Pediatric Annals

Congenital Hypothyroidism

Annette Gruters, MD

Abstract

Only 10 years before the year 2000, the most frequent congenital thyroid disorder leading to permanent central nervous system (CNS) damage worldwide is still endemic cretinism caused by iodine deficiency. Although this disease was first described by Paracelsus (1493-1541) and iodine deficiency was recognized as its cause as early as 1850 by the French chemist Chatin,1 we still have not been able to provide iodine supplementation to the many iodine-deficient areas in the world and thereby prevent this frequent cause of mental retardation.

The most common congenital thyroid disorder in areas with sufficient iodine supply is sporadic congenital hypothyroidism, which was first described by Curlings in 1850.2 He noted major differences between this disease and endemic cretinism, namely its sporadic occurrence, the usually healthy parents, the lack of goiter, and the absence of thyroid tissue in postmortem examinations. In 1897, Osier reviewed 60 North American patients with sporadic congenital hypothyroidism and found that different types of congenital thyroid disorders can result in symptoms of congenital hypothyToidism. These include the absence of the thyroid gland (which "was not developed in fetal life or was completely wasted"), atrophy of the gland, or neonatal goiter. Osier was the first to recognize the familial occurrence of sporadic congenital hypothyroidism in the nonendemic regions of North America and the female preponderance of the disease.

In the same study, Osier reported successful treatment with desiccated thyroid, describing improvement in growth and mental development, as well as the dependency of outcome on the time of onset of treatment: "As a rule the younger the case the more marked is the mental change."

Today, it is well known that the final outcome of the mental development of patients with congenital hypothyroidism is inversely correlated with the duration of thyroid hormone deficiency, with a better prognosis when treatment is started before 3 months of age.3 This and the fact that only a few patients were diagnosed on the grounds of clinical symptoms before the age of 3 months were the reasons for establishing neonatal screening programs for congenital hypothyroidism. Pediatricians in the United States and in other developed countries with screening programs should all be aware of the disease because several recent reports have estimated the number of cases missed by screening programs to be as high as 10%.4

In some patients, TSH levels remain elevated despite adequate T4 dosages. This might be the result of reduced gastrointestinal tract absorbtion of 1thyroxine given in tablet form. Therefore, lower T4 dosages are needed when T4 solutions are administered rather than tablets. Thyroid-stimulating hormone elevations may persist throughout the first two decades of the patient's life, and it has been postulated that patients in whom this occurs have a prenatally acquired difference in the setpoint of TSH suppression, although the precise mechanism for this remains unclear. Because TSH secretion is regulated by the intrapituitary T3 concentration, a reduced intrapituitary monodeiodination of T4 could be a cause; this is supported by the observation that administering T3 alone in a dose of 40 ^gfmtlday or increasing the T4 dose to 15 µg/kg suppresses the elevated TSH levels.31

The T4 dose is progressively increased with age to reach up to 200 µg/day in adolescents. The dose per kilogram of body weight, however, progressively decreases to 2 to 3 µg/kg/day Table 4).

Therapy should be monitored at 4- to 6-week intervals during the first 6 months of life by measuring T4 and TSH levels. From 6 to 24 months, the child should be seen at 3 -month intervals and then twice a year, if sufficient parental compliance has been experienced. An x-ray for bone age…

Only 10 years before the year 2000, the most frequent congenital thyroid disorder leading to permanent central nervous system (CNS) damage worldwide is still endemic cretinism caused by iodine deficiency. Although this disease was first described by Paracelsus (1493-1541) and iodine deficiency was recognized as its cause as early as 1850 by the French chemist Chatin,1 we still have not been able to provide iodine supplementation to the many iodine-deficient areas in the world and thereby prevent this frequent cause of mental retardation.

The most common congenital thyroid disorder in areas with sufficient iodine supply is sporadic congenital hypothyroidism, which was first described by Curlings in 1850.2 He noted major differences between this disease and endemic cretinism, namely its sporadic occurrence, the usually healthy parents, the lack of goiter, and the absence of thyroid tissue in postmortem examinations. In 1897, Osier reviewed 60 North American patients with sporadic congenital hypothyroidism and found that different types of congenital thyroid disorders can result in symptoms of congenital hypothyToidism. These include the absence of the thyroid gland (which "was not developed in fetal life or was completely wasted"), atrophy of the gland, or neonatal goiter. Osier was the first to recognize the familial occurrence of sporadic congenital hypothyroidism in the nonendemic regions of North America and the female preponderance of the disease.

