THYROID DISEASE IN INFANCY

Congenital Hypothyroidism

Non endemic congenital hypothyroidism is one of the commonest treatable causes of mental retardation and occurs in approximately 1 in 3000-4000 infants worldwide (37). 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 (115,116). 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's that the importance of early treatment in diminishing the neuro-psychological abnormalities of congenital hypothyroidism was demonstrated convincingly (115,116). 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. 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(117). It was not until the development by Dussault et al of a sensitive and specific radioimmunoassay for the measurement of T4 in dried whole blood eluted from filter paper (and later tests for T4 and TSH using 1/8" discs) that the technical means to screen all newborns for congenital hypothyroidism prior to the development of clinical manifestations became available (118-120).

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) (71). 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 in the United States, Canada, Western Europe, Israel, Japan, Australia, and New Zealand and are under development in Eastern Europe, South America, Asia, Oceania and Africa. It is estimated that as of 1992, some 50 million infants had been screened for congenital hypothyroidism worldwide with 6,000 cases detected annually (71). Although there continues to be some disagreement as to whether minor neurointellectual 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 (71,72). 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, favored in North America, 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 % (T4<6 µg/dL or 77 nmol/L)) was employed, most programs now use the 10th% (T4 9 ug/dL or 116 nmol/L) or even the 20% as a threshold to measure TSH (121,122). This has been done in order to detect patients with subclinical hypothyroidism, a frequent finding in 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 congenital hypothyroidism and are recalled immediately (121). 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 (121,122).

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 are recalled immediately (71,121). 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 (123). A primary T4 /backup TSH program will detect overt primary hypothyroidism (1 in 3500), secondary or tertiary hypothyroidism (1 in 50,000 to 100,000 livebirths), babies with a low T4 but delayed rise in the TSH concentration (7.5% of infants), TBG deficiency and hyperthyroxinemia; this approach may, however, miss compensated hypothyroidism (121). A primary TSH strategy, on the other hand, will detect both overt and compensated 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) (124). This pattern has been termed ‘atypical’ CH or ‘delayed TSH rise’ 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. 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 CH cases, but this practice greatly increases the cost of screening(125). 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. The latter programs report a 14-fold increased incidence of this problem in very low birth weight infants(126). 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(126a). In the latter group of infants, fetal cord mixing may occur and initially mask the presence of CH.

In both screening strategies there is the possibility for human error in failing to identify affected infants 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 (127). In practice, the choice of program utilized varies depending on individual preference. 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.

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, however, has resulted in a greater proportion of babies being tested before this time. For example, it has been estimated that in North America at the present time, 25% or more of newborns are discharged within 24 hours of delivery and 40% in the second 24 hours of life (121). Because of the neonatal TSH surge and the dynamic changes in 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% (122). Similarly, very low birth weight infants account for 8% of all TSH assays performed in a primary T4 program (122). In the last decade, normal values according to gestational age (and/or birth weight) for cord blood T4, free T4, TSH and TBG(Figure 15-5) (26), screening values for T4 (Table 15-2)(63) and serum free T4 and TSH in the first week of life (Table 15-3) (128), the latter using newer more sensitive assay techniques, have been published.

Causes of Permanent Congenital Hypothyroidism

Thyroid Dysgenesis

The causes of congenital hypothyroidism and their relative frequencies are listed in Table 15-4. Unlike in iodine-deficient areas of the world where endemic cretinism continues to be a major health hazard, the majority (80-85%) of cases in North America, Western Europe and Japan are due to thyroid dysgenesis, a sporadic disease. 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 (1 in 32,000) and more common among Hispanics (1 in 2000)(129). Although originally a slightly higher incidence was reported in Western Europe (1 in 3300) and a slightly lower figure was reported in Japan (1 in 5700) than in North America (1 in 4500), these differences have decreased more recently as the original screening protocols have been modified (122).

