH during infancy and childhood (43) . Younger children tend to have slightly higher serum concentrations of T3 and TSH, so age-specific normative values should always be consulted. The serum concentration of reverse T3 remains unchanged or increases slightly. Serum Tg levels also fall over the first year of life reaching concentrations typical of adults by about 6 months of age. Another important aspect of thyroid physiology in the infant and child is the markedly higher T4 turnover in this age group relative to that in the adult. In infants, T4 production rates are estimated to be on the order of 5 to 6 mcg/kg per day decreasing slowly over the first few years of life to about 2 to 3 mcg/kg/day at ages 3 to 9 years. This is to be contrasted with the production rate of T4 in the adult which is about 1.5 1.5mcg/kg/day. The size of the infant thyroid gland increases quite slowly. The thyroid gland of the newborn weighs approximately 1 gram and increases about 1 gram per year until age 15 when it has achieved its adult size of about 15 to 20 g. In general, the size of the thyroid lobe is comparable to that of the terminal phalanx of the infant or child ’ thumb.

Thyroid Disease in Infancy

Congenital Hypothyroidism

Non endemic congenital hypothyroidism is one of the commonest treatable causes of mental retardation. Although in the initial studies, an incidence of between 1 in 3000 and 1 in 4000 infants worldwide was obtained, the current estimate is even higher ( >1 in 2,500) (44) . Worldwide, w hether this higher figure is due to a greater sensitivity of present screening methods or the inclusion of infants with transient disease is not clear. In New England, these excess numbers are due mostly to the inclusion of mildly affected infants and those with delayed presentation ( ‘ atypical congenital hypothyroidism ’ ) but the incidence of severe permanent congenital hypothyroidism has not changed (44b) . The proportion of patients with transient disease is not known with certainty.

The association between goitrous hypothyroidism and mental retardation was first noted more than 400 years ago by Paracelsus in 1527, and Thomas Curling first described sporadic nongoitrous hypothyroidism in 1850. However, despite the demonstration by Murray in 1891 that thyroid extract could ameliorate many of the features of untreated cretinism, it was not until the 1970 ’ that the importance of early treatment in diminishing the neuro-psychological abnormalities of congenital hypothyroidism was demonstrated convincingly. In a study by Klein et al, 78% of infants with congenital hypothyroidism treated before 3 months of age but 0% treated after 6 months of age had an intelligence quotient (IQ) above 85, the mean IQ of the early treated group being 89, compared with an IQ of 54 in those treated late (45). Unfortunately, only 10% of affected infants were diagnosed clinically within the first month of life and only 35% within the first 3 months of life. The development by Dussault et al of a sensitive and specific radioimmunoassay f or the measurement of T4 in dried whole blood eluted from filter paper (and later tests for T4 and TSH using 1/8 ″ discs) provided the technical means to screen all newborns for congenital hypothyroidism prior to the development of clinical manifestations (46) .

Thus, as summarized by Delange, congenital hypothyroidism includes all the characteristics of a disease for which screening is justified: 1) it is common (4-5 times more common than phenylketonuria for which screening programs were initially developed); 2) to prevent mental retardation, the diagnosis must be made early, preferably within the first few days of life; 3) at that age, clinical recognition is difficult if not impossible; 4) sensitive, specific screening tests and 5) simple, cheap effective treatment are available; and 6) the benefit-cost ratio is highly favorable (approximately 10/1, a ratio that does not include the loss of tax income that would result from impaired intellectual capacity in the untreated, but non-institutionalized, person) (47) . Since the development of the first pilot screening program for the detection of congenital hypothyroidism in Quebec in 1972, newborn screening programs have been introduced throughout the industrialized nations and are under development in many other parts of the world. It has been estimated that as of 1999, some 150 million infants had been screened for congenital hypothyroidism worldwide with 42,000 cases detected (46) . Although there continues to be some disagreement as to whether minor neuro-intellectual sequelae remain in the most severely affected infants, accumulating evidence suggests that a normal outcome is possible even in the latter group of babies as long as treatment is started sufficiently early and is adequate ( 48-50) Certainly, the main objective of screening, the eradication of mental retardation, has been achieved. An additional benefit of newborn screening has been the elucidation of the prevalence of the various causes of congenital hypothyroidism, including a series of transient disorders found predominantly in premature infants.

Screening Strategies for Congenital Hypothyroidism

Measurement of T4 and/or TSH is performed on an eluate of dried whole blood collected on filter paper by skin puncture on day 1-4 of life. Two screening strategies for the detection of congenital hypothyroidism have evolved. In the primary T4 /backup TSH method, still favored in much of North America and the Netherlands, T4 is measured initially while TSH is checked on the same blood spot in those specimens in which the T4 concentration is low. Whereas initially a cutoff of the 3rd percentile (T4 <6 mcg/dL or 77 nmol/L) was employed, most programs now use the 10th percentile (T4 9 ug/dL or 116 nmol/L) or even the 20th percentile as a threshold to measure TSH. This has been done in order to detect patients with subclinical hypothyroidism, a finding in some infants with ectopic thyroids (the most common cause of permanent congenital hypothyroidism). Babies in whom the initial blood TSH concentration is >40 mU/L are likely to have permanent congenital hypothyroidism and are recalled immediately (51) . On the other hand, approximately 75% of infants whose initial TSH concentration is between 20 and 39 mU/L will have a normal value (<20mU/L) on repeat testing ( “ false positive ” ). Therefore a confirmatory dried blood specimen only is requested initially in the latter group of babies.

In the primary TSH approach, favored in most parts of Europe and Japan, blood TSH is measured initially. The T4 concentration is measured in the initial blood spot in all babies in whom the screening TSH is between 20 and 50 mU/L. Babies whose initial serum TSH is >50 mU/L or whose screening TSH is 20-49 mU/L but whose T4 value is <64 nmol/L (5 mcg/dL) are recalled immediately (47) . Similar to the experience with the primary T4 /backup TSH method, babies whose initial TSH is >50 mU/L are most likely to have permanent congenital hypothyroidism while a TSH between 20 and 49 mU/L is frequently a false positive, or represents transient hypothyroidism, a problem that is particularly common in premature infants in borderline iodine deficient areas of Europe.

Each screening strategy has its advantages and disadvantages, but the two approaches appear to be equivalent in the detection of babies with permanent forms of congenital hypothyroidism (52) . A primary T4 /backup TSH program will detect overt primary hypothyroidism, secondary or tertiary hypothyroidism, babies with a low serum T4 level but delayed rise in the TSH concentration, TBG deficiency and hyperthyroxinemia; this approach may, however, miss subclinical hypothyroidism . A primary TSH strategy, on the other hand, will detect both overt and subclinical hypothyroidism, but will miss secondary or tertiary hypothyroidism, a delayed TSH rise, TBG deficiency and hyperthyroxinemia. There are fewer false positives with a primary TSH strategy. Both programs will miss the rare infant whose T4 level on initial screening is normal but who later develops low T4 and elevated TSH concentrations (<0.5% of infants, most commonly premature babies with transient hypothyroidism). This pattern has been termed ‘ atypical ’ congenital hypothyroidism or ‘ delayed TSH ’ and is observed most commonly in premature babies with transient hypothyroidism or infants with less severe forms of permanent disease. Some programs have responded by performing a second screen on all infants at the time of their return visit to their pediatrician at 2 to 6 weeks of age (53) . In addition, some of these programs request follow up serum on any baby with a very low T4 value (<3rd percentile) on two occasions or a very low filter paper T4 below a critical value (<3 ug/dL) on one occasion. Programs that perform a second screen report the detection of an additional 10% of congenital hypothyroidism cases, but this practice greatly increases the cost of screening.

Other screening programs routinely perform a second screen only on patients at high risk of delayed TSH elevation, such as very low birth weight infants and babies in the neonatal intensive care unit (54) . The latter programs report a 14-fold increased incidence of atypical hypothyroidism in very low birth weight infants. As noted previously, in some of these cases, it may not be certain as to whether the elevated TSH level is pathological or represents an appropriate compensatory response following hypothyroxinemia secondary to sick euthyroid syndrome. Other groups at high-risk of delayed TSH rise are babies with cardiovascular anomalies, patients with Down syndrome and monozygotic twins (55) . In the latter group of infants, fetal cord mixing may occur and initially mask the presence of congenital hypothyroidism.

A further refinement in screening is one employed by the Netherlands where, in addition to a primary T4 /backup TSH approach, TBG is assessed in those filter paper specimens with the lowest 5% of T4 values (56) . The T4 /TBG ratio is used as an indirect reflection of the free T4, which cannot be measured directly in dried blood spots. This approach has been reported to result in improved sensitivity and specificity in detecting milder cases of primary congenital hypothyroidism that might otherwise be missed. An additional reported advantage was the identification of >90% of infants with central hypothyroidism compared with only 22% with primary T4 screening and none with a primary TSH approach . Since on subsequent testing > 80% of the babies with central hypothyroidism had multiple pituitary hormone deficiencies, a disorder associated with high morbidity and mortality for which effective treatment exists (57), and i n view of an apparent frequency (1 in 16,000) similar to that of phenylketonuria (1 in 18,000 ), the authors have argued that the goals of newborn thyroid screening should be extended to include the detection of babies with central hypothyroidism. In contrast to the Dutch experience, in a retrospective study of 42 children with central hypothyroidism identified in Indiana over a 17 year period during time which a combined T4/TSH screening strategy was employed only 8 documented cases (19%) had an initial T4 concentration <5 mcg/dL leading the authors to caution that an initially normal T4 concentration on newborn screen might led to a false sense of security.

Recently with the development of more sensitive, non-radioisotopic TSH assays, Canada and some states in the United States have switched to a primary TSH program. In practice, the screening strategy utilized is chosen by the screening program.

Newborn screening was performed initially at between 3 and 4 days of life and the normal values that were derived reflected this postnatal age. The practice of early discharge from the hospital of otherwise healthy full term infants has resulted in a greater proportion of babies being tested before this time. For example, it has been estimated that in North America 25% or more of newborns are now discharged within 24 hours of delivery and 40% in the second 24 hours of life (51) . Because of the neonatal TSH surge and the dynamic changes in serum T4 and T3 concentrations that occur within the first few days of life, early discharge increases the number of false positive results. In California, the ratio of false positive to confirmed congenital hypothyroidism has increased from 2.5:1 to approximately 5:1, an approximate doubling. Some programs have responded by increasing their threshold value for TSH within the first day of life. A potential problem, however, is the possibility of missing infants with a slowly rising TSH. Another complicating factor for newborn screening programs in recent years is the dramatically increased survival of very premature infants, due, in part, to the advent of surfactant therapy. Very premature infants greatly increase the cost of screening programs for two reasons. As discussed in detail above, blood T4 concentrations are lower and the incidence of transient hypothyroidism is much higher in them as compared with full term babies. It has been estimated that whereas very low birth weight infants constitute only 0.8% of the population, they increase the number of T4 assays in a primary TSH program by 9% (40) . Similarly, very low birth weight infants account for 8% of all TSH assays performed in a primary T4 program.

Physicians caring for infants need to appreciate that there is always the possibility for human error in failing to identify affected infants, whichever screening program is utilized. This can occur due to poor communication, lack of receipt of requested specimens, or the failure to test an infant who is transferred between hospitals during the neonatal period (58). Therefore if the diagnosis of hypothyroidism is suspected clinically, the infant should always be tested (Figure 5).

Similarly, as is obvious from the discussion earlier in the chapter, adult normative values, provided by many general hospital laboratories, differ from those in the newborn period and should never be employed. Normal values according to both gestational and postnatal age for cord blood T4, free T4, TBG, T3, reverse T3, and TSH up to 28 days of life (10) are shown in Figure 3. Normal serum levels of Tg in premature and full-term infants (13, 14 ) and normal serum levels of free T4 and TSH in the first week of life (59) have also been published, though it should be noted that precise values may vary somewhat, depending on the specific assays used.


Figure 15-5 . Three month old male infant who was diagnosed clinically when he presented with a history of poor feeding at 3 months of age. The child was born in Puerto Rico prior to the development of newborn screening and moved to the United States shortly thereafter. Note the dull facies, periorbital edema and large tongue.

