Chapter 527. Hypothyroidism in the Infant

Causes of hypothyroidism are listed in Table 527-1. Transient neonatal hypothyroidism occurs in premature infants, and may be caused by drugs or maternal antibodies. The most common cause of nonendemic congenital hypothyroidism is defective thyroid embryogenesis. Inborn defects in thyroid hormone synthesis or action are the second most common cause of congenital hypothyroidism.1-13 Other causes include intrauterine exposure to goitrogenic agents and hypothalamic-pituitary disorders. These usually occur in the setting of panhypopituitarism, but isolated defects in thyrotropin-releasing hormone (TRH) or thyroid-stimulating hormone (TSH) do occur.5-7

Premature infants are defined by gestational age (GA) and weight. By weight, premature infants are classified as low birth weight (LBW, 2500–1500 g), very low birth weight (VLBW, 1500–1000 g), and extremely low birth weight (ELBW, < 1000 g); they range from 34 to 35 weeks’ to 23 to 24 weeks’ GA (the current threshold of viability).3Most premature infants have some degree of hypothyroxinemia (T4 < 6.5 μg/dL, 84 nmol/L). The prevalence of T4 values < 6.5 μg/dL approximates 50% in VLBW infants. These infants have a relatively immature hypothalamic-pituitary-thyroid axis, immature metabolic systems, and high prevalence of neonatal morbidities, including respiratory distress, hypoxia, undernutrition, gastrointestinal and cardiac dysfunction, sepsis, and cerebral pathology. As result, they are predisposed to development of transient primary hypothyroidism and the syndrome of transient hypothyroxinemia of prematurity (THOP), which probably represents transient hypothalamic-pituitary hypothyroidism and/or nonthyroidal illness (NTI; the low T3 syndrome).

Transient Primary Hypothyroidism

Transient primary hypothyroidism is characterized by low serum T4 and high thyroid-stimulating hormone (TSH) concentrations.3 The prevalence of transient hypothyroidism among premature neonates depends on the extent of iodine deficiency in the environment. Term infants can have transient neonatal hypothyroidism in areas of low iodine intake (endemic goiter). In Belgium, approximately 20% of premature infants have transient hypothyroidism. In North America, the incidence is less than 1%, presumably due to higher average iodine intake. Transient primary hypothyroidism develops during the first 1 to 2 weeks of extrauterine life and is superimposed on the usual state of transient hypothyroxinemia characteristic of prematurity. Urinary iodine excretion and thyroid iodine content are reduced, suggesting that the acquired primary hypothyroidism is the result of relative iodine deficiency. Iodine supplementation of neonates in areas of iodine deficiency prevents transient hypothyroidism.

Administration of iodine-containing drugs to the mother or amniotic injection of radiographic contrast agents for amniofetography can induce hypothyroidism. Premature infants are also particularly susceptible to transient, iodine-induced hypothyroidism. In a series of transient primary hypothyroidism infants treated with T3 (5 μg/kg/d in three divided doses), serum T4 levels increased spontaneously during the period of T3 treatment, indicating spontaneous recovery of thyroid functional capacity.3 The average time to recovery of function and discontinuation of treatment was 50 days. The hypothyroidism is transient but may persist for several weeks; thus, thyroxine (6–8 μg/kg/d) treatment is recommended.

Transient Hypothyroxinemia of Prematurity

Relative to term infants at birth, serum thyroid-binding globulin (TBG) and total T4 concentrations in premature infants are lower, the neonatal thyroid-stimulating hormone (TSH) surge is obtunded, tissue iodothyronine monodeiodinase 1 (MDI-1) activity and serum T3 levels are lower, postnatal TSH and free T4 concentrations are lower, bioinactive thyroid hormone analog levels are higher, brown adipose tissue thermogenic mechanisms are immature, and tissue thyroid hormone response systems are variably immature.3The extent of these immaturities is related inversely to gestational age. In extremely low birth weight (ELBW) and very low birth weight (VLBW) infants, the TSH surge and the early thyroidal response are limited and followed by a progressive decrease in serum total T4 with nadir values at 7 to 10 days of postnatal life. VLBW infants manifest a negative iodine balance during the early postnatal weeks, suggesting that following birth they are unable to adapt with an increase thyroidal iodine uptake and T4 secretion, such as that seen in the term infant.