Both genetic and environmental factors have been implicated in the etiology of thyroid dysgenesis, but 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 (130) all suggest that genetic factors might play a role in some cases. The transcription factors TTF-1, TTF-2 and Pax-8 would appear to be obvious candidate genes in the etiology of thyroid dysgenesis 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. A heterozygous deletion of the TTF-1 gene has been described in a newborn infant with compensated hypothyroidism, a normal-sized thyroid gland on scan, normal magnetic resonance imaging of the brain, and respiratory failure (131). These findings are of particular interest in view of the findings of abnormal thyroid, lung, pituitary, and forebrain development in mice with a targeted disruption of the TTF-1 gene (7). However no germline mutations in the TTF-1 gene were found in a total of 76 CH patients studied by 2 different groups of investigators in Italy (132,133). Similarly, germline mutations of the Pax-8 gene were found in only 2 of 145 Italian patients with sporadic thyroid dysgenesis studied in one large series (134). 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. Also, a missense mutation in the TTF-2 gene has been reported recently in 2 siblings with the combination of thyroid agenesis, cleft palate, spiky hair and choanal atresia (135), abnormalities reminiscent of the findings in TTF-2 knock out mice which develop thyroid dysgenesis and cleft palate (12). The rarity of abnormalities in the TTF-1, TTF-2 and Pax-8 genes in patients with thyroid dysgenesis could be due to several reasons. It is possible that, analogous to some mice with a targeted disruption in this gene, mutation of the TTF-1 gene is not compatible with life. Alternatively thyroid dysgenesis could be due to a somatic rather than a germline neo-mutation of one or other of these genes, an abnormality that would not be identified by genetic analysis of peripheral lymphocytes. More likely, the etiology of thyroid dysgenesis is multigenic (i.e., abnormalities in several genes might be necessary to produce the phenotype) and/or multifactorial (both genetic and environmental factors might be involved) (136,136a).

Maternal autoimmunity has also been invoked as a potential cause of permanent congenital hypothyroidism but its role is controversial. There is no increased prevalence in the maternal circulation of thyroid peroxidase,TPO, (formerly called thyroid anti-microsomal) antibodies, often used as a marker of autoimmunity (137). Although both thyroid growth-blocking immunoglobulins (138) and cytotoxic antibodies (139) have been reported to be present in some mothers of babies with thyroid dysgenesis, evidence is lacking at present for an etiological role. Furthermore, these original reports have not been confirmed (140).

Inborn Errors of Thyroid Hormonogenesis

Inborn errors of thyroid hormonogenesis are responsible for most of the remaining cases (10-15%) of neonatal hypothyroidism. A number of different defects have been characterized and include: 1) decreased thyrotropin (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 thyroglobulin synthesis or transport, and 5) abnormal iodotyrosine deiodinase activity (141, 142). The association of an organification defect with sensorineural deafness is known as Pendred's syndrome. Unlike thyroid dysgenesis, a sporadic condition, these inborn errors of thyroid hormonogenesis tend to have an autosomal recessive form of inheritance consistent with a single gene mutation. It is not surprising, therefore, that a molecular basis for many of these abnormalities has now been identified (141, 142)^. These include mutations in the genes for the TSH receptor, sodium-iodide symporter, thyroid peroxidase enzyme, and thyroglobulin, respectively; the gene for the iodotyrosine deiodinase enzyme has not been cloned to date. Pendred's syndrome has now been shown to be due to a defect in the pendrin gene on chromosome 7q22-31, a newly identified porter of iodide on the apical surfice of the thyroid follicular cell with sequence homology to several sulfate transporters(143, 143a). Inborn errors of thyroid hormonogenesis are discussed in further detail in Chapter 16. Mutations in THOX2, important in hydrogen peroxide generation, have been shown recently to cause both transient and permanent forms of congenital hypothyroidism associated with a defect in organification (143b).