Causes of Permanent Congenital Hypothyroidism

Thyroid Dysgenesis

Unlike in iodine-deficient areas of the world where endemic cretinism continues to be a major health hazard, the majority (85 to 90%) of cases of permanent congenital hypothyroidism in North America, Western Europe and Japan are due to an abnormality of thyroid gland development ( thyroid dysgenesis ). Thyroid dysgenesis may result in the complete absence of thyroid tissue (agenesis) or it may be partial (hypoplasia); the latter often is accompanied by a failure to descend into the neck (ectopy). Females are affected twice as often as males. In the United States, thyroid dysgenesis, is less frequent among African Americans and more common among Hispanics and Asians. Babies with congenital hypothyroidism have an increased incidence of cardiac anomalies, particularly atrial and ventricular septal defects (60) . An increased prevalence of renal and urinary tract anomalies has also been reported recently (61) .

Most cases of thyroid dysgenesis are sporadic. Although both genetic and environmental factors have been implicated in its etiology, in most cases the cause is unknown. The occasional familial occurrence, the higher prevalence of thyroid dysgenesis in babies of certain ethnic groups and in female versus male infants as well as the increased incidence in babies with Down syndrome (62) all suggest that genetic factors might play a role in some patients. The transcription factors NKX 2.1 ( TTF 1), FOXE 1 ( TTF 2) and PAX 8 would appear to be obvious candidate genes in view of their important role in thyroid organogenesis and in thyroid-specific gene expression. To date, however, abnormalities in these genes have been found in only a small proportion of affected patients, usually in association with other developmental abnormalities. For example, the syndrome of congenital hypothyroidism associated with unexplained neonatal respiratory distress, ataxia, and developmental delay has been found in a number of patients with genetic abnormalities of NKX 2.1, analogous to the findings of abnormal thyroid, lung, pituitary, and forebrain development in mice with a targeted disruption of this gene (63) . In contrast, no germline mutations in NKX 2.1 gene were found in a total of 76 patients with isolated CH ( 64, 65 ). A similar situation has been found with FOXE 1 ( TTF 2), a mutation which has been reported in 2 siblings with the combination of thyroid agenesis, cleft palate, spiky hair and choanal atresia (66) . In a different study, germline mutations of PAX 8 were found in only 2 of 145 Italian patients with sporadic thyroid dysgenesis studied. In one of these latter patients, the thyroid gland was hypoplastic and ectopic while in the other patient the thyroid gland was hypoplastic but located in a normal position in the neck. Since PAX 8 is also involved in renal development it will be important to determine whether this gene is related to the increased prevalence of renal urinary tract anomalies that has been noted recently. It is possible that thyroid dysgenesis is a polygenic disease with variable penetrance depending on the genetic background (67) . Alternately, epigenetic modifications, early somatic mutations or stochastic developmental events may play a role. Table 1. summarizes known molecular defects in transcription factors and other causes of congenital hypothyroidism.

Table 1 . Genetic causes of permanent congenital hypothyroidism.
Abnormality Gene Gene locus Inheritance
Abnormal thyroid gland development/migration §
TTF1/NKX2.1 # 14q13 AD*
TTF2/FOXE1 # 9q22 AR**
PAX8 2q11.2 AD
Abnormal thyroid hormonogenesis
Decreased T4 synthesis
NIS 19p12-13.2 AR
TPO 2p25 AR
DUOX2 15q15.3 AR
TG 8q24 AR,AD
DEHAL1 6q24-25 AR
SLC26A4/PDS 7q31 AR
Decreased TSH synthesis
Other pituitary hormone deficits
PROP1 5q AR
POU1F1 3p11 AR,AD
LHX3 9q34.3 AR
LHX4 1q25 AR,AD
HESX1 3p21.2-p21.2 AR,AD
Isolated decreasedTSH
TRH 3p AR
TRHR 14q31 AR
TSH β 1p13 AR
Decreased TSH response
TSHR 14q31 AR
Gs α 20q13.2 AD
Abnormal thyroid hormone action
TR β 3p24.3 AD
MCT8 Xq13.2 X-linked
SECISBP2 9q22.2 AR

§usually sporadic, *AD, autosomal dominant, ** AR, autosomal recessive, # usually syndromic permanent when biallelic, transient when monoallelic,

Inborn Errors of Thyroid Hormonogenesis

Inborn errors of thyroid hormonogenesis are responsible for most of the remaining cases (15%) of neonatal hypothyroidism. A number of different defects have been characterized and include: 1) decreased TSH responsiveness, 2) failure to concentrate iodide, 3) defective organification of iodide due to an abnormality in the peroxidase enzyme or in the H2O2 generating system, 4) defective Tg synthesis or transport, and 5) abnormal iodotyrosine deiodinase activity (68) . The association of an organification defect with sensorineural deafness is known as Pendred syndrome. Though usually included in causes of congenital hypothyroidism because it is caused by a genetic defect, Pendred syndrome rarely presents in the newborn period.

Unlike thyroid dysgenesis, a sporadic condition, these inborn errors of thyroid hormonogenesis are commonly associated with an autosomal recessive form of inheritance, consistent with a single gene abnormality. It is not surprising, therefore, that a molecular basis has now been identified in all of them. These include defects in the genes for the TSH receptor ( TSHR ), the sodium-iodide symporter ( NIS ), TPO , dual oxidase (DUOX) 2, Tg, and iodotyrosine deiodinase ( DEHAL1 ). Pendred syndrome is now known to be caused by mutations in the pendrin gene ( PDS , now called SLC26A 4), which encodes a sulfate transporter of iodide on the apical surface of the thyroid follicular cell as well as the cochlea ( 68). Mutations in this gene have also been found to be an important genetic cause of isolated sensorineural deafness. Mutations in DUOX2 , important in hydrogen peroxide generation, have been shown to cause both transient and permanent forms of congenital hypothyroidism, depending upon whether the mutation is monoallelic or biallelic. Inborn errors of thyroid hormonogenesis are summarized in Table 1 and discussed in further detail in elsewhere.

All of the inborn errors of thyroid hormonogenesis except decreased TSH responsiveness are associated with a normally placed ( ’ eutopic ’ thyroid gland that may be increased in size at birth and this feature forms the basis for the clinical distinction from thyroid dysgenesis. In contrast, most babies with TSH resistance have a normal or hypoplastic, eutopic gland that may in some cases mimic an abnormality of thyroid gland development ( 69, 70 ); in rare cases no thyroid gland at all is discernible on thyroid imaging, a picture indistinguishable from thyroid agenesis (71). Similar to the variability observed in thyroid gland size in this condition, the clinical findings in TSH resistance have varied from subclinical to overt hypothyroidism depending on the severity of the functional defect. Some of these patients have been found to have a loss of function mutation of the TSH receptor, analogous to the hyt/hyt mouse (72) . In a few affected infants, a discrepancy between presumed athyreosis on thyroid scintigraphy and the detection of either a ‘ normal ’ serum Tg concentration or glandular tissue on ultrasound examination has been noted (71) , a feature that may be helpful diagnostically.

The relative frequency of TSH receptor gene mutations as a cause of TSH resistance is not known. In one study, inactivating mutations of the TSH receptor gene were found in only 1 of 100 patients with congenital hypothyroidism, indicating that abnormalities in this gene are not a common cause of thyroid hypoplasia or aplasia (73) . A similar conclusion may be drawn from the failure to demonstrate linkage to the TSH receptor gene in 23 families in a majority of which there were two or more children affected by congenital hypothyroidism and in whom there was appreciable consanguinity of the parents (74) . However, a recent study suggests that mutations in this gene may be more common, particularly in certain populations (75) . Most familial cases of TSH resistance have an autosomal recessive form of inheritance. Rarely TSH resistance may be due to an inactivating mutation of the stimulatory guanine nucleotide-binding protein (Gs alpha-gene (pseudohypoparathyroidism, type la or Albright ’ s hereditary osteodystrophy). Usually the latter patients have transient hypothyroidism in the newborn period or a mild functional defect that results in subclinical hypothyroidism later in life (76) . Albright ’ s hereditary dystrophy has an autosomal dominant inheritance with variable expression depending upon whether the mutant gene is paternally or maternally derived.

Secondary and/or Tertiary Hypothyroidism

Central hypothyroidism was previously thought to occur in 1 in 50,000 to 1 in 100,00 0 newborn infants, but, as noted previously, it may be much more common ( 44). TSH deficiency may be isolated or it may be associated with other pituitary hormone deficiencies. Familial cases of both TSH deficiency and TRH deficiency have been described. A reported cause of isolated TSH deficiency is the CAGYC mutation in the gene for the TSH beta molecule. A mutation in the TRH receptor gene has also been described in a child in whom secondary hypothyroidism was missed on newborn screening. In the latter patient, the diagnosis was suspected clinically because of an absent TSH and prolactin response to TRH despite a normal pituitary gland on imaging (77) (Table 1).

TSH deficiency in association with other pituitary hormone deficiencies may be associated with abnormal midline facial and brain structures (particularly cleft lip and palate, and absent septum pellucidum and/or corpus callosum) and should be suspected in any male infant with microphallus and persistent hypoglycemia (78) . One of the more common of these syndromes, septo-optic dysplasia, has been related in some cases to a mutation in the HESX 1 homeobox gene in some cases (79) . Other genetic causes of congenital hypopituitarism include molecular defects in the genes for the transcription factors LHX3 ( 80) , LHX4, POU1F 1 (81) or PROP 1 (81) . POU1F 1 (Pit-1 in mice) is essential for the differentiation of both thyrotrophs, lactotrophs and somatotrophs while PROP 1, a homeodomain protein that is expressed briefly in the embryonic pituitary, is necessary for POU1F 1 expression. The molecular basis for pituitary hypoplasia associated with an ectopic posterior pituitary gland (78) has not been elucidated .

Decreased T 4 Action

Until recently, the only known cause of decreased thyroid hormone action was a molecular defect in the thyroid hormone receptor (TR) beta that rendered the cell unable to respond. Recently two additional causes have been recognized: inadequate intracellular T4 transport, and an abnormality in the synthesis of D2 leading to a defect in T4 to T3 conversion.

i) Decreased Cellular Transport

Decreased T4 uptake into brain cells is a newly recognized congenital abnormality of thyroid hormone action. In this syndrome mutations in the monocarboxylate transporter 8 ( MCT 8 gene, located on the X-chromosome, have been associated with male- limited hypothyroidism and severe neurological abnormalities, including global developmental delay, dystonia, central hypotonia, spastic quadriplegia, rotary nystagmus and impaired gaze and hearing (82) . Heterozygous females had a milder thyroid phenotype and no neurological defects.

ii) Thyroid Hormone Resistance

Generalized resistance to thyroid hormone (GRTH), the classical cause of inadequate T4 action, is usually diagnosed later in life, but may be identified in the newborn period by neonatal screening programs that determine primarily TSH ( 83). Affected babies usually are not symptomatic; later in life they may fail to thrive, have attention deficit disorder, a small goiter and unexplained tachycardia. Most cases of GRTH result from a mutation in the TR beta gene and follow an autosomal dominant pattern of inheritance. Recently a patient with a de novo heterozygous nonsense mutation in the gene encoding TR alpha has been described (83b). In this patient, adverse effects on growth and skeletal development were more prominent. Thyroid hormone resistance is discussed in greater detail elsewhere.

iii) Abnormal thyroid hormone metabolism

Decreased T4 action may be the result of a homozygous mutation in SECISBP 2, a gene required for the incorporation of selenocysteine into D284. This results in decreased activation of T4 to T3. Affected patients have abnormal thyroid function but are otherwise normal.

Causes of transient neonatal hypothyroidism

Transient neonatal hypothyroidism should be distinguished from a ‘ false positive ’ result in which the screening result is abnormal but the confirmatory serum sample is normal. In North America, the original estimate was 1 in 40,000 infants, equivalent to approximately 10% of all cases of congenital hypothyroidism. Recent data suggest that the condition is now more than three-fold more common (1 in 11,000 to 1 in 12,000) ( 44), probably due, at least in part, to the survival of increasingly premature infants.

Causes of transient abnormalities of thyroid function in the newborn period are listed in Table 2. While iodine deficiency, iodine excess, drugs and maternal TSH receptor blocking antibodies are the most common causes of transient hypothyroidism, in some cases the cause is unknown.

i) Iodine Deficiency or Excess

Transient hypothyroidism due to both iodine deficiency and iodine excess is more common in relatively iodine-deficient areas of Europe than in North America, an iodine-sufficient region ( 47). In Belgium, for example, prior to the institution of routine iodine supplementation in premature infants, transient hypothyroidism was reported in 20% of premature infants, an 8-fold higher prevalence than in North America. Premature infants are unusually susceptible to the effects of iodine deficiency not only because of decreased thyroidal iodine stores accumulated in utero, but because of immaturity in both the capacity for thyroid hormonogenesis, the hypothalamic-pituitary-thyroid axis, and in the ability to convert T4 to the more metabolically active T3 . Furthermore, premature infants are in negative iodine balance for the first 1 or 2 weeks of postnatal life ( 39).