These infants also have a low serum T3 concentration secondary to decreased T4 to T3 conversion, and decreased T4 concentrations. TBG levels tend to be low, and there may be an inhibitor of T4 binding to TBG as seen with nonthyroidal illness (low T3 syndrome). Free T4 levels are variable especially in VLBW infants, where levels below 10 and 12.5 pmol/L (0.8–1.0 ng/dL) are seen in 15% to 20%. Serum TSH concentrations are normal or low.

Van Wassenaer et al showed that a serum free T4 level, measured by immunoassay, less than 10 pmol/L (0.78 ng/dL) will trigger an increase in serum TSH concentration in most VLBW infants.4This suggests a functional hypothalamic-pituitary axis and favors a major contribution of non-thyroidal illness. The impact of THOP on brain maturation is not clear. In a placebo-controlled treatment study of VLBW infants, van Wassenaer et al showed that a subgroup of 13 thyroxine-treated ELBW infants with gestational ages 25 to 26 weeks, manifested a higher developmental quotient at 24 months than did 18 placebo-controlled infants. In a later analysis of IQ and neurologic function data at 5.7 years of age, mean IQ in the treated and control children were statistically similar, although some neurologic dysfunction persisted, especially in infants with free T4 levels in the 10.1 and 12.5 pmol/L (0.78–0.97 ng/dL) range. The infant cohorts were small, however, and the results must be considered preliminary. It is difficult to differentiate the contribution of nonthyroidal illness versus hypothalamic-pituitary immaturity in the pathogenesis of transient hypothyroidism of prematurity, and there is no consensus regarding treatment. Thyroxine supplementation is not used in most neonatal intensive care units (NICUs). In the van Wassenaer et al study thyroxine was administered at a dose of 8 μg/kg/d given parenterally over a 6-week period,.4

Ingestion of goitrogenic substances by a mother can cause fetal goiter and neonatal hypothyroidism.5-7 The most frequently ingested drug is iodide, usually prescribed in expectorants or as therapy for maternal thyrotoxicosis. Common goitrogenic agents are listed in Table 527-2. The fetus is unusually sensitive to iodide-induced hypothyroidism, probably because of the immature mechanisms for decreasing thyroid iodide uptake to compensate for high plasma iodide levels. Other goitrogens that have caused neonatal goiter include the thioureas, sulfonamides, and hematinic preparations containing cobalt. Neonatal goiters caused by propylthiouracil are uncommon unless large doses (more than 150 mg/d near term) are given to the mother. Transient hypothyroidism is also caused by transplacentally acquired maternal antithyroid antibodies. These can be measured as thyroid-stimulating hormone (TSH)–binding inhibiting immunoglobulin (TBII) or as cAMP (TSH)-blocking antibodies (TBA). These mothers usually have atrophic thyroiditis. The antibody half-life in the neonate approximates 2 to 3 weeks, and hypothyroidism can persist for 2 to 4 months.

The term thyroid dysgenesis describes ectopia or hypoplasia of the thyroid gland (or both) or total thyroid agenesis.

Epidemiology

Thyroid dysgenesis is the cause of decreased thyroid function among most infants with permanent congenital hypothyroidism detected by neonatal screening programs. The prevalence approximates 1 in 4000 newborns.5-7 Thyroid dysgenesis is more prevalent among girls than among boys (ratio approximates 2:1), less prevalent among black infants (1 in 11,000 births), and more prevalent among Hispanics relative to white infants. The prevalence is also high among infants with Down syndrome. A seasonal incidence, peaking during summer, has been reported in Japan and Australia.

Pathophysiology and Genetics

The pathogenesis in most patients is unclear. Although the disorder is usually sporadic, familial examples have been described. These are presumably caused by mutations of the homeobox genes, TTF-1 (NKF2.1), TTF-2 (FOXE1), and PAX-8, which are involved in thyroid gland embryogenesis and are associated with developmental defects in other tissues.2More recently, mutations in GL153, another transcription factor, have been described as the cause of a rare syndrome of neonatal diabetes, congenital hypothyroidism, and congenital glaucoma.8First-degree relatives of children with thyroid dysgenesis have an increased prevalence of thyroglossal duct cysts, pyramidal thyroid lobe, thyroid hemiagenesis, and ectopic thyroid. These abnormalities are compatible with an autosomal-dominant mode of inheritance with a low penetrance estimated at 21%, supporting the hypothesis of a genetic predisposition for a larger proportion of congenital hypothyroidism than is accountable by the homeobox gene syndromes noted previously.