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 (144-146); in rare cases no thyroid gland at all is discernible on thyroid imaging, a picture indistinguishable from thyroid agenesis (147). Similar to the variability observed in thyroid gland size in this condition, the clinical findings in TSH resistance have varied from compensated 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 (148). In a few affected infants, a discrepancy between presumed "athyreosis" on thyroid scintigraphy and the detection of either a "normal" serum thyroglobulin concentration or glandular tissue on ultrasound examination has been noted (147). The latter features may be helpful diagnostically. It is of interest that the discordance between the size of the thyroid gland and the thyroglobulin concentration derives, in part, from the fact that the regulation of thyroglobulin secretion is not solely dependent on TSH.

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 (149). 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 (150). 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_a-gene (pseudohypoparathyroidism, type la or Albright's hereditary osteodystrophy) although usually these patients have transient hypothyroidism in the newborn period or a mild functional defect that results in compensated hypothyroidism later in life (151). Albright's hereditary dystrophy has an autosomal dominant inheritance with variable expression. Loss of function mutations of the TSH receptor are discussed in further detail in Chapter 16.

Secondary and/or Tertiary Hypothyroidism

TSH deficiency due to either a pituitary or hypothalamic abnormality accounts for <5% of cases of congenital hypothyroidism detected by newborn screening. 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 (141). 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 (Table 15-5) (152).

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 prolonged hypoglycemia (153). Recently, one of the more common of these syndromes, septo-optic dysplasia, has been shown to be due to a mutation in the HESX-1 homeobox gene in some cases (154). Non dysmorphic causes of congenital hypopituitarism include pituitary hypoplasia, a disorder that is often associated with an ectopic posterior pituitary gland (153), and molecular defects in the genes for the transcription factors LHX, POU1F1 or PROP-1 (155,156). POU1F1 (formerly called Pit-1) 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 POU1F1 expression. (Table 15-5).

Decreased T4 Cellular Transport

Decreased T4 cellular transport into the brain is a newly recognized congenital abnormality of thyroid hormone action(156a). In this syndrome mutations in the monocarboxylate transporter 8 (MCT8) 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. Heterozygous females had a milder thyroid phenotype and no neurological defects

Thyroid Hormone Resistance

Generalized resistance to thyroid hormone (GRTH), although usually diagnosed later in life, may be identified in the newborn period by neonatal screening programs that determine primarily TSH (157) Affected babies usually are not symptomatic. Most cases of GRTH result from a mutation in the TRβ gene and follow an autosomal dominant pattern of inheritance (158). Thyroid hormone resistance is discussed in greater detail in Chapter 16.

Causes of transient neonatal hypothyroidism

Estimates of the frequency of transient neonatal hypothyroidism vary greatly depending on the manner in which the condition is defined. For example, when defined on the basis of all infants with a single screening blood TSH concentration of >40 mU/L minus those in whom a permanent cause of congenital hypothyroidism is found, the incidence of transient hypothyroidism in the New England screening program was calculated to be 1: 4200 (122). However, in the majority of these cases, the repeat value is normal. Thus, other authors consider transient hypothyroidism to be present only when a low T4 and elevated TSH are found in both the screening and confirmatory serum sample, associated with disappearance of the condition within a few weeks with or without replacement therapy; a blood specimen in which the screening value is abnormal but the confirmatory serum sample is normal is considered to be a "false positive". When the latter definition was used, only 4% of recalled infants in another program had transient hypothyroidism while 77.2% were false positives; in 14.5% of the recalled infants the congenital hypothyroidism was permanent (71). In North America, a frequently quoted estimate for transient hypothyroidism is 10% of cases identified as having congenital hypothyroidism, or 1 in 40,000 neonates (37). As noted earlier, transient hypothyroidism is most common in premature infants, the frequency increasing the greater the degree of prematurity. Causes of transient neonatal hypothyroidism are listed in Table 15-6. 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.Among children who have transient neonatal hyperthyrotropinemia, up to 43% are found to have subclinical hypothyroidism at age 5 years. (Leonardi D, Polizzotti N, Carta A, Gelsomino R, Sava L, Vigneri R, Calaciura F. Longitudinal study of thyroid function in children with mild hyperthyrotropinemia at neonatal screening for congenital hypothyroidism. J Clin Endocrinol Metab. 2008 Jul;93(7):2679-85)