Table 2 . Causes of Transient Abnormalities of Thyroid Function in the Newborn Period

Primary hypothyroidism

Prenatal or postnatal iodine deficiency or excess

Maternal antithyroid medication

Maternal TSH receptor blocking antibodies

Monoallelic mutation in DUOX 2

Central hypothyroidism

Prenatal exposure to maternal hyperthyroidism

Prematurity (particularly <27 weeks gestation)

Drugs

Miscellaneous

Isolated hyperthyrotropinemia

Sick euthyroid syndrome

Malnutrition

TBG deficiency

In addition to iodine deficiency, both the fetus and newborn infant are sensitive to the thyroid-suppressive effects of excess iodine, whether administered to the mother during pregnancy, lactation or directly to the baby ( 85). This occurs, in part because, as noted earlier, recovery from the thyroid-suppressive effect of iodine does not mature before 36 weeks gestation; however, other factors, including increased skin absorption are also likely to play a role. Reported sources of iodine have included drugs (e.g., potassium iodide, amiodarone), radiocontrast agents and antiseptic solutions (e.g., povidone-iodine) used for skin cleansing or vaginal douches. In contrast to Europe, iodine-induced transient hypothyroidism has not been documented frequently in North America ( 86).

ii) Maternal Antithyroid Medication

Transient neonatal hypothyroidism may develop in babies whose mothers are being treated with antithyroid medication (either propylthiouracil, PTU or methimazole, MMI) for the treatment of Graves ’ disease. Even maternal PTU doses of 200 mg or less have been associated with an effect on neonatal thyroid function, illustrating the increased fetal sensitivity to these drugs ( 87). Babies with PTU- or MMI-induced hypothyroidism characteristically develop an enlarged thyroid gland and if the dose is sufficiently large, respiratory embarrassment may occur. Both the hypothyroidism and goiter resolve spontaneously with clearance of the drug from the baby ’ s circulation. Usually replacement therapy is not required.

iii) Maternal TSH Receptor Antibodies

Maternal TSH receptor blocking antibodies, a population of antibodies closely related to the TSH receptor stimulating antibodies in Graves disease, may be transmitted to the fetus in sufficient titer to cause transient neonatal hypothyroidism. The incidence of this disorder has been estimated to be 1 in 180,000 ( 88). TSH receptor blocking antibodies most often are found in mothers who have been treated previously for Graves disease or who have the non goitrous form of chronic lymphocytic thyroiditis (primary myxedema). Occasionally these mothers are not aware that they are hypothyroid and the diagnosis is made in them only after congenital hypothyroidism has been recognized in their infants ( 89). Unlike TSH receptor stimulating antibodies that mimic the action of TSH, TSH receptor blocking antibodies inhibit both the binding and action of TSH (see below). Because TSH-induced growth is blocked, these babies do not have a goiter. Similarly, inhibition of TSH-induced radioactive iodine uptake may result in a misdiagnosis of thyroid agenesis ( 90). Usually the hypothyroidism resolves in 3 or 4 months. Babies with TSH receptor blocking-antibody induced hypothyroidism are difficult to distinguish at birth from the more common thyroid dysgenesis but they differ from the latter in a number of important ways (Table 3). They do not require lifelong therapy, and there is a high recurrence rate in subsequent offspring due to the tendency of these antibodies to persist for many years in the maternal circulation. Unlike babies with thyroid dysgenesis in whom a normal cognitive outcome is found if postnatal therapy is early and adequate, babies with maternal blocking-antibody induced hypothyroidism may have a permanent deficit in intellectual development if feto-maternal hypothyroidism was present in utero ( 27).

iv DUOX 2

Whereas a biallelic mutation in DUOX2 is associated with permanent congenital hypothyroidism, when a monoallelic mutation is found the course of the congenital hypothyroidism is transient.

Table 3.Clinical features of thyroid dysgenesis versus TSH receptor blockingantibody-induced Congenital Hypothyroidism.
Dysgenesis Blocking Ab
Severity of CH + to ++++ + to ++++
Palpable thyroid No No
123I uptake None to low None to normal
Clinical Course Permanent Transient
Familial risk No Yes
TPO Abs Variable Variable
TSH Receptor Abs Absent Potent
Prognosis Normal May be delayed

Transient Central Hypothyroidism

i) Maternal hyperthyroidism

Occasionally, babies born to mothers who were hyperthyroid during pregnancy develop transient hypothalamic-pituitary suppression ( 91). This hypothyroxinemia is usually self-limited, but in some cases it may last for last years and require replacement therapy ( 92). In general the titer of TSH receptor stimulating antibodies in this population of infants is lower than in those who develop transient neonatal hyperthyroidism (see below).

ii) Prematurity

Hypothyroxinemia in the presence of a ‘ normal ’ TSH occurs most commonly in premature infants in whom it is found in 50% of babies of less than 30 weeks gestation. Often the free T4 when measured by equilibrium dialysis is less affected than the total T4 (93). The reasons for the hypothyroxinemia of prematurity are complex. As well as hypothalamic-pituitary immaturity mentioned earlier, premature infants frequently have TBG deficiency due to both immature liver function and undernutrition, and they may have “ sick euthyroid syndrome ” . They may also be treated with drugs that suppress the hypothalamic-pituitary-thyroid axis.

iii) Drugs

Drugs that suppress the hypothalamic-pituitary axis include known agents such as steroids and dopamine, but also aminophylline, caffeine and diamorphine, other commonly used in sick premature infants ( 94).

Miscellaneous Abnormalities

i) Idiopathic hyper thyrotropinemia

An elevated serum TSH concentration with normal circulating T4 and free T4 levels has been noted, often in screening programs that utilize a primary TSH method and is most common in premature infants. As a group, babies diagnosed with hyperthyrotropinemia in infancy have a higher serum TSH concentration compared to control children when reexamined in early childhood ( 95). In addition these infants have a higher prevalence of both thyroid morphological abnormalities, antithyroid antibodies, and mutations in thyroperoxidase and TSH receptor genes than do controls ( 96), suggesting that the elevated serum TSH concentration is related to mild hypothyroidism. Subclinical hypothyroidism needs to be distinguished from delayed maturation of the hypothalamic- pituitary axis ( 97), a transient condition, and the cold-induced TSH surge observed postnatally. Several years ago, a maternal heterophile antibody that cross-reacted in the TSH radioimmunoassay in routine use at the time was implicated (98) .

Clinical Manifestations

Clinical findings are usually difficult to appreciate in the newborn period except in the unusual situation of combined maternal-fetal hypothyroidism. Many of the classic features (large tongue, hoarse cry, facial puffiness, umbilical hernia, hypotonia, mottling, cold hands and feet and lethargy), when present, are subtle and develop only with the passage of time. In addition to the aforementioned findings, nonspecific signs that should suggest the diagnosis of neonatal hypothyroidism include: prolonged, unconjugated hyperbilirubinemia, gestation longer than 42 weeks, feeding difficulties, delayed passage of stools, hypothermia or respiratory distress in an infant weighing over 2.5 kg ( 99). A large anterior fontanelle and/or a posterior fontanelle > 0.5 cm is frequently present in affected infants but may not be appreciated.

In general, the extent of the clinical findings depends on the cause, severity and duration of the hypothyroidism. Babies in whom severe feto-maternal hypothyroidism was present in utero tend to be the most symptomatic at birth. Similarly, babies with athyreosis or a complete block in thyroid hormonogenesis tend to have more signs and symptoms at birth than infants with an ectopic thyroid, the most common cause of congenital hypothyroidism. Unlike acquired hypothyroidism, babies with congenital hypothyroidism are of normal size. However, if diagnosis is delayed, subsequent linear growth is impaired. The finding of palpable thyroid tissue suggests that the hypothyroidism is due to an abnormality in thyroid hormonogenesis or in thyroid hormone action, or that it will be transient.

Laboratory Evaluation

Infants found to have abnormal thyroid function tests by newborn screening should have a confirmatory serum sample evaluated without delay, preferably within 24 hours. The diagnosis of neonatal hypothyroidism is confirmed by the demonstration of a decreased concentration of free T4 for age and an elevated TSH level (> 20 mU/L after one day of life) in serum As noted previously, most infants with permanent abnormalities of thyroid function have a serum TSH concentration >40 mU/L. In some screening programs infants with milder thyroid abnormalities, particularly premature infants, are followed with repeat filter paper specimens in anticipation that the abnormality will be transient. Postnatal and gestational age-related normative values should always be used and not the adult values that are commonly provided in many general hospital laboratories. Measurement of T3 is of little value in the diagnosis of congenital hypothyroidism.

A bone age may be performed as a reflection of the duration and severity of the hypothyroidism in utero but is performed much less frequently now than in the past . A radionuclide scan (either 123I or pertechnetate) provides information about the location, size and trapping ability of the thyroid gland; ectopic thyroid glands, frequently sublingual, may be located anywhere along the pathway of thyroid descent from the foramen cecum to the anterior mediastinum. Thyroid imaging is helpful in verifying whether a permanent abnormality is present and aids in genetic counseling since thyroid dysgenesis is almost always sporadic condition whereas abnormalities in thyroid hormonogenesis tend to be autosomal recessive. Scintigraphy with 123I, if available, is usually preferred because of the greater sensitivity and because, 123I, unlike pertechnetate is organified. Therefore, imaging with this isotope allows quantitative uptake measurements and tests for both iodine transport defects and abnormalities in thyroid oxidation. The lowest possible dose of 123I, usually 25 mcCi, should be used. Advantages of pertechnetate, on the other hand, are that it is cheaper and more widely available. Therapy need not be delayed as long as scintiscan is performed within 5 to 7 days, and/or the serum TSH concentration is >30 mU/L. If there is no uptake on scintiscan, an ultrasound study should be performed to confirm the absence of thyroid tissue.

There is some disagreement as to whether a thyroid scan should be performed in all babies because of the unknown risk of radiation exposure, particularly in centers where only 131 -I is used and relatively large doses of isotope are administered. Partly for this reason, ultrasonography has become an increasingly popular alternative to thyroid scintigraphy to provide information about the size and location of the thyroid gland and so, distinguish abnormalities of thyroid development (almost always sporadic conditions) from either abnormalities of thyroid hormonogenesis (mostly autosomal recessive) or transient abnormalities. Ultrasound appears to be somewhat less sensitive than a radionuclide scan in detecting ectopic thyroid tissue and does not provide information about function, so interpretation of the results needs to be combined with other information, e.g., the serum Tg concentration. In one report, color Doppler ultrasonography was almost as good as scintiscan, a finding that needs to be confirmed ( 100).

Occasionally, apparent thyroid agenesis is due to the presence of maternal TSH receptor blocking antibodies, which, if present in a sufficiently high titer, completely inhibit TSH-induced thyroidal uptake of radioisotope (90) . In these cases, thyroid ultrasound reveals the presence of a normal or small, eutopic gland. The presence of autoimmune thyroid disease in the mother or a history of a previously affected sibling should alert the physician to the possibility of this diagnosis but this information is not always known and should not be relied upon. A radio-receptor or ELISA assay is appropriate for screening; a commercial bioassay for blocking Abs has recently become available in the United States. This topic is discussed in further detail later in the chapter. In cases of TSH receptor antibody-induced congenital hypothyroidism, the blocking activity is extremely potent, half-maximal TSH binding-inhibition being reported with as little as a 1/20 to 1/50 dilution of serum; a weak or borderline result should cause a reconsideration of this diagnosis. Similarly, TPO antibodies, although frequently detectable in babies with blocking antibody-induced congenital hypothyroidism, are neither sensitive nor specific in predicting the presence of transient congenital hypothyroidism (90).

Other disorders that may mimic thyroid agenesis on thyroid scintigraphy include loss of function mutations of the TSH receptor, iodine excess, or an iodide concentrating abnormality. Potential clues to the diagnosis of a loss of function mutation of the TSH receptor include a normal Tg and/or evidence of a thyroid gland on ultrasound examination despite the failure to visualize thyroid tissue on imaging studies ( 71). Ultimately verification of this diagnosis resides in the demonstration of a genetic abnormality in the TSH receptor gene. Measurement of urinary iodine is helpful if a diagnosis of iodine-induced hypothyroidism is suspected. An iodide-concentrating defect should be suspected in patients with a family history of congenital hypothyroidism, particularly if an enlarged thyroid gland is present. A suggested evaluation of infants is shown in Figure 6 .