In rare instances, thyroid dysgenesis has occurred in association with maternal autoimmune thyroiditis. However, this appears to be coincidence; there is no correlation between thyroid dysgenesis and the presence of maternal autoimmune thyroiditis or circulating thyroid antimicrosomal or antithyroglobulin autoantibodies.

Clinical Features

Some thyroid tissue is present among 40% to 60% of these infants and represents a spectrum of severity of thyroid deficiency. Thyroid isotope scanning or ultrasonography may not be sensitive enough to detect small amounts of residual functioning thyroid tissue. In such infants, normal or near-normal circulating levels of T3 in the face of a low T4 value suggest residual thyroid tissue, as do measurable levels of serum thyroglobulin. An increased prevalence (8–10%) of nonthyroidal anomalies, including cardiac anomalies, nervous, musculoskeletal, digestive and urologic systems, cleft palate, and eye, are reported in infants with congenital hypothyroidism.9

Most infants with thyroid dysgenesis have no symptoms; perhaps 15% to 20% have suggestive signs of hypothyroidism during the first 2 to 3 weeks of life.5-7 Most affected infants have low serum T4 and high thyroid-stimulating hormone (TSH) concentrations in cord blood or in filter paper blood spots collected in newborn screening programs. An additional group of infants has T4 levels in the low-normal or normal range and increased TSH values. These infants usually have ectopic thyroid tissue on scans and may constitute 10% to 15% of infants with congenital thyroid dysgenesis. One percent to 5% of infants with congenital hypothyroidism have a delayed increase in serum TSH. They manifest a low serum TSH level at birth with an increase to primary hypothyroid TSH levels during the first 2 to 3 months of life. These infants may be missed by the newborn screening programs. Treatment is discussed as follows.

Permanent congenital hypothyroidism caused by a decrease in effective thyroid-stimulating hormone (TSH) stimulation of thyroid hormone is associated with a low serum T4 concentration and a low or normal range TSH level. Potential causes include abnormal hypothalamic or pituitary development (panhypopituitarism discussed in Chapter 523), hypothalamic hypothyroidism with thyrotropin-releasing hormone (TRH) deficiency or resistance, and sporadic and familial deficiency in TRH or TSH secretion (Table 527-1).7,10,11 The combined prevalence of these abnormalities approximates 1 in 60,000 to 100,000 births.

Isolated TSH deficiency is rare, but several cases of congenital hypothyroidism have been reported with low T4 and T3 levels and unmeasurable TSH in the presence of normal levels of other pituitary hormones. The thyroid gland responds to TSH, but there is no TSH response to TRH. Several mutations of the TSHβ gene have been described in these patients.12 If TSH deficiency is suspected, measurements of serum cortisol and growth hormone levels are indicated to detect panhypopituitarism. A cranial CT or MRI scan is useful in characterizing hypothalamic-pituitary anomalies.

Decreased Thyroid-Stimulating Hormone Responsiveness

Resistance to thyroid-stimulating hormone (TSH) is caused by mutations of the TSH receptor gene.12The clinical phenotype ranges from mild TSH receptor resistance with euthyroid hyperthyrotropinemia to rare congenital hypothyroidism. Patients have elevated serum TSH, decreased T4 and thyroglobulin levels, and a thyroid gland in the normal location with reduced radioiodine or technetium uptake. The disorder is usually transmitted as a recessive trait, most resistant patients being compound heterozygotes. Non-TSH receptor, non-TSHβ, and non–G-protein–mediated TSH resistance has been reported in three families with dominant rather than recessive inheritance.