In the same study, Osier reported successful treatment with desiccated thyroid, describing improvement in growth and mental development, as well as the dependency of outcome on the time of onset of treatment: "As a rule the younger the case the more marked is the mental change."

Today, it is well known that the final outcome of the mental development of patients with congenital hypothyroidism is inversely correlated with the duration of thyroid hormone deficiency, with a better prognosis when treatment is started before 3 months of age.3 This and the fact that only a few patients were diagnosed on the grounds of clinical symptoms before the age of 3 months were the reasons for establishing neonatal screening programs for congenital hypothyroidism. Pediatricians in the United States and in other developed countries with screening programs should all be aware of the disease because several recent reports have estimated the number of cases missed by screening programs to be as high as 10%.4

Figure I. The maternal-placental-fetal unit.

Figure I. The maternal-placental-fetal unit.

However, since the introduction of screening programs, pediatricians have fewer opportunities to diagnose congenital hypothyroidism and, because of a lack of clinical signs and symptoms in newboms, they have become dependent on laboratory tests to make the diagnosis. This carries the risk that the pediatrician who is not aware of the 10% raise-negative results of the screening tests or of the clinical signs and symptoms of the disease will try to collect more laboratory data directed at determining other possible causes of developmental delay. This will not only increase the already high cost of medical care, it will also add the burden of unnecessary hospitalizations, venipunctures, and diagnostic studies for their patients and their families. This can be avoided by teaching pediatricians to recognize the full clinical picture of congenital hypothyroidism, which is the most frequent congenital endocrine disorder Table 1).

PATHOPHYSIOLOGY AND ETIOLOGY

To understand the symptoms and consequences of sporadic congenital hypothyroidism, it is important to be familiar with the development of the human thyroid gland and its functions. The thyroid gland originates as a derivative of the digestive tract and starts to develop 3 weeks after conception. The primordial thyroid, an epithelial thickening, is connected by the thyroglossal duct to the pharynx. Thirty days after conception, the bilobar structure of the organ can be recognized, and at 5 weeks the thyroglossal duct disrupts and atrophies. During the downward migration from the pharynx to its definitive position, the developing thyroid is in close contact with the heart and aorta. At 7 weeks, the ultimobranchial bodies are incorporated into the lateral lobes, and the gland's definitive shape and position in the neck is achieved.

Interestingly, this proHferative development occurs in the absence of thyroid-stimulating hormone (TSH), which is histochemically identifiable in the pituitary only at 10 weeks of gestation. At that time, plasma TSH concentrations are nearly undetectable and only start to increase at 18 to 20 weeks. At 8 to 10 weeks, follicles filled with colloid are formed within the thyroid gland. Between the 10th and 12th week, iodine organification starts and thyroid hormone synthesis is possible. Also, T4 levels remain low until week 20 when they start to increase. While T3 levels are nearly undetectable throughout gestation and in umbilical cord blood, reverse T3 is elevated because of the outer ring deiodinase activity of the placenta and fetal liver. Pituitary feedback regulation is functioning around the 30th week; however, complete maturation extends into the neonatal period. Premature infants (<30 weeks of gestation) have low T^, T3, and TSH levels so that their state of thyroid function is described at best as a physiological, transient tertiary hypothyroidism due to immaturity of the hypothalamus. However, TSH is clearly elevated in premature infants with thyroid dysgenesis or transient hypothyroidism due to iodine contamination.

Within 30 minutes after birth, TSH levels rise acutely and then slowly decrease. This TSH increase, possibly triggered by exposure to a cold environment, is followed by an increase of T4 and T3 levels, which peak during the first 2 days of life.5

Figure 2. Ultrasound of a newborn with athyrosis (2a) compared with an ultrasound of a normal newborn (2b).

Figure 2. Ultrasound of a newborn with athyrosis (2a) compared with an ultrasound of a normal newborn (2b).

It was formerly recommended that TSH screening for congenital hypothyroidism should not be performed before the 5th day of life, but recent data with improved screening methods indicate that earlier screening is possible when age-adjusted reference values are available. Early screening is important because early discharge from the neonatal nursery has become increasingly popular.6

While thyroid hormones are crucial for postnatal development, especially for mental development, it has not been determined whether human embryogenesis and fetal growth are dependent on them. It is remarkable that even infants who presumably have been unable to produce any T4 throughout a greater part of gestation (eg, athyrosis and total organification detect) are normal at birth and have a completely normal outcome when treatment is started shortly after birth. However, these infants develop severe symptoms and signs (eg, growth retardation and mental retardation) when treatment is delayed.