Iodine Deficiency and Iodine 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 (71,159). In Belgium, for example, transient hypothyroidism was reported in 20% of premature infants, an 8-fold higher prevalence than in North America (71). 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 (60,160). Furthermore, premature infants are in negative iodine balance for the first 1 or 2 weeks of postnatal life (62).

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 or directly to the baby. This occurs, in part because, as noted earlier, the fetus is unable to decrease thyroidal iodine uptake in response to an iodine load before 36 weeks gestation; however, other factors, including increased skin absorption and decreased renal clearance of iodine in premature infants, are also likely to play a role (161). Reported sources of iodine have included drugs (e.g., potassium iodide, amiodarone), radiocontrast agents (e.g., for intravenous pyelogram, oral cholecystogram, or amniofetography) and antiseptic solutions (e.g., povidone-iodine) used for skin cleansing or vaginal douches. In contrast to Europe (162, 163,), iodine-induced transient hypothyroidism has not been documented frequently in North America (161).

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. Results of a prospective study analyzing this issue in 11 mothers receiving 200 mg PTU or less per day are illustrated in Figure 15-9 (164). Despite the relatively modest dose of PTU, well within the allowable dose according to current guidelines, there was clear-cut impairment of thyroid function in the newborn infants as evidenced by a lower neonatal T4 surge and higher TSH at 3 days of age. Babies with PTU- or MMI-induced hypothyroidism characteristically develop an enlarged thyroid gland. At times this goiter may be sufficiently large to cause respiratory embarassment, particularly when higher PTU doses are used. Both the hypothyroidism and goiter resolve spontaneously with clearance of the drug from the baby's circulation. Usually replacement therapy is not required.

Figure 15-9. Effects of PTU treatment on maternal and neonatal serum thyroid hormone and TSH concentrations. Bars indicate the standard error of the mean (SEM). Where bars are absent, the SEM is smaller than the symbol. Open circles denote PTU-treated mothers and infants, and solid symbols, control values from several sources. An asterisk indicates a significant difference from normal (p < 0.05). T4 denotes thyroxine, T3 triiodothyronine, and rT3 reverse triiodothyronine. (From Cheron et al. (136), with permission).

Maternal Thyrotropin 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 (165). 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. 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. 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 15-7). 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 (85, 166)).

Transient Secondary and/or Tertiary Hypothyroidism

Occasionally, babies born to mothers who were hyperthyroid during pregnancy develop transient hypothalamic-pituitary suppression. This hypothyroxinemia is usually self-limited, but in some cases it may last for last years and require replacement therapy (167,168). 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). Other causes of transient 2^o and 3^o hypothyroidism include prematurity (particularly infants <27 weeks gestation, discussed below) and drugs frequently used in the neonatal intensive care unit (steroids, dopamine).

Other abnormalities of thyroid function discovered on newborn screening

Isolated Hyperthyrotropinemia

Isolated hyperthyrotropinemia has been described in screening programs that utilize a primary TSH method and is most common in premature infants. While some of these babies represent cases of "compensated" hypothyroidism, in other instances the etiology is not clear. The etiology appears to be diverse. As a group, babies diagnosed with hyperthyrotropinemia in infancy have a higher serum TSH compared to control children when reexamined in early childhood (168a, 168b). Also, these infants have a higher prevalence of both thyroid morphological abnormalities, antithyroid antibodies, and mutations in thyroperoxidase and TSH receptor genes than do controls. In babies whose blood specimen is obtained within the first day or two of life because of early discharge, isolated hyperthyrotropinemia may be due to 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 (169). Isolated hyperthyrotropinemia of unknown etiology has been reported in babies in Japan. In these cases, the TSH normalized without treatment within the first year of life (170).