Thyroid Iodide Transport Defects

Defective iodide transport due to defects in the sodium-iodide symporter (NIS) has been reported in about 50 total patients with congenital hypothyroidism.13-18 The diagnosis is based on the presence of goiter, limited or absent radioiodine uptake, and elevated serum thyroid-stimulating hormone (TSH). Other iodine-concentrating tissues (salivary glands, gastric mucosa) also fail to concentrate iodide from the circulation. Lugol solution ameliorates the hypothyroidism by increasing serum iodide to high levels and increasing intrathyroidal inorganic iodide concentration by diffusion. Partial defects have also been described. Thyroid radioiodine uptake was decreased but not absent in these patients and did not respond to TSH. The salivary-to-plasma ratio of radioiodine was also reduced but not entirely absent. Nonetheless, the patients were hypothyroid with mental retardation.

Cloning of the gene for the thyroid hormone NIS was reported in 1996.15Secondary structure prediction suggests a membrane protein with 12 transmembrane helices. The transporter gene is expressed in thyroid and salivary tissues and gastric mucosa, where functional protein has been demonstrated. Transporter RNA (tRNA) is present in a variety of other tissues that do not show iodide uptake; the functional significance of the symporter messenger RNA (mRNA) in these tissues is not clear. Several reports have documented mutations in the NIS gene in patients with congenital hypothyroidism. Affected individuals demonstrate homozygous or compound heterozygous mutation patterns. Heterozygous family members were not clinically affected. The timing of onset of hypothyroidism tends to correlate with the genotype and specific residual sodium-iodide symporter activity. Neonatal onset is likely with mutations associated with lower radioactive iodine uptake.

A defect in the chloride-iodide transport protein, Pendrin, is associated with Pendred syndrome, which includes familial goiter and congenital eighth nerve deafness or high tone deafness, goiter of variable degree appearing in mid- or late childhood, and euthyroidism or mild hypothyroidism. The degree of impaired iodide organification is mild to moderate. One third of patients have the complete syndrome; the remainder present with hearing loss or mild goiter. This disorder is transmitted as an autosomal-recessive trait with a prevalence of 1.5 to 3 cases per 100,000 schoolchildren. One in 60 persons has one abnormal Pendrin gene and is a carrier. Infants with the syndrome are usually not detected unless in an iodine-deficient environment. Goitrous children manifest a positive perchlorate discharge with normal thyroid peroxidase (TPO) activity. Atypical patients without an abnormal perchlorate discharge have been described.

The disorder was more recently mapped to chromosome 7, and molecular studies in more than 20 affected families from different geographic areas show independent point mutations and no large deletions. The etiology of the deafness remains controversial. The available information suggests that Pendrin gene mutations can give rise to either syndromic or nonsyndromic deafness.

Defects in Thyroglobulin Synthesis

Thyroglobulin synthesis defects occur in about 1 in 80,000 to 1 in 100,000 newborns.13Goiter and hypothyroidism are usually manifest at birth, but mild defects may be associated with later onset. The functional defects have included defective thyroglobulin transport with carbohydrate-deficient thyroglobulin sequestered in Golgi or cytoplasmic membranes, thyroglobulin with deficient tyrosine residues or tyrosine residues buried within the molecule and not available for iodination, and sialic acid–deficient thyroglobulin (due to a sialyltransferase deficiency) containing monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT), but manifesting defective coupling.

Peroxidase System Defects (Organification Defects)

Defective organification of iodide has been reported in about 200 patients.13The defects include quantitative deficiency of thyroid peroxidase (TPO), or abnormal, functionally defective TPO or THOX proteins. The complete defect can be detected by a perchlorate discharge test. Perchlorate is administered 1 to 2 hours after a dose of radioiodine. If organification is impaired, there is a rapid and marked discharge of the trapped thyroidal radioiodine during the following 1- to 2-hour period. Patients with partial TPO deficiency have a lesser discharge. The test is not specific, however, and more definitive molecular testing is necessary for a precise diagnosis.

Thyroid peroxidase is a glycoprotein located at the apical membrane of the thyroid follicular cell. The gene is located on chromosome 2 and contains three kilobases of coding sequence over 17 exons coding for a protein of 933 amino acids. The variable molecular defects account for the clinical and biochemical heterogeneity in patients with defective iodine organification. Premature termination codons prevent translation of the protein. Other mutations affect the structure of the protein and perhaps its cellular location. Milder or transient organification defects have been associated with compound heterozygosity.