It is still unknown why congenital hypothyroidism has different consequences before and after birth. This can be explained either by the assumption that thyroid hormones are not essential for fetal CNS development or that the fetus is supplied with ade* quate amounts of T4 from alternate fetal or maternal sources, protecting it from severe damage. However, until recently, the placental transfer of maternal thyroid hormones in humans has been repotted as negligible,7 although studies in rats and guinea pigs have shown that fetal hypothyroidism caused by propylthiouracil administration to the mother can be prevented by simultaneous T4 injections.8 Recently, it has been shown that human newborns with athyrosis or total organification defects have measurable plasma T4 concentrations. These concentrations decline dur> ing the first days of life having a half-life of 3.6 days.9 Therefore, these data indicate that there is at least as much maternal T4 as needed to prevent the fetus from severe retardation.

Table

TABLE 1Epidemiology of Congenital Hypothyroidism

TABLE 1

Epidemiology of Congenital Hypothyroidism

Iodine, antithyroid drugs such as propylthiouracil or metimazol, and maternal antithyroid antibodies also can cross the placenta and influence the fetal thyroid gland. Placental human chorionic gonadotropin seems to stimulate both maternal and fetal thyroid function. The role of human chorionic gonadotropin and growth factors such as insulin-like growth factor- 1 and epidermal growth factor in fetal thyroid growth is still unknown (Figure 1 ).

In the majority of sporadic congenital hypothyroidism cases, the thyroid gland is unable to supply the organism with sufficient amounts of thyroid hormones. TKe diminished serum concentrations of T4 and T3 lead to a stimulation of hypothalamic thyrotropin releasing hormone (TRH) and pituitary TSH secretion. However, congenital hypothyroidism is not one disease entity, but a spectrum of different disorders (Table 2).

At first, the pediatrician must distinguish the cases of permanent congenital hypothyroidism from those with a transitory, self-limiting course. The permanent cases can be divided into a group with maldevelop' ment of the thyroid gland and a group with genetically determined thyroid dyshormonogenesis. Rare causes of permanent congenital hypothyroidism are syndromes of thyrotropin or thyroid hormone resis' tance and pituitary thyrotropin deficiency.

PERMANENT CONGENITAL HYPOTHYROIDISM

Thyroid Dysgenesis

The most common cause in 80% to 90% of patients with sporadic congenital hypothyroidism is a maldeveloptnent of the thyroid gland (thyroid dysgenesis). In so-called athyreotic patients, either no trace of thyroid tissue is demonstrable or small, nonfunctioning tissue remnants can be seen on ultrasound studies, but not by radionuclide imaging (RNI) studies in the absence of a normal gland (Figure 2).

Table

TABLE 2Classification of Congenital Hypothyroldism

TABLE 2

Classification of Congenital Hypothyroldism

In cases with dystopic thyroids, aberrant thyroid tissue somewhere along the thyroglossal duct can be visualized with RNI studies, while ectopie glands can be demonstrated distant from the thyroglossal duct.

In cases of thyroid hypoplasia, small, eutopic thyroid remnants can be seen with RNI studies.

For a long time, it was generally accepted that these cases of congenital hypothyroidism were caused by defective embryonic organ development. However, since the early 1960s, many authors have considered the remnants of thyroid tissues to be the result of infectious or autoimmune destructive processes. This consideration was supported by the demonstration of severa! antithyroid antibodies in maternal and neonatal sera of patients with congenital hypothyroidism (TSH-receptor blocking, growth-blocking, and cytotoxic antibodies). At least one of these antibodies was demonstrated in 20% to 50% in the studied patients.10''2 Moreover, a causal relationship of maternal antithyroid antibodies and congenital hypothyroidism was convincingly demonstrated in several case reports of familial forms of congenital hypothyroidism.13

However, the routinely measured antibodies (microsomal and thyroglobulin antibodies) are not overrepresented in newboms with congenital hypothyroidism, and the familial occurrence of thyroid dysgenesis, which has been described in monozygotic and dizygotic twins as well as in mother-newborn pairs, is the exception rather than the rule. The genetic predisposition is weak, and the risk of familial occurrence is below 1%. In favor of the opinion that congenital thyroid dysgenesis may be caused by antithyroid antibodies is the fact that females are overrepresented in sporadic congenital hypothyroidism, since all other autoimmune thyroid disorders are also more prevalent in females. In all published series, the female to male ratio is 2 to 3:1, while in the group of dyshormonogenesis the ratio is 1:1, as could be expected from the autosomal recessive mode of inheritance. However, the autoimmune pathogenesis of thyroid dysgenesis is still controversial, since the antibodies can also be regarded as epiphenomena to an underlying malformation, and the high risk of pitfalls in their determination by cytochemical and bioassays has to be considered.