Measurement of Tg is most helpful when a defect in Tg synthesis or secretion is being considered. In the latter condition the serum Tg concentration is low or undetectable despite the presence of a normal or enlarged, eutopic thyroid gland. Serum Tg concentration also reflects the amount of thyroid tissue present and the degree of stimulation. For example, Tg is undetectable in most patients with thyroid agenesis, intermediate in babies with an ectopic thyroid gland and may be elevated in patients with abnormalities of thyroid hormonogenesis not involving Tg synthesis and secretion. Considerable overlap exists, and so, the Tg value needs to be considered in association with the findings on imaging. In patients with inactivating mutations of the TSH receptor a discordance between findings on thyroid imaging and the serum Tg concentration has been described in some but not all studies ( 71).

In babies in whom hypothyroxinemia unaccompanied by TSH elevation is found, a free T4 should be measured, preferably by a n equilibrium dialysis method and the TBG concentration should be evaluated as well. The finding of a low free T4 in the presence of a normal TBG may suggest the diagnosis of central hypothyroidism. Pituitary function testing and brain imaging should also be performed in these infants. The utility of TRH testing, used for many years to distinguish between a hypothalamic or pituitary defect, has been questioned ( 101). In any case, TRH is no longer available for testing in the US. In premature, low birth weight or sick babies in whom a low T4 and a ‘ normal ’ TSH are found, the free T4 when measured by a direct dialysis method, frequently is not as low as the total T4. In the latter infants T4 (and/or free T4), and TSH should be repeated every 2 to 4 weeks until the T4 normalizes because of the rare occurrence of delayed TSH rise ( 53, 102 ). Similarly, any baby suspected of being hypothyroid clinically should have repeat thyroid function testing because of rare errors in the screening program.

Therapy

Replacement therapy with L-thyroxine sodium should be begun as soon as the diagnosis of congenital hypothyroidism is confirmed. In babies whose initial results on newborn screening are suggestive of severe hypothyroidism (e.g., T4 <5 mcg/dL 64 nmol/L) and/or TSH >50 mU/L), therapy should be begun immediately without waiting for the results of the confirmatory serum. As noted above, treatment need not be delayed in anticipation of performing thyroid imaging studies as long as the latter are done within 5-7 days of initiating treatment (before suppression of the serum TSH). Parents should be counseled regarding the causes of congenital hypothyroidism, the importance of compliance and the excellent prognosis in most babies if therapy is initiated sufficiently early and is adequate and educational materials should be provided ( 103).

An initial dosage of 10-15 mc­g/kg is generally recommended so as to normalize the T4 as soon as possible. A recent study in a small group of patients has suggested that an even higher initial dose (12 to 17 mc­g/kg, equivalent to 50 mc­g in a full term baby) may be even better ( 104). Babies with mild hypothyroidism should be started on the lower dosage, while those with severe congenital hypothyroidism (e.g., T4 <5 mcg/kg/dL (64 nmol/L)), such as those with thyroid agenesis, should be started on the higher dosage. Thyroid hormone may be crushed and administered with juice or formula, but care should be taken that all of the medicine has been swallowed. Thyroid hormone should not be given with substances that interfere with its absorption, such as iron, soy, or fiber. Many babies will swallow the pills whole or will chew the tablets with their gums even before they have teeth. Reliable liquid preparations are not available commercially in the US, although they have been used successfully in Europe.

The aims of therapy are to normalize the T4 as soon as possible, to avoid hyperthyroidism where possible, and to promote normal growth and development. When an initial dosage of 10-15 mc­g/kg is used, the T4 will normalize in most infants within 1 week and the TSH will normalize within 1 month. When a higher dosage is used (12-17 mc ­g/kg) normalization is even faster (3 days and 1 week, respectively) ( 104). Subsequent adjustments in the dosage of medication are made according to the results of thyroid function tests and the clinical picture. Often small increments or decrements of L-thyroxine (12.5 mcg) are needed. This can be accomplished by 1/2 tablet changes, by giving an alternating dosage on subsequent days, or by giving an extra tablet once a week. Some infants will develop supraphysiologic serum T4 values on this amount of thyroid replacement but the serum T3 concentration usually remains normal, affected infants are not symptomatic, and available information suggests that these short-term T4 elevations are not associated with any adverse effects on growth, bony maturation, or cognitive development.

A persistently elevated serum TSH level associated with a normal or increased serum T4 concentration is seen less often now than in the past, possibly because of the higher initial L-thyroxine dose employed. Relative pituitary resistance has been implicated as a cause of this finding, but noncompliance should always be excluded. In these cases, the T4 value is used to titrate the dosage of medication. One usually aims to maintain the T4 above 10 mc­g/dL (128.7 nmol/L) and the TSH at less than 10 mU/L. Close follow-up is necessary. Current recommendations are to repeat the T4 and TSH at 2 and 4 weeks after the initiation of L-thyroxine treatment, every 1-2 months during the first year of life, every 2-3 months between 1 and 3 years of age, and every 3-12 months thereafter until growth is complete. In hypothyroid babies in whom an organic basis was not established at birth and in whom transient disease is suspected, a trial off replacement therapy can be initiated after the age of 3 years when most thyroxine-dependent brain maturation has occurred. Alternatively, recombinant hTSH, which has the advantage that therapy need not be discontinued, may become the preferred method in the future ( 105).

Whether or not premature infants with hypothyroxinemia should be treated remains controversial at the present time ( 106). Although several retrospective, cohort studies have documented a relationship between severe hypothyroxinemia and both developmental delay and disabling cerebral palsy in preterm infants <32 weeks gestation a causal relationship could not be determined since the serum T4 in premature infants, as in adults, has been shown to reflect the severity of illness and risk of death ( 106). In the most thorough study to date, Van Wassenaer et al carried out a placebo-controlled, double blind trial of L-thyroxine treatment, 8 mcg /kg per day for 6 weeks in 200 infants less than 30 weeks gestation ( 107). Although overall no difference in cognitive outcome was found, there was an 18-point increase in the Bayley Mental Development Index score in the subgroup of T4 -treated infants <27 weeks gestation when reevaluated at 2 years of age. Of some concern was the additional finding that treatment was associated with a 10-point decrease in mental score (p=0.03) in infants >27 weeks gestation. When the cohort was reevaluated at 10 years of age the difference in IQ was no longer significant, although modest differences in motor achievement and the need for special education persisted ( 108). In a recent multicenter collaborative pilot study L-thyroxine, at a dosage of 8 mc­g/kg/day coupled with T3 for the first 2 weeks of postnatal life was associated with suppression of TSH and an increased incidence of necrotizing enterocolitis, suggesting that this dose might be excessive. While the cognitive outcome data of these babies is not yet known , it is clear that more data are needed. In the meantime, it would seem reasonable to treat only premature infants with hypothyroxinemia and a normal TSH only in the context of a clinical trial. In all premature every effort should be made to assure adequate iodine intake, treat the primary illness and to avoid, if possible, drugs (e.g.,dopamine, steroids, aminophylline, caffeine and diamorphine) that have been shown to suppress TSH ( 106), with close follow up of circulating thyroid hormone levels until they normalize. Whether or not these infants should be treated with T4 and at what dosage remains to be determined.

Prognosis

Although all are agreed that the mental retardation associated with untreated congenital hypothyroidism has been eradicated by newborn screening, controversy persists as to whether subtle cognitive and behavioral deficits remain, particularly in the most severely affected infants ( 48, 49, 109-112 ). Both the initial treatment dose (at least 10 mcg-15 mcg/kg) and early onset of treatment (before 2 weeks) are important. Time to normalization of circulating thyroid hormone levels, the initial free T4 concentration, maternal IQ, socioeconomic and ethnic status have also been related to outcome ( 48, 110, 112 ). The long term problems for these babies appear to be in the areas of memory, language, fine motor, attention and visual spatial. Inattentiveness can occur both in patients who are overtreated and those in whom treatment was initiated late or was inadequate. In addition to adequate dosage, assurance of compliance and careful longterm monitoring are essential for an optimal developmental outcome.

Hyperthyroidism

Causes of Transient Neonatal Hyperthyroidism

Unlike congenital hypothyroidism which usually is permanent, neonatal hyperthyroidism almost always is transient and results from the transplacental passage of maternal TSH receptor stimulating antibodies. Hyperthyroidism develops only in babies born to mothers with the most potent stimulatory activity in serum ( 113, 114 ). This corresponds to 1-2% of mothers with Graves disease, or 1 in 50,000 newborns, an incidence that is approximately four times higher than is that for transient neonatal hypothyroidism due to maternal TSH receptor blocking antibodies. Some mothers have mixtures of stimulating and blocking antibodies in their circulation, the relative proportion of which may change over time. Not surprisingly, the clinical picture in the fetus and neonate of these mothers is more complex and depends not only on the relative proportion of each activity in the maternal circulation at any one time but on the rate of their clearance from the neonatal circulation postpartum. Thus, one affected mother gave birth, in turn, to a normal infant, a baby with transient hyperthyroidism, and one with transient hypothyroidism ( 115). In another neonate, the onset of hyperthyroidism did not become apparent until 1-2 months postpartum when the higher affinity blocking antibodies had been cleared from the neonatal circulation ( 116). In the latter case, multiple TSH receptor stimulating and blocking antibodies were isolated from the maternal peripheral lymphocytes. Each monoclonal antibody recognized different antigenic determinants ( “ epitopes ” ) on the receptor and had different functional properties ( 117).

Occasionally, neonatal hyperthyroidism may even occur in infants born to hypothyroid mothers. In these situations, the maternal thyroid has been destroyed either by prior radioablation, surgery or by coincident destructive autoimmune processes so that potent thyroid stimulating antibodies, present in the maternal circulation, are silent in contrast to the neonate whose thyroid gland is normal ( 117).

Clinical manifestations

Although maternal TSH receptor antibody-mediated hyperthyroidism may present in utero, most often the onset is during the first week of life. This is due both to the clearance of maternally-administered antithyroid drug (propylthiouracil, PTU, methimazole or carbimazole) from the infant ’ s circulation and to the increased conversion of T4 to the more metabolically active T3 after birth. Rarely, as noted earlier, the onset of neonatal hyperthyroidism may be delayed until later if higher affinity blocking antibodies are also present. Fetal hyperthyroidism is suspected in the presence of fetal tachycardia (pulse greater than 160/min) especially if there is evidence of failure to thrive. In the newborn infant, characteristic signs and symptoms include tachycardia, irritability, poor weight gain, and prominent eyes (Figure 7). Goiter, when present, may be related to maternal antithyroid drug treatment as well as to the neonatal Graves disease itself.


Figure 15-7. A baby with neonatal hyperthyroidism secondary to maternal Grave's disease. Note the prominent eyes in the baby and mother in whom Graves disease developed after radioiodine therapy for Hodgkins disease. In contrast, the father was unaffected.

 

Rarely, infants with neonatal Graves disease present with thrombocytopenia, jaundice, hepatosplenomegaly, and hypoprothrombinemia, a picture that may be confused with congenital infections such as toxoplasmosis, rubella, or cytomegalovirus ( 118). In addition, arrhythmias and cardiac failure may develop and may cause death, particularly if treatment is delayed or inadequate. In addition to a significant mortality rate that approximates 20% in some older series, untreated fetal and neonatal hyperthyroidism is associated with deleterious long-term consequences, including premature closure of the cranial sutures (cranial synostosis), failure to thrive, and developmental delay ( 119). The half-life of TSH receptor antibodies is 1 to 2 weeks. The duration of neonatal hyperthyroidism, a function of antibody potency and the rate of their metabolic clearance, is usually 2 to 3 months but may be longer.

Laboratory Evaluation

Because of the importance of early diagnosis and treatment, fetuses and infants at risk for neonatal hyperthyroidism should undergo both clinical and biochemical assessment as soon as possible. Situations that should prompt consideration of neonatal hyperthyroidism are listed in Table 4. A high index of suspicion is necessary in babies of women who have had thyroid ablation because in them a high titer of TSH receptor antibodies would not be evident clinically. Similarly, women with persistently elevated TSH receptor antibodies and with a high requirement for antithyroid medication are at an increased risk of having an affected child. The diagnosis of hyperthyroidism is confirmed by the demonstration of an increased concentration of circulating T4 (and free T4, and T3, if possible) accompanied by a suppressed TSH level in neonatal or fetal blood. The latter can be obtained by cordocentesis if someone experienced in this technique is available. Results should be compared with normal values during gestation . Fetal ultrasonography may be helpful in detecting the presence of a fetal goiter and in monitoring fetal growth. Demonstration in the baby or mother of a high titer of TSH receptor antibodies will confirm the etiology of the hyperthyroidism and, in babies whose thyroid function testing is normal initially, indicate the degree to which the baby is at risk.