Several patients have been described who were euthyroid or mildly hypothyroid but manifested goiter and partial discharge of radioiodine following perchlorate administration. In these patients, the thyroid gland contained no peroxidase activity, but such activity could be restored by adding hematin, the noncovalently bound prosthetic group of the peroxidase. This suggested an abnormal peroxidase apoenzyme deficient in binding to its heme moiety. In other patients, the organification defect was associated with defective H2O2 generation. The H2O2 generation defect is rare. More recently, two genes encoding nicotinamide adenosine dinucleotide phosphate (NADPH) oxidases have been cloned and referred to as THOX1 and THOX2.17 They are closely linked on chromosome 15 and predict proteins of 1551 and 1558 amino acids, respectively. The proteins colocalize with TPO at the apical membrane of thyroid follicular cells. Inactivating mutations in THOX2 have been described in several patients associated with transient or severe congenital hypothyroidism.

Iodotyrosine Deiodinase Defects

Deficiency of the iodotyrosine dehalogenase enzyme can produce a rare hereditary defect that causes either congenital hypothyroidism or a less severe form of familial goiter.13 Failure to deiodinate thyroid monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT) as they are released from thyroglobulin leads to severe iodine wastage because these nondeiodinated iodotyrosines diffuse out of the thyroid and are excreted in urine. The patients originally described were hypothyroid with goiters presenting at birth or shortly thereafter. They manifested early rapid thyroid radioiodine uptake and rapid spontaneous discharge; by 48 hours, most of the thyroidal radioiodine was discharged.

The serum in such patients contains high concentrations of iodotyrosines. They excrete essentially all of an intravenous dose of labeled iodotyrosine directly into urine, whereas normal subjects excrete the level almost entirely as free iodide. Partial defects have been described (1) in both thyroid and peripheral tissues, (2) in peripheral tissues only, or (3) in thyroid tissue only. In patients with mild defects, compensation may be possible in a high iodine environment; a goiter may appear only if iodine intake is limited.

More recently, the gene encoding the iodothyronine dehalogenase (DEHAL1) was cloned. DEHAL1 is localized to the apical thyroid membrane close to the thyroglobulin iodination site, closely linking tyrosine deiodination with the organification process. Mutations of the DEHAL1 gene have been identified in patients with congenital hypothyroidism from three different families. The phenotype is variable, depending on the residual DEHAL1 enzyme activity, but can include severe congenital hypothyroidism.

Iodothyronine Monodeiodinase Deficiency

To date, no defects have been identified in the genes encoding the iodothyronine monodeiodinase (MDI) enzymes. All are selenoproteins requiring the incorporation of selenocysteine (sec) during biosynthesis. However, defects in the selenocysteine insertion sequence have been described in two families with a phenotype of hyperthyroxinemia, decreased serum T3, increased reversed T3, and mildly increased thyroid-stimulating hormone (TSH) levels.

Incorporation of selenocysteine into the MDI enzymes requires several components: a selenocysteine insertion sequence (SECIS) element, a SECIS-binding protein (SECISBP2), a selenoprotein-specific elongation factor (EFSec), and its transfer RNA (tRNAsec).18 Three of seven siblings ages 4, 7, and 14 years from a Bedouin Saudi family presented with a phenotype of hyperthyroxinemia, decreased serum T3, increased reverse T3, and mildly increased TSH concentrations. The children were clinically euthyroid. The parents and four other siblings had normal thyroid function parameters. Patient fibroblasts showed reduced MDI-2 activity not linked to the MDI-2 locus, and linkage analysis of the genes involved in MDI synthesis revealed a homozygous missense mutation in SECISBP2. An unrelated Irish child age 6 years with a similar phenotype carried compound heterozygous mutations in SECISBP2. Serum selenoprotein levels were low in affected and normal in unaffected individuals in both families.