Thyroid Dyshormonogenesis

Newborns with iodide transport defects (trapping defects that prevent iodine from reaching the thyroid gland) are hypothyroid at birth. They have normalsize eutopic glands. The occurrence of neonatal goiter is rare. Patients are further characterized by an absent RNI and a decreased saliva-to-plasma ratio of administered radioiodine.

Newboms with iodide organification defects (inability of the thyroid gland to assimilate iodine), caused by defects in the thyroperoxidase and H2O2 generating system, have normal or only slightly enlarged thyroid glands and are characterized by a rapid and increased discharge of radioiodine after KClCX administration. The combination of an organification defect with sensorineural deafness is called Pendred's syndrome.

A thyroglobulin synthetase defect in which the thyroid gland is unable to synthesize thyroglobulin adequately is suspected when a newborn with congenital hypothyroidism and a normal or slightly enlarged gland has absent or very low plasma thyroglobulin levels and an active radioiodine uptake with a normal perchlorate discharge test.

Patients with an iodotyrosine deiodinase defect, which interferes with the iodination of thyroglobulin, are born with a goiter and have an increased iodine loss by excreting large amounts of monoiodotyrosine and diidotyrasine. These patients can be treated with iodine alone.

Thryotropin resistance syndromes are rare and were first described by Stanbury. These syndromes are characterized by the presence of normal thyroid glands, and absent or low levels of thyroglobulin in plasma, making them difficult to distinguish from thyroglobulin synthetase defects.

General resistance to thyroid hormones (in both peripheral and pituitary tissue) results in high thyroid hormone levels with moderately increased TSH concentrations and overt clinical hypo thyroid ism. In contrast, isolated pituitary resistance, which is also accompanied by elevated thyroid hormone and TSH levels, may result in clinical hyperthyroidism.

The difficulties in the differential diagnosis of thyroid hormone synthesis defects are due to the fact that thyroid tissue expressing the defects is usually not available. Therefore, investigations are restricted to the use of blood and urine. Recently, restriction fragment linked polymorphism studies in white blood cells have become possible, since probes for thyroglobulin, thyroidperoxidase, and the TSH receptor are now available.

Finally, inherited disorders of thyroid hormone synthesis have been reviewed by Stanbury and Dumont elsewhere.14

Thyrotropin and TRH Deficiency

It is usually difficult to determine whether the hypothalamus or the pituitary is the level of the lesion in thyrotropin deficiency. Plasma levels of thyroid hormones and TSH are low, especially after stimulation with TRH. Since at least some autonomous T, production is present in the thyroid gland, which is usually small, most patients will not suffer from severe mental retardation unless other hormone deficiencies (adrenocorticotropic hormone and growth hormone) result in severe neonatal hypoglycemia. These congenital defects will be detected in screening programs that measure T4, but not in TSH screening programs; however, the occurrence of such defects is rare (1:100000) compared with primary hypothyroidism (1:4000).

Thyrotropin deficiency must be distinguished from thyroxine-binding globulin deficiency. These patients also have extremely low total T1, concentrations in the presence of low TSH levels, but their free T4 is normal, and thyroxine-binding globulin is virtually absent. In contrast to thyrotropin deficiency, these patients are euthyroid and do not need thyroid hormone replacement.

TRANSIENT CONGENITAL HYPOTHYROIDISM

Transient congenital hypothyroidism is a disease that has become more frequently recognized since the introduction of neonatal screening programs. In cases with transient hypothyroidism, no thyroid dysgenesis or dyshormonogenesis can be demonstrated, although TSH levels are high and thyroid hormone levels are low. Elevated TSH levels in the presence of normal thyroid hormone levels, excluding the thyroid hormone resistance syndromes, should be defined as transient hyperthyrotropinemia, not as hypothyroidism.