Table 4. Situations That Should Prompt Consideration of Neonatal Hyperthyroidism
  • Unexplained tachycardia, goiter or stare
  • Unexplained petechiae, hyperbilirubinemia, or hepatosplenomegaly
  • History of persistently high TSH receptor antibody titer in mother during pregnancy
  • History of persistently high requirement for antithyroid medication in mother during pregnancy
  • History of thyroid ablation for hyperthyroidism in mother
  • History of previously affected sibling

As noted in the case of TSH receptor blocking antibody-induced congenital hypothyroidism, the radioreceptor assay or ELISA is a cost-effective, rapid and technically feasible approach. If desired, bioassay can be performed subsequently to demonstrate the biological activity of the antibodies if the binding assay is positive. In general, babies likely to become hyperthyroid have the highest TSH receptor antibody titer whereas if TSH receptor antibodies are not detectable, the baby is most unlikely to become hyperthyroid ( 119-121). In the latter case, it can be anticipated that the baby will be euthyroid, have transient hypothalamic-pituitary suppression or have a transiently elevated TSH, depending on the relative contribution of maternal hyperthyroidism versus the effects of maternal antithyroid medication, respectively ( 120). Therapy is rarely necessary. This is true whether TSH receptor antibodies are measured by a binding assay or by bioassay. On the other hand, if TSH receptor antibody potency is intermediate, it is likely that the baby will be euthyroid, have a transiently elevated T4 or have transient hypothalamic pituitary suppression ( 120-122). It is important to appreciate that the sensitivity of TSH receptor assays in different laboratories varies. Therefore, specific values that are recommended in the literature should be interpreted with caution and, ideally, each laboratory should determine its own range. Close follow up of all babies with abnormal thyroid function tests or detectable TSH receptor antibodies is mandatory.

Therapy

In the fetus, treatment is accomplished by maternal administration of antithyroid medication. Until recently PTU was the preferred drug for pregnant women in North America, but current recommendations suggest the use of MMI rather than PTU after the first trimester because of concerns about potential PTU-induced hepatotoxicity ( 123) (discussed under Graves disease, below). The goals of therapy are to utilize the minimal dosage necessary to normalize the fetal heart rate and render the mother euthyroid or slightly hyperthyroid.

In the neonate, treatment is expectant. Either PTU (5 to10 mg/kg/day) or MMI (0.5 to 1.0 mg/kg/day) has been used initially in 3 divided doses. If the hyperthyroidism is severe, a strong iodine solution (Lugols solution or SSKI, 1 drop every 8 hours) is added to block the release of thyroid hormone immediately. Often the effect of PTU and MMI is not as delayed in infants as it is in older children or adults, a consequence of decreased intrathyroidal thyroid hormone storage. Therapy with both antithyroid drug and iodine is adjusted subsequently, depending on the response. Propranolol (2 mg/kg/day in 2 or 3 divided doses) is added if sympathetic overstimulation is severe, particularly in the presence of pronounced tachycardia. If cardiac failure develops, treatment with digoxin should be initiated, and propranolol should be discontinued. Rarely, prednisone (2 mg/kg/day) is added for immediate inhibition of thyroid hormone secretion. Measurement of TSH receptor antibodies in treated babies may be helpful in predicting when antithyroid medication can be safely discontinued ( 114). Lactating mothers on antithyroid medication can continue nursing as long as the dosage of PTU or MMI does not exceed 400 mg or 40 mg, respectively. The milk/serum ratio of PTU is 1/10 that of MMI, a consequence of pH differences and increased protein binding, so one might anticipate less transmission to the infant, but concerns about potential PTU toxicity need to be considered. At higher dosages of antithyroid medication, close supervision of the infant is advisable.

Permanent neonatal hyperthyroidism

Rarely, neonatal hyperthyroidism is permanent and is due to a germline mutation in the TSH receptor resulting in its constitutive activation ( 124-127). A gain of function mutation of the TSH receptor should be suspected if persistent neonatal hyperthyroidism occurs in the absence of detectable TSH receptor antibodies in the maternal circulation. Most cases result from a mutation in exon 10 which encodes the transmembrane domain and intracytoplasmic tail of the TSH receptor, a member of the G protein coupled receptor superfamily ( 124-127). Less frequently, a mutation encoding the extracellular domain has been described ( 128). An autosomal dominant inheritance has been noted in many of these infants; other cases have been sporadic, arising from a de novo mutation. Early recognition is important because the thyroid function of affected infants is frequently difficult to manage medically ( 125-127), and, when diagnosis and therapy is delayed, irreversible sequelae, such as cranial synostosis and developmental delay may result ( 127). For this reason early, aggressive therapy with either thyroidectomy or even radioablation has been recommended.

Thyroid Disease in Childhood and Adolescence

Hypothyroidism

Causes of Hypothyroidism in childhood and adolescence

Chronic Lymphocytic Thyroiditis

The causes of hypothyroidism after the neonatal period are listed in Table 5.The most common cause is chronic lymphocytic thyroiditis an autoimmune disease that is closely related to Graves disease. chronic lymphocytic thyroiditis, like Graves disease is a complex genetic disorder in which as many as 20-60 immunosusceptibility genes, each with small effect, have been postulated ( 129) and in which the trigger is unknown. Both thyroid-specific genes and genes involved in immune recognition and/or response have been identified ( 130). Some genes are common to both disorders and some tend to predominate only in Graves disease. Whereas in chronic lymphocytic thyroiditis, lymphocyte and cytokine-mediated thyroid destruction predominates, in Graves disease antibody-mediated thyroid stimulation occurs, but overlap may occur in some patients.

Both a goitrous (Hashimotos thyroiditis) and a nongoitrous (atrophic thyroiditis, also called primary myxedema) variant of chronic lymphocytic thyroiditis have been distinguished. The disease has a striking predilection for females and a family history of autoimmune thyroid disease (both chronic lymphocytic thyroiditis and Graves disease) is found in 30% to 40% of patients. During childhood the most common age at presentation is adolescence, but the disease may occur at any age, even infancy ( 131). There is an increased prevalence of chronic lymphocytic thyroiditis in patients with insulin dependent diabetes mellitus, 20% of whom have positive thyroid antibodies and 5% of whom have an elevated serum TSH level ( 132). chronic lymphocytic thyroiditis may also occur as part of an autoimmune polyglandular syndrome (APS) ( 133). In APS 1, a poly glandular autoimmune disorder that tends to present in childhood, chronic lymphocytic thyroiditis is found in approximately 10% of patients. APS 1, is characterized primarily by mucocutaneous candidiasis, hypoparathyroidism and adrenal deficiency and results from a mutation in the AIRE (autoimmune regulator) gene ( 134, 135 ). Chronic lymphocytic thyroiditis and diabetes mellitus with or without adrenal insufficiency (APS 2, also referred to as Schmidt syndrome) tends to occur later in childhood or in the adult. Chronic lymphocytic thyroiditis has also been described in children with immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a polyglandular disorder characterized by early-onset diabetes and colitis (135b). In addition to these polyglandular syndromes, there is an increased incidence of chronic lymphocytic thyroiditis in patients with certain chromosomal abnormalities (Down syndrome, Turner syndrome, Klinefelter syndrome) as well as in patients with Noonan syndrome.CLT may be associated with chronic uriticaria ( 136) and rarely with with immune-complex glomerulonephritis ( 137).

Antibodies to Tg and TPO, the thyroid antibodies measured in routine clinical practice, are detectable in over 95% of patients with chronic lymphocytic thyroiditis. Therefore, they are useful as markers of underlying autoimmune thyroid damage, TPO antibodies being more sensitive. TSH receptor antibodies also are found in a small proportion of patients with chronic lymphocytic thyroiditis. When stimulatory TSH receptor antibodies are present, they may give rise to a clinical picture of hyperthyroidism, the coexistence of chronic lymphocytic thyroiditis and Graves disease being known as Hashitoxicosis. In one study, b locking antibodies were found in <10% of children and adolescents with chronic lymphocytic thyroiditis, patients overall, but in 17.8% of those with severe hypothyroidism (defined as a serum TSH concentration >20 mU/L). Unlike in adults, they were found in goitrous as well as nongoitrous patients , and, when present at a high concentration, appeared to persist indefinitely, suggesting that the presence of potent TSH receptor blocking Abs in adolescent females might identify patients at risk of having babies with transient congenital hypothyroidism in the future (138).

Table 5. Differential Diagnosis of Juvenile Hypothyroidism

Chronic Lymphocytic Thyroiditis

-Goitrous (Hashimoto’s)

-Atrophic (Primary Myxedema)

Congenital Abnormality

-Thyroid dysgenesis

-Inborn error of thyroid hormonogenesis

Iodine Deficiency (endemic goiter)

Drugs or Goitrogens

- Antithyroid drugs (PTU, MMI, carbimazole)

- Anticonvulsants

- Other (lithium, thionamides, aminosalicylic acid, aminoglutethimide)

- Goitrogens (cassava, water pollutants, cabbage, sweet potatoes, cauliflower, broccoli, soya beans)

Miscellaneous

-C ystinosis

-Langerhans Cell Histiocytosis

-Irradiation of the Thyroid ( radioactive iodine , external irradiation of nonthyroid tumors )

-Surgery

Goiter, present in approximately two-thirds of children with chronic lymphocytic thyroiditis results primarily from lymphocytic infiltration and in some patients, from a compensatory increase in TSH. The role of antibodies in goitrogenesis is controversial ( 139).

Children with chronic lymphocytic thyroiditis may be euthyroid, or may have subclinical or overt hypothyroidism. Occasionally, children may experience an initial thyrotoxic phase due to the discharge of preformed T4 and T3 from the damaged gland. Alternatively, as indicated above, thyrotoxicosis may be due to concomitant thyroid stimulation by TSH receptor stimulatory antibodies (Hashitoxicosis).

Long term follow up studies of children with chronic lymphocytic thyroiditis have suggested that while most children who are hypothyroid initially remain hypothyroid, spontaneous recovery of thyroid function may occur, particularly in those with initial compensated hypothyroidism ( 140-143). On the other hand, some initially euthyroid patients will become hypothyroid with observation. Therefore, close follow up is necessary.

Thyroid Dysgenesis and Inborn Errors of Thyroid Hormonogenesis

Occasionally, patients with thyroid dysgenesis will escape detection by newborn screening and present later in childhood with non goitrous hypothyroidism or with an enlarging mass at the base of the tongue or along the course of the thyroglossal duct. Similarly, children with inborn errors of thyroid hormonogesis may only be recognized later in childhood because of the detection of a goiter.

Drugs or Goitrogens

In addition to antithyroid medication, a number of drugs used in childhood may affect thyroid function, including certain anticonvulsants, lithium, amiodarone, aminosalicylic acid, aminoglutethimide and sertraline ( 144, 145 ). Similarly, a large number of naturally occurring goitrogens (broccoli, cabbage, sweet potatoes, cauliflower, soya beans, cassava and water pollutants) have been identified. Both radioiodine therapy and thyroidectomy, occasionally used in childhood for the definitive treatment of Graves disease, frequently cause permanent hypothyroidism.

Worldwide, iodine deficiency continues to be an important cause of hypothyroidism, affecting at least 800 million people living largely in developing countries. In addition, even in certain parts of Europe, an estimated 100-120 million individuals are thought to have borderline iodine deficiency ( 146). Although one rarely sees iodine deficiency in North America, an iodine sufficient area, a 6 year old boy with goitrous hypothyroidism has been described in whom iodine deficiency was due to multiple food allergies and severe dietary restriction ( 147). In addition, the child consumed a large intake of thiocyanate-containing foods that blocked organification of iodine.

Miscellaneous Causes of Acquired Hypothyroidism

Rarely, the thyroid gland may be involved in generalized infiltrative or infectious disease processes that are of sufficient severity to result in a disturbance in thyroid function (e.g., (Langerhans cell histiocytosis) ( 148). Alternatively, hypothyroidism may be a long term complication of mantle irradiation for Hodgkins disease or lymphoma. External irradiation of brain tumors in the posterior fossa of the brain may be associated with both primary and secondary hypothyroidism because of the inclusion of the neck in the radiation field. Rarely, hypothyroidism has been reported in infants with large hemangiomas ( 149). In these cases, the hypothyroidism was shown to be due to increased inactivation of T4 by the D3 activity of these tumors.