Thyroid Hormone Resistance

Patients with thyroid hormone resistance associated with thyroid hormone TRβ1 receptor defects classically present with increased circulating levels of T4 and T3 with a normal or increased serum thyroid-stimulating hormone (TSH) concentration.13,19 TSH levels are mildly to moderately increased, and such infants may be detected in newborn screening programs where TSH is measured directly. More than 1000 cases have been reported and a prevalence approximating 1 in 40,000 newborns is suggested. Patients are classified into three phenotypes: generalized resistance to thyroid hormone (GRTH), pituitary resistance to thyroid hormone (PitRTH), and peripheral resistance to thyroid hormone (PRTH). Inheritance is usually autosomal dominant, and 15% to 20% of cases appear sporadically. Many patients are asymptomatic or demonstrate nonspecific symptoms. Deafness is observed in 20%, and a syndrome of attention-deficit hyperactivity has been documented in half of affected patients. Hypothyroid features include growth retardation, delayed bone maturation, and intellectual impairment. Some children exhibit features of thyrotoxicosis, including failure to thrive, accelerated growth, and hyperkinetic behavior.

Two genes coding for the thyroid receptor (TR) proteins have been described, an alpha gene on chromosome 17 and a beta gene on chromosome 3.19The molecular defect in all cases studied to date has involved the TRβ1 gene on chromosome 3. In most affected subjects, specific TRβ gene mutations have been demonstrated; more than 120 different defects have been described. There has been considerable variation of thyroid effects among tissues within family members with identical TRβ mutations. Thyroid receptors, like other steroid hormone superfamily receptors, bind to DNA response elements as monomers, homodimers, or heterodimers, and heterodimerization can involve another TR, including the inactive TRα2 receptors or other transactivation factors. The ability of the defective receptor to bind T3, to bind to other TR, or to other factors appears to determine the effect of the defective receptor in a given tissue. Affected members usually have one normal and one abnormal TRβ allele. The abnormal TRβ with minimal or reduced T3 binding fails to mediate T3-regulated transcription and may block the action of the normal allele. This has been referred to as a dominant-negative effect, presumably mediated by binding of the defective allele with normal TRβ producing an inactive homodimer. More recent studies of patients with the PitRTH phenotype have revealed point mutations and decreased T3 binding of TRβ-1 receptors similar to defects described in GRTH patients. The apparent selective pituitary resistance and the generalized resistance phenotypes are not qualitatively different syndromes but rather reflect a continuous spectrum of a similar molecular defect with variable tissue resistance.

Thyroid Hormone Membrane Transporter Defects

The Allan-Herndon-Dudley syndrome (AHDS) is an X-linked mental retardation syndrome associated with mutations in the SLC16A2 (MCT8) thyroid hormone transporter gene.20 By mid-2006, 22 patients from 11 families with AHDS and SLC16A2 mutations had been characterized. The patients present during infancy or childhood with hypotonia, poor head control, involuntary athetoid and dystonic movements, hyperreflexia, nystagmus, and severe mental retardation. There are no other signs of hypothyroidism. Serum T3 is elevated, serum T4 and free T4 are low, and thyroid-stimulating hormone (TSH) concentrations are normal or slightly elevated. Much of the brain damage occurs in utero, and the phenotype resembles that in severe endemic cretinism. There is little information currently regarding effective treatment.

Newborn Screening for Congenital Hypothyroidism

Newborn screening is routine in most industrialized areas of the world.19 Screening is conducted either with combined T4 and thyroid-stimulating hormone (TSH) testing or with TSH testing alone. Screening and follow-up evaluation are usually accomplished within 2 weeks. Ten percent to 15% of infants with congenital hypothyroidism have T4 values in the normal range (7–10 μg/dL, or 90–127 nmol/L). Some infants may have an elevated TSH, but clinicians need to remember that 3% to 5% of infants with congenital hypothyroidism escape detection in newborn screening programs and that the diagnosis in these cases must be made on clinical grounds.

Evaluation of Infants with Presumptive Positive Screening Results

A positive screening report for congenital hypothyroidism in a newborn demands prompt evaluation of the infant, including a history, physical examination, and laboratory testing.6,7 A history of autoimmune thyroid disease in the family suggests the possibility of transient congenital hypothyroidism, either drug or maternal thyroid-stimulating hormone (TSH) receptor autoantibody induced. Recurrent congenital hypothyroidism in the same sibship may also suggest maternal autoantibody-mediated disease. A history of familial congenital thyroid disease suggests thyroid dyshormonogenesis, which is usually transmitted as an autosomal-recessive trait.