Maternal and Postnatal Use of Iodine-Containing Compounds

Since the pioneering work of Wolff and Chaikoff in 1948,15 we have known that excessive amounts of iodine inhibit the iodination of thyroglobulin, thereby making thyroid hormone synthesis a defense mechanism against iodine-induced hyperthyroidism. The response to the decrease in thyroid hormone synthesis is an increase in TSH secretion. This inhibition is known as the Wolff Chaikoff effect. In susceptible adults, a load of 1 tng iodine may induce this effect, but its duration is usually short because the mature thyroid gland has the capability of "escaping" from this effect. Fetuses and neonates, however, are more susceptible to develop longstanding, usually goitrous hypothyroidism because their thyroids are not able to escape from the blockage of thyroid hormone synthesis. From animal studies, it can be concluded that iodine-deficient fetuses or newborns are more prone to develop hypothyroidism after iodine excess.16 Since the placenta and the mammary glands have an active iodide transport mechanism, iodine accumulates easily in the fetus and in breast milk after maternal exposure.17

The hypersensitivity of the fetus and newborn to iodine excess is illustrated by the numerous reports of transient congenital hypothyroidism after prenatal or postnatal exposure to iodine excess.18,19

The maternal ingestion of potassium iodide in the therapy of bronchial asthma or of Graves' disease has been a common cause of transient congenital hypothyroidism. In recent years, the prenatal and postnatal use of povidone-iodine as a disinfectant (eg, vaginal application in obstetrics, caesarean section, skin disinfection, and pediattic surgery), and the use of amidar' one has become the most frequent cause of transient congenital hypothyroidism.

The use of iodine-containing radiographie contrast agents is another cause of transient hypothyroidism induced prenatally (amniofetography)20 or postnatally (angiocardiography and examinations of the digestive or genitourinary tract). Premature infants in intensive care have an increased risk of developing hypothyroidism because they are more immature regarding the thyroid autoregulation and are frequently exposed to both radiographie contrast agents and skin disinfectants.21

Figure 3. A 10-day-old infant with athyrosis and no clinical signs of hypothyroidism

Figure 3. A 10-day-old infant with athyrosis and no clinical signs of hypothyroidism

Maternal Antithyroid Drugs

Antithyroid drugs such as propylthiouracil, methimazol, and carbimazol can easily cross the placenta and block fetal thyroid function. Although they are also excreted in breast milk, their use in normal doses during pregnancy and lactation is clinically insignificant since neonatal hypothyroidism from this cause is very rare.22 However, there are case reports of transient, goitrous neonatal hypothyroidism following maternal use of antithyroid drugs, but some of these mothers were treated with combinations of antithyroid drugs and potassium iodide. The precise role of propylthiouracil and other antithyroid drugs in the development of fetal hypothyroidism and goiter is difficult to establish. The major problems of newborns of mothers with hyperthyroidism are due to maternal stimulating, blocking, or cytotoxic antibodies.

Maternal Antithyroid Antibodies

As already mentioned for cases of permanent congenital hypothyroidism, maternal antithyroid antibodies are also capable of inducing transient forms of hypothyroidism. In the case of cytotoxic antibodies, one would have to postulate that the gland of the newborn is able to recover after the maternal antibodies have disappeared from the infant's circulation, as proposed by Blizzard in 1960.23

With the development of assays to measure TSHreceptor antibodies, many cases of transient hypothyroidism (even familial forms) have been described in which transient hypothyroidism was conclusively related to maternal TSH-receptor antibodies that blocked thyroid function, but not its growth and development.24 Therefore, mothers with high titers of TSH-receptor antibodies of the function-blocking type are at risk to give birth to newborns with transient hypothyroidism.

CLINICAL FEATURES

Thyroid hormones are necessary at all ages, but short-term effects of hypothyroidism are usually reversible. One of the main manifestations of hypothyroidism in childhood is growth retardation. This growth retardation is accompanied by a retarded skeletal maturation. Interestingly, patients with congenital hypothyroidism usually have a normal or even increased height and body weight at birth, but bone age is frequently retarded and, therefore, regarded as an indicator of the severity of fetal hypothyroidism.

The principal development of the human CNS is postnatal, with the maximum development occurring during the first 6 months of life. This critical period of development is dependent on an adequate supply of thyroid hormones. Since different parts of the CNS have a different timing of maturational processes, the consequences of thyroid hormone deficiency depend on the age when hypothyroidism is present. Knowledge of the consequences of fetal and neonatal hypothyroidism is primarily based on animal studies, which have shown that delay in cerebral cortical maturation is reversible when thyroid hormones are replaced soon after birth. Whereas heart, kidney, and muscles obtain their Tj directly from the plasma, the cerebral cortex is dependent on an adequate supply of T4, which is converted to T3 by 5'deiodinases in CNS tissues.