Secondary or Tertiary Hypothyroidism

Secondary or tertiary hypothyroidism in less severely affected children with the congenital abnormalities noted earlier in this chapter, may be recognized only later in childhood. Alternatively, secondary or tertiary hypothyroidism may develop as a result of acquired damage to the pituitary or hypothalamus, e.g., by tumors (particularly craniopharyngioma), granulomatous disease, head irradiation, infection (meningitis), surgery or trauma. Usually other trophic hormones are affected, particularly growth hormone.

Thyroid Hormone Resistance

In contrast to the neonatal period, children with thyroid hormone resistance usually come to attention when thyroid function tests are performed because of poor growth, hyperactivity, a learning disability or other nonspecific signs or symptoms. A small goiter may be appreciated. Affected patients have a high incidence of attention deficit hyperactivity disorder ( 150). Thyroid hormone resistance has also been described in patients with cystinosis ( 151).

Clinical Manifestations

The onset of hypothyroidism in childhood is insidious. Affected children often are recognized either because of the detection of a goiter on routine examination or because of a poor interval growth rate present for several years prior to diagnosis. Because the deceleration in linear growth tends to be more affected than weight gain, these children are relatively overweight for their height, although they rarely are significantly obese (Figure 8). If the hypothyroidism is severe and longstanding, immature facies with an underdeveloped nasal bridge and immature body proportions (increased upper-lower body ratio) may be noted. Dental and skeletal maturation are delayed, the latter often significantly. Patients with central hypothyroidism tend to be even less symptomatic than are those with primary hypothyroidism.


Figure 15-8 . Sequential changes in physical appearance in a young girl who presented at 15 years of age with amenorrhea and hyperprolactinemia secondary to severe hypothyroidism. Note her poor linear growth since at least 11 years of age.

The classical clinical manifestations of hypothyroidism can be elicited on careful evaluation, though they often are not the presenting complaints. These include lethargy, cold intolerance, constipation, dry skin or hair texture, and periorbital edema. School performance is not usually affected, in contrast to the severe irreversible neuro-intellectual sequelae that occur frequently in inadequately treated babies with congenital hypothyroidism. Causes of hypothyroidism associated with a goiter (CLT, inborn errors of thyroid hormonogenesis, thyroid hormone resistance) should be distinguished from non goitrous causes (primary myxedema, thyroid dysgenesis, central hypothyroidism). The typical thyroid gland in chronic lymphocytic thyroiditis is diffusely enlarged and has a rubbery consistency. Although the surface is classically described as ’ pebbly ’ or bosselated, occasionally asymmetric enlargement occurs and must be distinguished from thyroid neoplasia. A palpable lymph node superior to the isthmus ( ‘ Delphian node ’ ) is often found and may be confused with a thyroid nodule. The thyroid gland, in thyroid hormone synthetic defects, on the other hand, tends to be softer and diffusely enlarged. A delayed relaxation time of the deep tendon reflexes may be appreciated in more severe cases.

In patients with severe hypothyroidism of longstanding duration, the sella turcica may be enlarged due to thyrotrope hyperplasia. There is an increased incidence of slipped femoral capital epiphyses in hypothyroid children. The combination of severe hypothyroidism and muscular hypertrophy which gives the child a ’ Herculean ’ appearance is known as the Kocher-Debre-Semelaign e syndrome ( 152).

Puberty tends to be delayed in hypothyroid children in proportion to the retardation in the bone age, although in longstanding severe hypothyroidism, sexual precocity has been described. Females with sexual precocity have menstruation, and breast development but relatively little sexual hair. Multicystic ovaries, the etiology of which is unknown, may be demonstrated on ultrasonography. In other cases, galactorrhea or severe menses have been the presenting features. In boys, testicular enlargement may be found ( 153). An elevation in serum prolactin, the latter possibly due to elevated TRH which is known to stimulate prolactin as well as TSH, has been described in some cases, but gonadotropin levels are not consistently elevated. It has been hypothesized that this syndrome of pseudopuberty in hypothyroid patients is due to cross- interaction of the extremely elevated serum TSH with the FSH receptor ( 154). Consistent with the latter hypothesis, there is little increase in serum testosterone as might be expected if the FSH, but not luteinizing hormone (LH) receptor is involved and serum gonadotropins are frequently not increased.

Laboratory Evaluation

Measurement of TSH is the best initial screening test for the presence of primary hypothyroidism. If the TSH is elevated, then evaluation of the free T4 or free T4 index (total T4 multiplied by the T3 resin uptake) will distinguish whether the child has subclinical (normal free T4 or free T4 index) or overt (low free T4 or free T4 index) hypothyroidism. Measurement of TSH, on the other hand, is not helpful in central hypothyroidism. In these cases hypothyroidism is demonstrated by the presence of a low free T4 (or free T4 index) accompanied by an inappropriately ‘’ TSH. In the past TRH testing (TRH 7 mcg/kg) was sometimes utilized to distinguish a hypothalamic versus pituitary origin of the hypothyroidism; in hypothalamic hypothyroidism there tends to be a delayed peak in TSH secretion ( 60-90 minutes versus the normal maximal response at 15-30 minutes) whereas in hypopituitarism there usually is little or no TSH response. TRH is no longer available in the USA, however. Furthermore, the reliability of this test in the pediatric range has been questioned ( 101). Occasionally mild TSH elevation is seen in individuals with hypothalamic hypothyroidism, a consequence of the secretion of a TSH molecule with impaired bioactivity but normal immunoreactivity. Thyroid hormone resistance is characterized by elevated levels of T4 and T3 and an inappropriately normal or elevated TSH concentration.

A diagnosis of chronic lymphocytic thyroiditis is made by the demonstration of elevated titers of anti- Tg and/or anti-TPO antibodies. Measurement of TSH receptor blocking antibodies should be considered in adolescent patients with severe hypothyroidism because of the potential risk of blocking antibody-induced hypothyroidism to any unborn child in the future ( 138). Imaging studies (thyroid ultrasonography and/or thyroid uptake and scan) may be performed if thyroid antibody tests are negative or if a nodule is palpable, but are rarely necessary. Occasionally the finding of heterogeneous echogenecity on ultrasound examination has been described prior to the appearance of antibodies. However, the typical picture of spotty uptake of radioactive iodine that is seen in adults is rare in children ( 155). If thyroid antibody tests are negative and no goiter is present, imaging studies are helpful in identifying the presence and location of thyroid tissue, and therefore, of distinguishing primary myxedema from thyroid dysgenesis. Inborn errors of thyroid hormonogenesis beyond a trapping defect are usually suspected by an increased radioiodine uptake, and a large gland on scan. Other etiologies of hypothyroidism usually are evident on history.

Therapy

In contrast to neonatal hypothyroidism, rapid replacement is not essential in the older child. This is particularly true in children with long standing, severe thyroid underactivity in whom rapid normalization may result in unwanted side effects (deterioration in school performance, short attention span, hyperactivity, insomnia, and behavior difficulties) ( 156). In these children it is preferable to increase the replacement dose slowly over several weeks to months. Severely hypothyroid children should also be observed closely for complaints of severe headache when therapy is initiated because of the rare development of pseudotumor cerebri ( 157). In contrast, full replacement can be initiated at once without much risk of adverse consequences in children with mild hypothyroidism.

Treatment of children and adolescents with subclinical hypothyroidism (normal free T4, elevated TSH) is controversial. In adults in whom the risk of progression to overt hypothyroidism is significant, particularly if they are over the age of 60 years, treatment has been recommended whenever the serum TSH concentration is >10 mU/L; if the TSH is 6-10 mU/L treatment on a case by case basis is suggested ( 158). In children and adolescents with subclinical hypothyroidism due to chronic lymphocytic thyroiditis, available data suggests a significant likelihood of remission, at least for several years. Consequently, if there is not a strong family history of hypothyroidism and the patient is not symptomatic, a reasonable option is to reassess thyroid function in 3- 6 months prior to initiating therapy because of the possibility that the thyroid abnormality will be transient.

The typical replacement dose of L-thyroxine in childhood is approximately 100 mc­g/M2 or 4 to 6 mc­g/kg for children 1 to 5 years of age, 3 to 4 mc ­g/kg for those ages 6 to 10 years, and 2 to 3 mc­g/kg for those 11 years of age and older. In patients with a goiter a somewhat higher L-thyroxine dosage is used so as to keep the TSH in the low normal range (0.3 to 1.0 mU/L in an ultrasensitive assay), and thereby minimize its goitrogenic effect.

T4 and TSH should be measured after the child has received the recommended dosage for at least 6-8 weeks. Once a euthyroid state has been achieved, patients should be monitored every 6 to 12 months. Close attention is paid to interval growth and bone age as well as to the maintenance of a euthyroid state. Thyroid hormone replacement is not associated with significant weight loss in overweight children, unless the hypothyroidism is severe ( 159). Some children with severe, long standing hypothyroidism at diagnosis may not achieve their adult height potential even with optimal therapy ( 160), emphasizing the importance of early diagnosis and treatment. Treatment is usually continued indefinitely.

Asymptomatic goiter

Causes

Chronic lymphocytic thyroiditis

Goiter, the most common thyroid disorder in pediatrics, occurs in 1.2% of school children in North America ( 140). Like thyroid disease in general, there is a female preponderance, the female: male ratio being 2 to 3:1. Patients with goiter may be euthyroid, hypothyroid or hyperthyroid, euthyroid goiters being by far the most common. The most frequent cause of asymptomatic goiter in North America is chronic lymphocytic thyroiditis, discussed above. Causes of goiter that are associated with abnormal thyroid function are discussed elsewhere in this chapter.

Colloid or Simple (Nontoxic) Goiter

Colloid goiter is the second most common cause of euthyroid thyroid enlargement in childhood. The etiology of colloid goiter is unknown. Not infrequently there is a family history both of goiter, chronic lymphocytic thyroiditis and Graves disease, leading to the suggestion that colloid goiter, too, might be an autoimmune disease. Immunoglobulins that stimulated thyroid growth in vitro have been identified in a proportion of patients with simple goiter ( 161), but their etiological role is controversial ( 139). It is important to distinguish patients with colloid goiter from chronic lymphocytic thyroiditis because of the risk of developing hypothyroidism in patients with chronic lymphocytic thyroiditis, but not colloid goiter. Whereas many colloid goiters regress spontaneously, others appear to undergo periods of growth and regression, resulting ultimately in the large nodular thyroid glands later in life.

Clinical Manifestations and Laboratory Investigation

Evaluation of thyroid function by measurement of the serum TSH concentration is the initial approach to diagnosis. In euthyroid patients, the most common situation, chronic lymphocytic thyroiditis should be distinguished from colloid goiter. Clinical examination in both instances reveals a diffusely enlarged thyroid gland. Therefore, the distinction is dependent upon the presence of elevated titers of TPO and Tg antibodies in chronic lymphocytic thyroiditis but not colloid goiter. All patients with negative thyroid antibodies initially should have repeat examinations because some children with chronic lymphocytic thyroiditis will develop positive titers with time.

Therapy

Thyroid suppression in children with a euthyroid goiter is controversial ( 162, 163 ). A significant decrease in goiter size in patients with chronic lymphocytic thyroiditis as assessed by standard deviation score on ultrasonography has been demonstrated recently in patients treated for 3 years ( 163). However, the absolute difference quantitatively was not reported and so, whether or not this difference was signicant clinically remains unclear. Given the variability in response in different patients, it would be reasonable to attempt a therapeutic trial in patients whose goiter is large.

Painful thyroid

Painful thyroid enlargement is rare in pediatrics and suggests the probability of either acute (suppurative) or subacute thyroiditis. Rarely chronic lymphocytic thyroiditis may be associated with intermittent pain and be confused with the latter disorders. In acute thyroiditis, progression to abscess formation may occur rapidly so prompt recognition and antibiotic therapy are essential. Recurrent attacks and involvement of the left lobe suggest a pyriform sinus fistula between the oropharynx and the thyroid as the route of infection ( 164). In the latter case, surgical extirpation of the pyriform sinus will frequently prevent further attacks. Subacute thyroiditis, rare in childhood, is discussed elsewhere.

Hyperthyroidism

Causes

Graves Disease

More than 95% of cases are due to Graves disease, an autoimmune disorder that, like chronic lymphocytic thyroiditis, is a complex genetic trait that occurs in a genetically predisposed population ( 130). There is a strong female predisposition, the female:male ratio being 6 to 8:1. Graves disease is much less common in childhood than in the adult. Although it can occur at any age in the pediatric range , it is most common in adolescence. Prepubertal children tend to have more severe disease, to require longer medical therapy and to achieve a lower rate of remission as compared with pubertal children ( 165). This appears to be particularly true in children who present at <5 years of age ( 166). Graves disease has been described in children with other autoimmune diseases, both endocrine and non endocrine. These include diabetes mellitus, Addison ’ s disease, vitiligo, systemic lupus erythematosis, rheumatoid arthritis, myasthenia gravis, periodic paralysis, idiopathic thrombocytopenia purpura and pernicious anemia. There is an increased risk of Graves disease in children with Down syndrome (trisomy 21) (167).