Clinical Features of Congenital Hypothyroidism in the Infant

Physical examination may reveal one of several early and subtle manifestations of hypothyroidism, including a large posterior fontanelle (> 1 cm diameter), prolonged jaundice (hyperbilirubinemia > 7 days), macroglossia, hoarse cry, distended abdomen, umbilical hernia, hypotonia, or goiter. Less than 5% of infants are diagnosed on clinical grounds before the screening report, but 15% to 20% of infants with congenital hypothyroidism have suggestive signs when carefully examined.

The diagnosis is confirmed by serum measurements of T4 and/or free T4 (FT4) and thyroid-stimulating hormone (TSH) concentrations (Fig. 527-1). In the neonatal period (2–6 weeks), serum T4, FT4, and TSH levels below 84 nmol/L (6.5 μg/dL), 10 pmol/L (0.8 ng/dL), and above 10 mU/L (10 uIu/mL), respectively, suggest congenital hypothyroidism. In infants with proven disease, 90% have TSH levels above 50 mU/L, and 75% have T4 and FT4 concentrations below 84 nmol/L (6.5 μg/dL) and 10 pmol/L (0.8 ng/dL), respectively. Perhaps 20% of affected infants have T4 and FT4 levels in the 84 to 165 nmol/L (6.5–13 μg/dL) range and 10 to 25 pmol/L (0.8–1.9 ng/dL), respectively, usually with clearly elevated TSH concentrations (> 30 mU/L). A few infants will manifest only modest TSH elevations (7–30 mU/L). Such infants may require repeat examinations in order to establish a diagnosis of congenital hypothyroidism. Serum T3 or rT3 concentrations have limited practical value in the diagnosis.

Hypothalamic-pituitary hypothyroidism is more difficult to diagnose.10,11Many such infants are missed in screening programs unless repeat testing at 5 to 6 weeks of age or a T4/TBG ratio measurement is included as a FT4 surrogate in the testing. The disorder is characterized by a low serum T4 concentration and low T4/thyroid-binding globulin (TBG) ratio with a normal or low-normal range TSH value. Measurements of serum FT4 concentrations will distinguish these possibilities. An infant or child with a low FT4 concentration and low TSH level should be carefully examined for evidence of hypothyroidism, and other tests of pituitary function should be conducted. A subnormal TSH response to thyrotropin-releasing hormone (TRH) confirms a diagnosis of pituitary TSH deficiency. If the peak level of TSH is normal and/or prolonged, and there is a good 4-hour T4 (thyroid) response to TSH, hypothalamic TRH deficiency is more likely. The TSH deficiency may be isolated or associated with other pituitary hormone deficiencies.

All infants with proven congenital hypothyroidism should undergo radionuclide scanning if possible, using either technetium or radioiodine. Radioiodine123 is preferred, provides greater isotope concentration, and allows later scanning (2–24 hours). The confirmation of an ectopic thyroid gland provides a definitive diagnosis of thyroid dysgenesis. The absence of uptake of radioisotope suggests thyroid gland agenesis, but some infants may have low radioisotope uptake and a nondetectable gland by scan due to a TSH receptor-blocking antibody (TBA). These infants or the mother should have blood drawn for measurement of TSH receptor-binding immunoglobulin (TBII) if there is a history of maternal autoimmune thyroid disease. Thyroid ultrasound, if available, will usually confirm thyroid gland dysgenesis.

A normal radioisotope scan and/or a palpable or ultrasound-positive thyroid gland in the presence of hypothyroidism indicates impaired thyroid hormone synthesis. Infants with mild to moderate TBA-mediated transient congenital hypothyroidism may have normal thyroid scan results (Fig. 527-1). The maternal and family histories should be carefully reviewed in such cases. A serum thyroglobulin measurement may be helpful in infants with absent uptake or normal scans. A very low or absent serum thyroglobulin level indicates thyroid agenesis in an infant with absent radioisotope uptake and suggests a defect in thyroglobulin synthesis in infants with a normal imaging study.