Without the specific effects of thyroid hormones on brain development, the myelination process is disturbed, and the structural and functional maturation of glial and neuronal membranes is impaired. This is reflected by severe mental retardation, poor motor development, and neurological disturbances such as ataxia, coordination disability, strabismus, choreiform movements, and sensorineural hearing loss. Electroencephalograms and auditory-evoked potentials are immature. These effects on CNS development are irreversible if the major part of the CNS growth spurt within the first months of life occurs in the absence of thyroid hormones. Manifestations in the newborn period are nonspecific, subtle, or even nonexistent (Figure 3).

Clinical studies in patients detected to be hypothyroid by newborn screening compared their signs and symptoms with those of control groups of nonaffected patients and established scoring systems of clinical symptoms. These scoring systems identified most of the hypothyroid newborns from normal newborns by clinical symptoms such as a large posterior fontanelle, typical facies, an enlarged tongue, an umbilical hernia, inactivity, and hypotonia.25 In these newborns, the diagnosis was established by the age of 4 weeks or later. In screening programs where the patients are diagnosed earlier and treatment is initiated by the end of the second week of life, it is more difficult to distinguish the hypothyroid newborn from normal controls (Table 3).

PROGNOSIS

When thyroid hormone replacement is started before the age of 3 months, severe damage can be prevented. The outcome of patients with more delayed treatment is sometimes paradoxically better than in cases of earlier, but still delayed treatment. This is so because the most severe cases are diagnosed earlier.

Since the introduction of newborn screening programs, treatment is started mostly within the first 3 weeks of life. Therefore, residual damage is nonexistent or minimal. The outcome of infants with congenital hypothyroidism and early treatment has been correlated to the skeletal maturity, the T4 levels at birth, and the type of congenital hypothyroidism. In particular; a retarded bone age has been suggested as an indicator of a poorer developmental outcome.26 However, conflicting findings have been reported concerning the value of the neonatal bone age as an indicator of the prognosis in congenital hypothyroidism. Clear negative influences on the outcome has been documented for delay in achieving euthyroidism, poor compliance, and a lack of positive social stimulation.27

DIAGNOSTIC EVALUATION

Because of the lack of signs and symptoms in the first weeks of life, the most important tool for the early diagnosis of congenital hypothyroidism is a newborn screening program. Effective screening programs should be centralized (at least 20 000 newborns/year), and confirmatory tests should be performed by a central laboratory. A decision tree should be available, and the infant with a positive confirmatory test should be seen by a pediatrie endocrinologist as soon as possible.

In each newborn with a positive screening result, a careful maternal and patient history should be obtained regarding health, diet, medication, and familial thyroid disorders. This information is important in identifying those patients who might have only transient hypothyroidism. The infant should be carefully examined because some congenital abnormalities such as congenital heart disease occur more frequently in children with congenital hypothyroidism.27

Table

TABLE 3Clinical Signs of Congenital Hypothyroidism That May Appear In the Neonatal Period and Beyond

TABLE 3

Clinical Signs of Congenital Hypothyroidism That May Appear In the Neonatal Period and Beyond

While T4 screening programs also detect rare cases of thyrotropin deficiency, TSH screening programs will miss these patients, but will detect patients with thyroid hormone or thyrotropin resistance syndromes as well as those with hyperthyrotropinemia.

Confirmatory tests (Figure 4) in newborns in T1, screening programs must distinguish between thyrotropin deficiency, physiological TRH immaturity in prematurely born infants, thyroxine-binding globulin deficiency, and primary hypothyroidism. In newboms with a positive screening result by TSH screening, a falsely elevated TSH level caused by maternal heterophilic antibodies must be excluded;28 permanent and transient hypothyroidism will be distinguished by the maternal history and additional tests.

If the additional tests confirm the diagnosis of congenital hypothyroidism, thyroid replacement is started immediately. If the confirmatory tests take more than 48 hours, treatment should be started after blood for the confirmatory tests has been drawn. To assess the severity of hypothyroidism, an x-ray of the knee and ankle region should be taken and skeletal age assessed using the method of Senecal et al.29

Ultrasound studies of the thyroid gland in the newborn should be performed by experienced technicians and should be performed with a high resolution 7.5 MHz transducer. Radionuclide imaging studies should be performed with 123I-iodide or 99Tc pertechnate. While 123I-iodide is preferred because of its organification in the thyroid gland with an optimal detection of thyroid tissue, it has the major disadvantage that it has to be obtained from a cyclotron. Treatment should never be delayed until RNI studies are possible, because the diagnosis should be reevaluated at 2 years of life except in patients with documented ectopie thyroid dysgenesis (Figure 5).