Unlike chronic lymphocytic thyroiditis in which thyrocyte damage is predominant, the major clinical manifestations of Graves disease are hyperthyroidism and goiter. Graves disease is caused by TSH receptor antibodies that mimic the action of TSH. Binding of ligand results in stimulation of adenyl cyclase and thyroid hormonogenesis and growth ( 168,169). As noted earlier, TSH receptor blocking antibodies, in contrast, inhibit TSH-induced stimulation of adenyl cyclase. Both stimulatory and blocking TSH receptor antibodies bind to the extracellular domain of the receptor and appear to recognize apparently discrete linear epitopes in the context of a three-dimensional structure ( 169). A number of different monoclonal stimulating Abs including one derived from a patient with Graves disease have now been generated ( 170) and the crystal structure of the human monoclonal stimulating TSH receptor Ab complexed with a portion of the TSH receptor ectodomain has been accomplished ( 171). Taken together, a picture has emerged of distinct but overlapping binding sites of both stimulating and blocking TSH receptor Abs and of TSH to the leucine rich TSH receptor ectodomain (172). Current evidence suggests that it is the shed A subunit rather than the intact, holoreceptor that induces TSH receptor Abs leading to hyperthyroidism ( 172). Studies employing monoclonal TSH receptor antibodies cloned from patients and recombinant mutant TSH receptor have demonstrated that there exist multiple TSH receptor antibodies each with different specificities and functional activities. There is evidence that stimulatory antibodies are mostly lambda and of the IgG1 subclass, strongly suggesting that they are monoclonal or pauciclonal ( 173). Blocking antibodies, on the other hand, are not similarly restricted.

Rarer causes of hyperthyroidism

Rarely, hyperthyroidism may be caused by a functioning thyroid adenoma, by constitutive activation of the TSH receptor or it may be seen as part of the McCune Albright syndrome (Table 6). Recently an adolescent female was described in whom hyperthyroidism resulted from an hCG-secreting hydatidiform mole ( 174). Hyperthyroidism also may be due to the inappropriate secretion of TSH by a pituitary adenoma but thyroid hormone resistance should be excluded. In adolescents, pregnancy may be associated with an elevation in circulating T4 and a low-normal or suppressed serum TSH concentration. When a high total T4 concentration is associated with a normal free T4 and TSH level, TBG excess, either genetic or acquired (e.g., due to oral contraceptive use) should be considered.

Miscellaneous causes of thyrotoxicosis include the toxic phase of chronic lymphocytic thyroiditis, mentioned above subacute thyroiditis and thyroid hormone ingestion (thyrotoxicosis factitia).

Clinical Manifestations

All but a few children with Graves disease present with some degree of thyroid enlargement, and most have symptoms and signs of excessive thyroid activity, such as tremors, inability to fall asleep, weight loss despite an increased appetite, proximal muscle weakness, heat intolerance and tachycardia. Often the onset is insidious. Shortened attention span, and emotional lability may lead to behavioral and school difficulties. Some patients complain of polyuria and of nocturia, the result of an increased glomerular filtration rate. Acceleration in linear growth may occur, often accompanied by advancement in skeletal maturation (bone age). Adult height is not affected. In the adolescent child, puberty may be delayed. If menarche has occurred, secondary amenorrhea is a common concomitant. If sleep is disturbed, the patient may complain of fatigue.

Table 6 . Differential diagnosis of thyrotoxicosis in childhood.

Hyperthyroidism

- Diffuse toxic goiter (Graves disease)

- Functioning thyroid adenoma

- Toxic multinodular goiter

- Gain of function mutation of TSH receptor

- McCune Albright disease

- Hydatidiform mole

TSH-induced hyperthyroidism

- TSH-producing pituitary adenoma

Causes of Transient Thyrotoxicosis

- Chronic lymphocytic thyroiditis

- Subacute thyroiditis

- Thyroid hormone ingestion

Miscellaneous

- Oral contraceptive use

- Pregnancy

- Congenital TBG excess

- Dysalbuminemic hyerthyroxinemia

- Thyroid hormone resistance

Physical examination reveals a diffusely enlarged, soft or “ fleshy ” thyroid gland, smooth skin and fine hair texture, excessive activity, and a fine tremor of the tongue and fingers. A thyroid bruit may be audible. In contrast, the finding of a thyroid nodule suggests the possibility of a toxic adenoma. The hands are often warm and moist. Tachycardia, a wide pulse pressure, and a hyperactive precordium are common. Café au lait spots, particularly in association with precocious puberty, on the other hand, suggests a possible diagnosis of McCune Albright syndrome while if a goiter is absent, thyrotoxicosis factitia should be considered. The ophthalmopathy characteristic of Graves disease in adults is considerably less common in children, although a stare and mild proptosis are observed frequently.

Laboratory Evaluation

The clinical diagnosis of hyperthyroidism is confirmed by the finding of increased concentrations of circulating thyroid hormones (T4 or, preferably, free T4 (or free T4 index) and T3). In hyperthyroidism, the circulating T3 concentration frequently is elevated out of proportion to the T4 because, like TSH, TSH receptor antibodies stimulate increased T4 to T3 conversion. Demonstration of a suppressed TSH excludes much rarer causes of thyrotoxicosis, such as TSH-induced hyperthyroidism and thyroid hormone resistance in which the TSH is inappropriately ’ normal ’ or slightly elevated. If the latter diseases are suspected, free alpha subunit should be measured. Alternatively, an elevated T4 level in association with an inappropriately ‘ normal ’ TSH may be due to an excess of thyroxine-binding globulins (either familial or acquired, for example a result of oral contraceptive use) or rarer binding protein abnormalities (for example, familial dysalbuminemic hyperthyroxinemia) ( 175). In the latter cases, serum TBG concentration or electrophoresis of T4 binding proteins, respectively, should be measured. If pregnancy or an hCG-secreting tumor are suspected, serum or urinary hCG concentration can be measured. A low serum Tg can be demonstrated if thyrotoxicosis factitia is suspected ( 176).

The diagnosis of Graves disease is confirmed by the demonstration of TSH receptor antibodies in serum. The availability of commercial kits, and the development of both molecularly-engineered cells, and a stimulating human anti-TSH receptor monoclonal antibody have greatly improved the performance of TSH receptor antibody assays available both clinically and in a research setting. Two main classes of assays can be distinguished. Competitive binding assays (radioreceptor assay or, more recently, enzyme-linked immunosorbent assay [ELISA], take advantage of the ability of these antibodies to inhibit the binding of TSH to either porcine thyroid membranes or to recombinant human TSH receptor transfected into Chinese hamster ovary (CHO) cells. Bioassays measure directly the stimulation (or inhibition) of TSH-induced stimulation of adenyl cyclase. The ELISA (also called ’ coated tube ’ assay) is more sensitive than the radioreceptor assay ( 177, 178 ), particularly when enzyme-linked monoclonal TSH receptor antibody is substituted for TSH as ligand ( 179). Since both stimulatory and blocking antibodies inhibit TSH binding to the receptor, the radioreceptor assay or ELISA are excellent screening methods to test for the presence of TSH receptor antibodies but they do not provide information about function.

Current ELISAs in clinical practice are highly sensitive and specific, being positive in up to 99% of adults and children with Graves disease ( 169, 177-179 ). Results in bioassays are more variable. Although bioassays are highly sensitive in a research setting ( 180), they are more fastidious and so results from some clinical laboratories appear to be less sensitive ( 181, 182 ). Recently, a sensitive commercial bioassay for TSH receptor antibodies has been developed that may improve the feasibility of measuring bioactivity (182b) . Bioassay is particularly useful in the occasional patient with Graves disease with negative TSH receptor antibodies by ELISA or in treated patients whose clinical picture is discordant with results in the binding assay. Properly performed, bioassays are the most definitive and sensitive method to document that the hyperthyroidism is due to stimulatory TSH receptor A bs, but the newer, improved methods are more expensive and so have not been universally adopted to date. TSH receptor antibodies measured by binding assay are called TSH receptor antibodies, TRAbs or TSH binding-inhibitory IgGs, TBII) whereas those measured by bioassay are usually referred to as thyroid-stimulating immunoglobulins, TSI, It must always be kept in mind that precise values obtained with different assays cannot be compared since results depend on the sensitivity of the assay used and there is no uniform standard employed.

Some individuals, initially reported to be negative in the radioreceptor assay, become positive several weeks later ( 180). It has been hypothesized that in these patients, TSH receptor antibody synthesis is restricted at first to within the thyroid gland itself, or, alternately, that TSH receptor antibodies escape detection because of binding by soluble TSH receptor circulating in serum. However, the proportion of patients who are TSH receptor antibody positive has increased with the introduction of 2nd generation and now 3rd generation assays, strongly suggesting that limited assay sensitivity is the most likely reason in most cases. Measurement of TSH receptor antibodies may be useful in distinguishing the toxic phase of chronic lymphocytic thyroiditis (TSH receptor antibody negative) from Graves disease. Tg and TPO antibodies are positive in 70% of children and adolescents with Graves disease but their measurement is not as sensitive or specific as measurement of TSH receptor antibodies. In contrast to adults, radioactive iodine uptake and scan are used to confirm the diagnosis of Graves disease only in atypical cases (for example, if measurement of TSH receptor antibodies is negative, or if a functioning thyroid nodule is suspected).

Therapy

The choice of which of the three therapeutic options (medical therapy, radioactive iodine, or surgery) to use, should be individualized and discussed with the patient and his/her family. Each approach has its advantages and disadvantages with respect to efficacy, both short and long term complications, the time required to control the hyperthyroidism, and the requirement for compliance. In general, medical therapy with methimazole (MMI) is the initial choice of most pediatricians although radioiodine is gaining increasing acceptance, particularly in non compliant adolescents, in children who are developmentally delayed, and in those about to leave home (for example, to go to college). Alternately, surgery, the oldest form of therapy, may be the initial choice in specific cases if an experienced pediatric thyroid surgeon is available.

Medical Therapy

The thiouracil compounds PTU, MMI and carbimazole (converted to MMI) exert their antithyroid effect by inhibiting the organification of iodine and the coupling of iodotyrosine residues on the Tg molecule to T3 and T4. MMI is generally preferred over PTU because for an equivalent dose it requires taking fewer tablets, it has a longer half-life (and so, requires less frequent medication) and because it has a more favorable safety profile. Recent reports have suggested that the risk of hepatotoxicity with PTU may be greater in the young ( 183-185), leading to the recommendation that PTU be used only in pediatric patients who are allergic to MMI, and in whom permanent forms of therapy are not possible ( 123). PTU use has also been advocated in the first trimester of pregnancy. Since PTU but not MMI inhibits the conversion of T4 to the more active isomer T3, PTU may have a role in the treatment of thyroid storm and/or if the thyrotoxicosis is severe. The initial dosage of MMI is 0.5 mg/kg/day given every 12 hours and of PTU is 5 mg/kg/day given every 8 hours. In severe cases, a beta-adrenergic blocker (atenolol, 25 to 50 mg daily or twice daily) can be added to control the cardiovascular overactivity until a euthyroid state is obtained.

Patients should be followed every 4 to 6 weeks until the serum concentration of T4 (or free T4 and total T3) normalizes. It should be noted that the TSH concentration may not return to normal until several months later. Therefore, measurement of TSH is useful as a guide to therapy only after it has normalized but not initially. Once the T4 and T3 have normalized, one can either decrease the dosage of thioamide drug by 30% to 50% or, alternatively, wait until the TSH begins to rise and add a small, supplementary dose of l-thyroxine (e.g., 1 mg/kg/day). Monotherapy has the advantage that disease activity can be assessed and a smaller drug dosage is used. The latter is an advantage since toxic reactions to MMI appear to be dose-related. Maintenance doses of MMI may be administered once daily. PTU may be given twice daily. Usually patients can be followed every 4-6 months once thyroid function has normalized.