Hypothyroxinemia

As noted earlier in this chapter, 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 (71). Often the free T4 when measured by equilibrium dialysis is less affected than the total T4 (60,160). As discussed previously in this chapter, 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". Transient neonatal hypothyroxinemia has been associated with subsequent problems in motor and cognitive development (60), raising the possibility that affected infants should be treated. Results of therapy to date have yielded mixed results (see below).

In addition to prematurity, abnormalities in thyroid-binding proteins, particularly TBG, may cause hypothyroxinemia without associated hyperthyrotropinemia. The incidence of TBG deficiency is 1 in 5,000 to 1 in 12,000.

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. This is illustrated in Figure 15-9 which compares the findings in a baby with untreated congenital hypothyroidism diagnosed clinically with an infant in whom the diagnosis was made by newborn screening. 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. 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 detected by newborn screening should be evaluated without delay, preferably within 24 hours. The diagnosis of neonatal hypothyroidism is confirmed by the demonstration of a decreased concentration of T₄ (<6.5 ug/dL; 3.7 nmol/L) and an elevated TSH level (> 20 mU/L) in serum. As noted previously, most infants with permanent abnormalities of thyroid function have a serum TSH concentration >40 mU/L. Physicians should be aware that the serum T₄ concentration is much higher in full term infants in the first 2 months of life (6.5 - 16.3 ug/dL; 37 - 210 nmol/L) than in adults for whom reference values are given in most laboratories) (171). Normal values for thyroid function in the neonatal period are given Table 15-7. Measurement of T3 is of little value in the diagnosis of congenital hypothyroidism.

A bone age is often performed as a reflection of the duration and severity of the hypothyroidism in utero. A radionuclide scan (either ¹²³I or ^99mTc0₄) 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 counselling 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 µCi, should be used. Advantages of pertechnetate, on the other hand, are that it is cheaper and more widely available. 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 ¹³¹I is used and relatively large doses of isotope are administered.

If there is no uptake on thyroid imaging, an ultrasound study should be performed to confirm the absence of thyroid tissue. Ultrasonography is also helpful as an alternative to thyroid scintigraphy to verify the presence of a eutopic thyroid gland if a transient abnormality is suspected or if a thyroid gland is palpable on clinical examination; this procedure is less sensitive than a radionuclide scan, however (71). Recently color Doppler ultrasonography has been demonstrated to be almost as sensitive as ¹²³I in detecting ectopic thyroid and may offer a non isotopic alternative to thyroid scintigraphy (171a).

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 (165). 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; bioassay can be done later if desired to demonstrate the biological action of the antibodies. 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, thyroid peroxidase (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 (165).

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. As noted above, potential clues to the diagnosis of a loss of function mutation of the TSH receptor include a normal thyroglobulin and/or evidence of a thyroid gland on ultrasound examination despite the failure to visualize thyroid tissue on imaging studies (147). 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. The detailed evaluation of infants suspected of having this and other abnormalities in thyroid hormonogenesis has been described in Chapter 16b and elsewhere (71,141,142).

Measurement of thyroglobulin is most helpful when a defect in thyroglobulin synthesis or secretion is being considered. In the latter condition the serum thyroglobulin concentration is low or undetectable despite the presence of an enlarged, eutopic thyroid gland. Serum thyroglobulin concentration also reflects the amount of thyroid tissue present and the degree of stimulation. For example, thyroglobulin 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 thyroglobulin synthesis and secretion. Considerable overlap exists, however, limiting the value of thyroglobulin measurement in the differential diagnosis of the aforementioned disorders. In patients with inactivating mutations of the TSH receptor a discordance between findings on thyroid imaging and the serum thyroglobulin concentration has been described in some but not other studies (147).