Because the outcome is not correlated with the type of congenital hypothyroidism present, these imaging studies are primarily of interest for their provision of a rapid, definitive diagnosis. Therefore, they are useful primarily in genetic counseling, and thus, replacement therapy should never be delayed while awaiting the results of these studies.

Treatment of confirmed cases should be monitored by measuring plasma TSH using sensitive assays and by measuring plasma T4 levels. While the T, levels should be kept at the upper normal range, TSH levels should not be suppressed, but kept between 1 and 2 mU/L. Skeletal maturation should be assessed only if TSH and T4 levels cannot be normalized or if clinical signs of inadequate or excessive treatment are demonstrable (eg, delayed or accelerated growth). Psychomotor development should be assessed by regular standardized tests (eg, Griffiths or Bayley test) since more data are necessary to determine the outcome of early treated patients with CH.

TREATMENT

Rapid, adequate thyroid hormone replacement is the primary goal in the therapy of newborns with congenital hypothyroidism detected by screening programs. The recommended thyroid hormone preparation is l-thyroxine, since, as already mentioned, T3 in brain cells is derived predominantly from local T4 monodeiodination. Therefore, therapy regimens using T3 alone should not be used; furthermore, T3 therapy carries a high risk for thyrotoxic symptoms.

Recently, increasing evidence indicates that it is necessary to normalize T4 levels as quickly as possible30 because a delay in T4 normalization is accompanied by poorer psychomotor and mental development. Normalization means that the T4 concentrations must be in the upper normal limits for newborns. Because newborns with congenital hypothyroidism lack thyroidal T3 production, which normally accounts for 20% of the total T3 production (80% is produced by hepatic monodeiodination), their T4 threshold for hepatic T4 conversion must be increased to compensate for the thyroidal lack. In the average newborn, weighing 3.5 to 4-5 kg, this can be achieved by administering 10 to 15 µg/kg of l-thyroxine per day, which corresponds to a daily total dose of 50 ^g. With this regimen, T4 and TSH levels will normalize rapidly, while when former recommendations of 6 to 9 (J-g/kg were followed, normalization did not occur until 2 to 3 months of age. In these patients, a delay in psychomotor and mental development has been demonstrated compared with newboms treated with 10 to 15 µg/day.

Table

TABLE 4Recommendation for LThyroxln Therapy In Congenital Hypothyroidism

TABLE 4

Recommendation for LThyroxln Therapy In Congenital Hypothyroidism

In some patients, TSH levels remain elevated despite adequate T4 dosages. This might be the result of reduced gastrointestinal tract absorbtion of 1thyroxine given in tablet form. Therefore, lower T4 dosages are needed when T4 solutions are administered rather than tablets. Thyroid-stimulating hormone elevations may persist throughout the first two decades of the patient's life, and it has been postulated that patients in whom this occurs have a prenatally acquired difference in the setpoint of TSH suppression, although the precise mechanism for this remains unclear. Because TSH secretion is regulated by the intrapituitary T3 concentration, a reduced intrapituitary monodeiodination of T4 could be a cause; this is supported by the observation that administering T3 alone in a dose of 40 ^gfmtlday or increasing the T4 dose to 15 µg/kg suppresses the elevated TSH levels.31

The T4 dose is progressively increased with age to reach up to 200 µg/day in adolescents. The dose per kilogram of body weight, however, progressively decreases to 2 to 3 µg/kg/day Table 4).

Therapy should be monitored at 4- to 6-week intervals during the first 6 months of life by measuring T4 and TSH levels. From 6 to 24 months, the child should be seen at 3 -month intervals and then twice a year, if sufficient parental compliance has been experienced. An x-ray for bone age determination should be obtained if there is accelerated or delayed growth or other signs of over or under treatment (eg, precocious puberty and developmental retardation).

A definitive reconfirmation of the diagnosis should be performed in all patients except those in whom an ectopie or dystopic gland was clearly detected during the newborn period. In all other cases, the possibility of transient hypothyroidism must be ruled out, since the uptake of IZ3I-iodine or 99Tc pertechnetate could have been blocked by maternal iodine or antibodies. For this purpose, T^ therapy should be withdrawn for 4 weeks at the age of 2 to 3 years when no risk to CNS development would be anticipated during this short period. After the withdrawal of T^, the diagnosis is confirmed when ?? levels become persistently low and TSH levels rise. Then ultrasound, RNI studies, and additional biochemical tests are performed to clarify the etiology. In patients who most likely have only transient hypothyroidism by their history or laboratory tests (eg, TSH receptor antibodies and elevated urinary iodine excretion), the withdrawal of treatment and révaluation should be performed at 6 to 1 2 months of age to avoid unnecessary, potentially harmful treatment. When this treatment regimen is followed, the risk of mental retardation in patients detected by screening programs is essentially nonexistent.