In most children and adolescents, circulating thyroid hormone levels can be normalized readily with antithyroid medication as long as compliance is not a problem. The optimal duration of therapy is controversial. There is no doubt that most children and adolescents, particularly prepubertal ones, require a longer course of therapy than adults. Therefore treatment guidelines developed for older individuals should not be applied to the young. In one retrospective study, TSH receptor Abs disappeared from the circulation in <20% of patients after 13-24 months of medical therapy ( 186) in contrast to adults in most of whom TSH receptor Abs normalize by 6 to 12 months (187-189). In another study, approximately 25% of children remitted with every 2 years of therapy up to 6 years of treatment ( 190). Equivalent results have been obtained by others ( 165).In a recent prospective trial of 154 children with newly diagnosed Graves disease treated with carbimazole , 20% of children remitted after 4 years of therapy, 37% after 6 years and 45% after 8 years. (165b). The median duration of therapy in most studies is 3 to 4 years years, but therapy should be individualized. In patients treated with antithyroid drugs alone, a small drug requirement, small goiter, and lack of orbitopathy are favorable indicators that drug therapy can be tapered gradually and withdrawn. Lower initial degree of hyperthyroxinemia (T4<20 mcg/dL (257.4 nmol/L); T3:T4 ratio <20) , lower initial TSH receptor Ab concentration (>4X upper limit of normal (165c) and postpubertal age are favorable prognostic indicators. Persistence of TSH receptor antibodies, on the other hand, indicates a high likelihood of relapse. Initial studies suggesting that combined therapy (i.e., antithyroid drug plus L-thyroxine) might be associated with an improved rate of remission ( 191) have not been confirmed (192).

Toxic drug reactions (erythematous rashes, urticaria, arthralgias, transient granulocytopenia, (<1500 granulocytes/mm3), have been reported in 5% to 14% of children. Rarely, more severe sequelae, such as hepatitis, a lupus like syndrome, thrombocytopenia, and agranulocytosis, (<500 granulocytes/mm3) may occur. Most reactions are mild and do not contraindicate continued use. The risk of agranulocytosis appears to be greatest within the first 3 months of therapy but it can occur at any time. There is some evidence that close monitoring of the white blood cell count during this initial time period may be useful in identifying agranulocytosis prior to the development of a fever and infection ( 193), but most authors do not consider the low risk to be worth the cost of close monitoring. Many clinicians prefer to check the white blood cell prior to therapy because Graves disease itself can be associated with abnormalities in these parameters. On the other hand, routine monitoring of liver function tests is not usually recommended. It is important to caution all patients to stop their medication immediately and consult their physician should they develop unexplained fever, sore throat, or gingival sores or jaundice. Unlike PTU, MMI is rarely associated with hepatocellular injury.

Approximately 10% of children treated medically will develop long term hypothyroidism, a consequence of coincident cell and cytokine-mediated destruction and/or the development of TSH receptor blocking antibodies.

Radioactive Iodine

Definitive therapy with either medical (radioactive iodine) or surgical thyroid ablation is usually reserved for patients who have failed drug therapy, developed a toxic drug reaction, or are noncompliant. In recent years, however, radioactive iodine is being favored increasingly, even as the initial approach to therapy ( 194). The advantages are the relative ease of administration, the reduced need for medical follow up and the lack of demonstrable long term adverse effects ( 194). Although a dose of 50 to 200 ï­Ci of 131I/estimated gram of thyroid tissue has been used, the higher dosage is recommended, particularly in younger children, in order to completely ablate the thyroid gland and thereby reduce the risk of future neoplasia. The size of the thyroid gland is estimated, based on the assumption that the normal gland is 0.5-1.0 gms/year of age, maximum 15-20 gms. The formula used is: Estimated thyroid weight in grams X 50-200 mcCi 131 -I/fractional 131I 24 hour uptake Radioactive iodine therapy should be used with caution in children <10 years of age and particularly in those <5 years of age because of the increased susceptibility of the thyroid gland in the young to the proliferative effects of ionizing radiation ( 195). Pretreatment with antithyroid drugs prior to RAI therapy is advisable if the hyperthyroidism is severe.

Editors note-It is of interesting to calculate the possible risk for induction of cancer using the data presented by Rivkees et al (194), who are proponents of use of RAI for therapy in young children..The risk of death from any cancer (not thyroid cancer) due specifically to radiation exposure is noted by these authors to be 0.16%/rem for children, and the whole body radiation exposure from RAI treatment at age 10 to be 1.45 rem/mCi administered. Rivkees et al advise treatment with doses of RAI greater then 160 uCi/gram thyroid, to achieve a thyroidal radiation dose of at least 150Gy(about 15000 rads). Assuming a reasonable RAIU of 50% and gland size of 40 gm, the administered dose would be 40(gm) x 160uCi/gm x 2 (to account for 50% uptake) =12.8 mCi. Thus the long term cancer death risk would be 12.8 (mCi) x 1.45 rem (per mCi) x 0.16% (per rem) = 3%. For a dose of 15mCi the incremental risk a of cancer mortality would be 4% at age 5, 2% at age 10, and 1% at age 15. Whether or not accepting a specific incremental 2-5% risk of death from cancer because of RAI treatment is of course a matter of judgment by the physician and family. However, this would seem to many persons to constitute a significant risk that should be avoided.

Thyroid hormone concentrations may rise transiently 4 to 10 days after RAI administration due to the release of preformed hormone from the damaged gland. Beta blockers may be useful during this time period. Similarly, analgesics may be employed if there is mild discomfort due to radiation thyroiditis. Other acute complications of RAI therapy (nausea, significant neck swelling) are rare. One usually sees a therapeutic effect within 6 weeks to 3 months. Worsening of ophthalmopathy, described in adults after RAI, does not appear to be common in childhood. However, if significant ophthalmopathy is present RAI therapy should be used with caution and pretreatment with steroids may be effective. Alternately, another permanent treatment modality (surgery) should be considered. In approximately 1000 children with Graves disease treated with RAI and followed for <5 to >20 years to date, there does not appear to be any increased rate of congenital anomalies in offspring nor in thyroid cancer. However, long term follow up data in a larger cohort are still lacking.

Surgery

Surgery, the third therapeutic modality, is performed less frequently now than in the past. An advantage of this form of therapy is the rapid resolution of the hyperthyroidism. Near-total thyroidectomy is the procedure of choice in order to minimize the risk of recurrence. Surgery usually is reserved for patients who have failed medical management, who have a markedly enlarged thyroid, who refuse radioactive iodine therapy, and for the rare patient with significant ophthalmopathy in whom radioactive iodine therapy is contraindicated. The most common potential complication is transient hypocalcemia which occurs in approximately 10% of patients. Other, less common potential complications are keloid formation (2.8%), recurrent laryngeal nerve paralysis (2%), hypoparathyroidism (2%), and, rarely (0.08%), death ( 194). There are fewer complications with an experienced surgeon and when modern methods of anesthesia and pain control are used ( 196). Prior to surgery, it is important to treat with antithyroid medication in order to render the child euthyroid and prevent thyroid storm. Iodides (Lugols solution, 5 to 10 drops tid or potasium iodide, 2 to 10 drops daily or Na ipodate, 0.5-1 gm every 3 days) are added for 7 to 14 days prior to surgery in order to decrease the vascularity of the gland.

Following both medical and surgical thyroid ablation most patients become hypothyroid and require lifelong thyroid replacement therapy. On the other hand, if therapy is inadequate, hyperthyroidism may recur. Therefore longterm followup is mandatory.

Thyroid nodules and cancer

Thyroid nodules are rare in the first 2 decades of life, but when found, they are more likely to be carcinomatous than are similar masses in adults ( 197). Follicular adenomas and colloid cysts account for the majority of benign nodules. Other causes of nodular enlargement include chronic lymphocytic thyroiditis and embryological defects, such as intrathyroidal thyroglossal duct cysts or unilateral thyroid agenesis. Like in adults, the most common form of thyroid cancer in childhood and adolescence is papillary thyroid carcinoma, but other histological types found in the adult may also occur ( 198).

A high index of suspicion is necessary if the nodule is painless, of firm or hard consistency, if it is fixed to surrounding tissues or if there is a family history of thyroid cancer. Other worrisome findings include a history of rapid increase in size, associated cervical adenopathy, hoarseness or dysphagia. Even the findings of a cystic component or a functioning nodule, commonly used as favorable signs in adult patients, do not completely exclude the possibility of neoplasia ( 199). Occasionally, thyroid cancer presents in childhood as unexplained cervical adenopathy, or neoplasia is found in patients who also have chronic lymphocytic thyroiditis ( 199). The possibility of a rare medullary thyroid carcinoma should be considered if there is a family history of thyroid cancer or pheochromocytoma or if the child has multiple mucosal neuromas and a marfanoid habitus, findings suggestive of multiple endocrine neoplasia (MEN) types 2A and/or 2B ( 200).

Children exposed previously to thyroid irradiation comprise a high-risk group. The increased risk of thyroid cancer in adults exposed during childhood to low levels of thyroid irradiation for benign conditions of the head and neck is well known ( 201). The increased incidence of both benign and carcinomatous nodules in patients with Hodgkin disease who had received radiotherapy to the neck during childhood is also being documented increasingly ( 202, 203 ). Thyroid cancer is now known to be the most common second malignancy in childhood survivors of Hodgkins and is also seen with increased frequency in leukemia survivors ( 204). Similarly, children exposed to high levels of radioactive iodine in the first decade of life or in utero, a consequence of the Chernobyl disaster, are at a markedly increased risk of developing papillary thyroid cancer ( 195). The risk of thyroid cancer is related to the dose of external irradiation and, unlike the 19 year average latency after low dose irradiation, the average latent period in survivors of Hodgkin disease appears to be only 9 years ( 203). In Chernobyl victims, the latency was only 4 years ( 195). As compared with adults, there appears to be a higher prevalence of gene rearrangements in children with differentiated thyroid cancer, the clinical significance of which is unclear ( 204).

Initial investigation of a thyroid nodule includes evaluation of thyroid function and TPO and Tg antibodies. A suppressed serum TSH concentration accompanied by an elevation in the circulating T4 and/or T3 suggests the possibility of a functioning nodule, which can be confirmed with a radionuclide scan. The finding of positive antibodies, on the other hand, usually indicates the presence of underlying chronic lymphocytic thyroiditis, but in some cases, positive antibodies may simply constitute evidence of an immune response to the presence of neoplastic cells. Ultrasonography provides information about whether the nodule is solid or cystic, and whether it is single or multifocal Fine-needle aspiration biopsy, popular in the investigation of thyroid carcinoma in adults, is gaining increasing acceptance and is now considered to be the procedure of choice in the evaluation of nodules >0.5 cm ( 205).

There is an increased incidence of both cervical node involvement and of pulmonary metastases at the time of diagnosis in children with thyroid carcinoma ( 198). Nonetheless, the long term cancer specific mortality rate is no greater in children than in adults <40 years of age ( 206). Thus, the approach to treatment is similar. (See also Chapter 18). Excision of the tumor or lobe is the appropriate treatment for benign tumors and cysts, whereas total thyroidectomy with preservation of the parathyroid glands and recurrent laryngeal nerves is the initial therapy for malignant thyroid tumors. The latter procedure is followed by radioablation if there is evidence of residual gland or tumor after surgery. The issue of prophylactic lymph node dissection is controversial ( 204). After radioiodine therapy, the dose of thyroxine is adjusted to keep the serum TSH concentration suppressed (between 0.05 mU/L and 0.1 mU/L in a sensitive assay). Measurement of serum Tg, a thyroid follicular cell-specific protein, is used to detect evidence of metastatic disease in differentiated forms of thyroid cancer, such as papillary or follicular carcinoma. This is best performed after a period (usually 6 weeks) of thyroxine withdrawal or after the exogenous administration of recombinant TSH ( 207). Management of differentiated thyroid cancer in children and adolescents has been described in detail recently ( 204, 204b ).

Measurement of circulating calcitonin is used as a tumor marker for medullary thyroid cancer (MTC), a C-cell derived malignancy ( 208). Mutations of the RET protooncogene, detectable in nearly all familial forms of MTC, is of value in screening family members ( 200, 208 ). In families affected with multiple endocrine neoplasia type 2, screening of children as young as 5 years followed by total thyroidectomy has been successful in curing patients with microscopic MTC, an otherwise highly malignant neoplasm with a poor prognosis ( 200).

Optimal monitoring of patients with a history of thyroid irradiation during childhood remains controversial. Because of the insensitivity of clinical palpation, regular assessment of thyroid function (TSH and, as necessary free T4) as well as ultrasound examinations should be performed. There is evidence that thyroid suppression is associated with a reduction in the development of new nodules after partial surgical resection of an irradiated thyroid gland ( 209) but whether it plays any role if the TSH is not elevated or in preventing neoplasia is unknown.

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