In babies in whom hypothyroxinemia unaccompanied by TSH elevation is found, a free T4 should be measured, preferably by a direct 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 2^o or 3^o hypothyroidism. In these cases, TRH testing (TRH, 7 µg/kg IV) is the classical approach recommended in the past to distinguish whether the abnormality is at the level of the pituitary gland or hypothalamus. A recent study, however, has questioned the utility of this test (171b). Pituitary function testing and brain imaging should also be performed in these infants. In premature, low birth weight or sick babies in whom a low T4 and "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 weeks until the T4 normalizes because of the rare occurrence of delayed TSH rise (124,172). Similarly, any baby suspected of being hypothyroid clinically should have repeat thyroid function testing because of rare errors in the screening program.

A suggested approach to the investigation of infants with abnormal results on newborn thyroid screening is presented in Figure 15-10.

Figure 15-10.

Therapy

Replacement therapy with levothyroxine sodium should be begun as soon as the diagnosis of congenital hypothyroidism is confirmed, and the parents should be counselled 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. Educational materials should be provided. 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). An initial dosage of 10-15 ug/kg is recommended so as to normalize the T₄ as soon as possible. Babies with compensated hypothyroidism may be started on the lower dosage, while those with severe CH (e.g., T4<5 µg/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. Unfortunately, liquid preparations are unstable.

The aims of therapy are to normalize the T4 as soon as possible, to avoid hyperthyroidism and to promote normal growth and development. When the aforementioned amount of levothyroxine is used, the T4 will normalize in most infants within 1 week and the TSH will normalize within 1 month. Whether more rapid correction is associated with an improved outcome has not been determined. 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 µg) 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. In rare infants, normalization of the TSH concentration may be delayed because of relative pituitary resistance. In such cases, characterized by a normal or increased serum T₄ and an inappropriately high TSH level, the T₄ value is used to titrate the dosage of medication, but noncompliance should be excluded (81). One usually aims at maintaining the T₄ above 10 ug/dL (128.7 nmol/L) and the TSH at less than 10 mU/L. Close follow-up is necessary. Current recommendations of both The American Academy of Pediatrics and the American Thyroid Association are to repeat 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 (121). 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.

Whether or not premature infants with hypothyroxinemia should be treated remains controversial at the present time. Early retrospective investigations failed to document a difference in cognitive outcome in premature infants with hypothyroxinemia as compared with controls, but small numbers were studied. More recently, 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 (60,160,173). Whether or not the poorer prognosis in these infants is causal or coincidental cannot be determined, however, since the serum T4 in premature infants, as in adults, has been shown to reflect the severity of illness and risk of death. In other studies, investigators have evaluated the effect of therapeutic intervention with T4 or T3 not only on neuro-cognitve outcome, but on mortality rate and respiratory function as well. A variety of dosage schedules have been used, but once again conflicting results have been obtained. In the most thorough study to date, Van Wassenaer et al carried out a placebo-controlled, double-blind trial of T4 treatment, 8 µg /kg per day for 6 weeks in 200 infants less than 30 weeks gestation. 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 (174). Of some concern was the additional finding that treatment with T4 was associated with a 10-point decrease in mental score (p=0.03) in infants >27 weeks gestation. Subsequent evaluation of the same cohort at early school age substantiated these findings (174a). While further studies are needed, it would seem reasonable at the present time to treat any premature infant with a low T4 and elevated TSH and to consider treatment of any infant <27 weeks with a low T4 whether or not the TSH is elevated. A dosage of 8 µg/kg/day in the latter group of infants has been recommended. Whether or not to treat older premature infants with hypothyroxinemia and what dosage to use remains uncertain.