Infants with thyroid dysgenesis have elevated serum thyroglobulin levels that relate to the mass of residual thyroid tissue and degree of stimulation. However, levels usually do not exceed 1000 pmol/L (660 ng/mL). Very high thyroglobulin levels (> 1000 pmol/L) may be observed in infants with congenital hypothyroidism due to defective thyroxine synthesis not involving the capacity for thyroglobulin production. Serum calcitonin levels are also low in congenital hypothyroidism (CH) infants with thyroid agenesis but offer no advantage over the thyroglobulin measurement in diagnosis. A bone age study is useful in assessing the extent of fetal hypothyroidism.

Management of Congenital Hypothyroidism

Initial evaluation, should be accomplished promptly and should require no more than 5 to 7 days. Treatment should be instituted with early, adequate thyroid hormone replacement therapy. Most of the requisite brain cell T3 is derived from local T4 to T3 conversion. Thus, the preferred thyroid hormone preparation for treatment of infants with congenital hypothyroidism is thyroxine.3,21The dosage of T4 should normalize the serum T4 level as quickly as possible. To guarantee adequate hormone to all infants, it is desirable to maintain the serum T4 and/or free T4 in the upper half of the normal range during therapy. The initial target range for the total T4 concentration is 130 to 210 nmol/L (10–16.3 μg/dL). This assumes a normal serum T4-binding globulin (TBG) concentration. This can be confirmed by measuring a normal range T3 resin uptake, free thyroxine, or TBG level at the time of the first posttreatment T4 measurement. The initial direct free T4 target concentration should also be in the upper half of the normal infant range. To rapidly normalize the serum T4 concentration in the congenital hypothyroid infant, an initial dose of Na-L-T4 of 10 to 15 μg/kg/d is recommended. For the average term infant of 3 to 4.5 kg, an initial dose of 50 μg (0.050 mg) daily is appropriate (Table 527-3).

Serum thyroid-stimulating hormone (TSH) concentrations in some treated infants with congenital hypothyroidism may remain relatively elevated despite adequate replacement T4 and normalized levels of T4 or free T4.21,22The relative elevation of serum TSH is more marked during the early months of therapy but can persist to some degree in about 10% of patients through the second decade of life. The elevated serum TSH concentration relative to T4 concentration in congenital hypothyroidism infants is presumably due to a resetting of the feedback threshold for T4 suppression of TSH release in these infants. This resetting occurs in utero.23Nonetheless, after the first few weeks of treatment serum, TSH is the most important marker for therapy management.

Physical growth and development of infants with congenital hypothyroidism are usually normalized by early adequate therapy.24,25IQ values and mental and motor development are also normalized in most infants with congenital hypothyroidism. However, low normal or occasionally low IQ values and motor or functional impairments have been reported in treated children with severe congenital hypothyroidism (very low serum T4 and delayed bone maturation at birth).26,27 This is more likely if treatment is delayed. The IQ deficit, although variable, amounts to several IQ points for every week of delayed early treatment. Overtreatment resulting in tachycardia, excessive nervousness, or disturbed sleep patterns may occur but can be eliminated by frequent dosage adjustment and carries little or no risk if transient.

Infants with presumed transient hypothyroidism caused by maternal goitrogenic drugs or maternal TSH receptor antibody do not need to be treated unless the low serum T4 and elevated TSH levels persist beyond the second week. The half-life of the maternal autoantibody approximates 2 weeks and, depending on the initial level, may require several months for degradation. In high titer cases, treatment is usually required for 2 to 5 months.

Infants with thyroid resistance are very difficult to manage, and treatment must be individualized. It is important to detect infants with generalized resistance to thyroid hormone (GRTH) as early as possible. Some patients will be adequately compensated by the TSH-mediated thyroid hyperplasia and hyperthyroxinemia. Other patients will be poorly compensated, and compensation will vary among tissues. The serum TSH level in GRTH patients may be elevated or within the normal range (albeit high in the face of the hyperthyroxinemia). An elevated TSH level in the absence of clinical evidence for thyrotoxicosis is an indication for treatment. Failure to thrive, delayed developmental milestones, or delayed bone maturation are other indications for treatment. The levothyroxine treatment dose must be based on the clinical and laboratory features of the individual patient and may be three to six times the usual replacement dose.