Prognosis

Numerous studies have been performed to evaluate the cognitive outcome of babies with congenital hypothyroidism detected on newborn screening. In the initial reports, despite the eradication of severe mental retardation, the intellectual quotient (IQ) of affected infants was nonetheless 6-19 points lower than control babies (72, 174b). Though this IQ deficit was small, it was nonetheless significant as judged by a 4-fold increase in the need for special education in affected children. In addition, sensorineuiral hearing loss, sustained attention problems, and various neuropsychological variables were noted in some patients, although the frequency and severity of these abnormalities were much less than in the pre-screening era. Those babies most likely to have permanent intellectual sequelae were infants with the most severe in utero hypothyroidism as determined by initial T4 level (<5µg/dL (64 nmol/L)) and skeletal maturation at birth. These findings led to the widely-held conclusion at the time that some cognitive deficits in the most severely affected babies might not be reversible by postnatal therapy (72).

In the initial programs, a levothyroxine dosage of 5µg-8µg/kg was used and treatment was not initiated until 4-5 weeks of age. In contrast, accumulating data from a number of different studies have demonstrated that when a higher initial treatment dose is used (10µg-15µg/kg) and treatment is initiated earlier (before 2 weeks) this "development gap" can be closed, irrespective of the severity of the congenital hypothyroidism at birth (174c). In the most compelling study to date, Bongers-Schokking et al have shown recently that even babies with severe congenital hypothyroidism can achieve normal psychomotor development at 10 to 30 months as long as treatment is initiated before 13 days of age and an initial dose of >9.5 µg/kg/day is used. However, if treatment is delayed or a lower dose is used, a 20 point deficit in both mental and psychomotor development is observed (174d). Long term studies have not yet been performed to determine whether these differences in cognitive outcome are maintained. Whether or not subtle abnormalities persist in the most severely affected babies remains controversial. For patients treated in the original screening programs, the long term problems appear to be in the areas of memory, attention and visual spacial problems (174e). In addition to adequate dosage, assurance of compliance is essential for an optimal developmental outcome. Combined therapy with T4 and T3 offers no advantage to T4 alone (174f).

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 (175,176). 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 (177). 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 (178). 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 (179). 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(179).

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. Goiter, when present, may be related to maternal antithyroid drug treatment as well as to the neonatal Graves' disease itself. Rarely, infants with neonatal Graves' disease present with thrombocytopenia, hepatosplenomegaly, jaundice, and hypoprothrombinemia, a picture that may be confused with congenital infections such as toxoplasmosis, rubella, or cytomegalovirus (180). 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 (181).

The half-life of TSH receptor antibodies is 1 to 2 weeks (182). 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 15-9. 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 (Figure 15-5)(26) 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.

As noted in the case of TSH receptor blocking antibody-induced congenital hypothyroidism, the radioreceptor assay or ELISA is the most 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 (175,183,184). 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 (183). 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 (168,183,184). 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. The minimal dosage of PTU (or MMI) necessary to normalize the fetal heart rate and render the mother euthyroid or slightly hyperthyroid is usually chosen. In the neonate, treatment is expectant. Either PTU (5 to10 mg/kg/day) or MMI (0.5 to 1.0 mg/kg/day) can be used initially in 3 divided doses. If the hyperthyroidism is severe, a strong iodine solution (Lugol's solution or SSKI, 1 drop every 8 hours) is added to block the release of thyroid hormone immediately because the effect of PTU and MMI may be delayed for several days. Therapy with both PTU 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. Alternately, sodium ipodate (0.5 gm every 3 days), an iodine-containing radiocontrast material that inhibits both thyroid hormone secretion and the conversion of T4 to T3, has been used successfully as the sole treatment of neonatal hyperthyroidism (185). Measurement of TSH receptor antibodies in treated babies may be helpful in predicting when antithyroid medication can be safely discontinued (176). 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. Since the milk/serum ratio of PTU is 1/10 that of MMI, a consequence of pH differences and increased protein binding, PTU is preferable to MMI. 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 (186-190). 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 (186-189). Less frequently, a mutation encoding the extracellular domain has been described (190). 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 (186,188,189), and, when diagnosis and therapy is delayed irreversible sequelae, such as cranial synostosis and developmental delay may result (186). For this reason early, aggressive therapy with either thyroidectomy or even radioablation has been recommended.