REFERENCES

1. Baumann E. Über Jus inumale Vorkommet] vim Jod im Thierkorper. Zeitschrift fur PhynaloKische Chemie. 189?;22:319-330.

2. Curling TB. Two cases ni absence of thyroid body and symmetrical swelling of fat llssue at sides of the neck, connected with defective cerebral development. Med Clin rurgTr. 1 850; 33:103-306.

3. Klein AH, Meiner S, Kenny FM. Improved prognosis in congenital hypothyroidism treated before age three months. ) Pediair. I972;8l:9l2-91 5.

4. Pvmarede R. CiemichiMr S\ Partiaux iP. Analyses des échecs du Jepuiage ije I'hypothyroidie congénitale par dosage delà TSH sur sang capillaire. Arch Fr Pedían·. 1986!»: 15- 18.

5. Fisher DA, Klein AH. Thyroid development and disorders of thyroid function in the newWn. N EngU Md. 1981^304:702-712.

6. Allen DB, Sieget JE. Litsheim T, Duck SC. Age-adjusted thyroimpin criteria tra neonatal screening for hypothyroidism. } Pedían. 1990;! 17:309-312.

7. Grumbanh MM, Werner SC. Transfer of thyroid hormones across the human placenta atterro. 1 Cím Endocrmol ?e??>. 1956;! 6:1 392-1395.

8. Morreaie de Escobar G. Obregon MJ, Ruii de Una C, Escobar del Rey E Transfer iif ihynwme from the mother to the rat fetus near term: effects on brain 3,5,3'triioduthy rimine deficiency. Enducrmuiiigy. 1988;122:1521-1531.

9. Vulsma T, Cons MH, de Vijliîet JJM. Maternal-fetal transfer of thyroxine in cimienta! bypurhyroidJAjj) due tu a turai nffiani/Jcatiun detect or thyroid dysgcnesis. N EtIjU MeJ. 1989;321:?-?6.

10. Brawn RS, feat Ing P. Mitchell E. Maternal thyroid- bloc k ing immunoglobulins in congenita! hypothyroidism. Clin Enlocrinoi MÍ lab. 199Oi 70:1341-1344.

1 1 . van der Gaag RD. Drexhage HA, Dussault JH. Role of maternal immunoglobulins blocking TSH-induced thyroid growth in sporadic forms oí congenital hypolhyruidism. Lancet. 1985;i:246-250.

12. Bogner U, Grüters A, Sigle B, Helge H. Schleusener H. Cytoioxic antibodies in congenital hypothyroidism. J Clin EndocriruJ Meiab. ?989;68:671-675.

13. Dussault JH, Letarte J, Guyda H, Labcrge C. Lack of influence of thyroid antibitdies raí thyroid function in the newborn infant and on a mass screening program for congenital hypothyroidism. J Pedían. 1980;96:385-389.

14. Stanbury JB, Dumont JE. Familial goirer and related disorders. In: Stanbury JB, Wyngaarden JB, Frederickson DS, Goldslein JL, Brown MS, eds. The Metabolic Basis o/ In/ierired Disease. 5th ed. New York, NY: McGraw-Hill Book Co; 1983:231.

15. Wolff J, ChailcofflL. GoliibergRC, Meier JR. Temporary nature of inhibitory action of excessive iodide on organic iodine synthesis in the normal thyroid. Endotrinn/igj 1949;45:504-513.

16. Theodoropoulos T, Braverman LE, Vagenakis AG. Iodide induced hypothyroidism: a potential hazard during perinatal life. Science. 1979;205:50Z-503.

17. Chanoine JR Boulvain M, Bourdoux R Increased recall rate at screening for congenital hypothyroidism in breast fed infants bom to iodine overloaded mothers. Arc* Dis Cfiild. 1988;6?:1207-1210.

18. Chabrolle JP, Rossier A. Goiter and hypothyroidism in the newburn after cutaneous absorption of iodine- Arch Dis CWId. 1978;5 1:495-498.

19. l'Allemand D, Grüiers A, Heidemann R Schümbrand P. lodine induced alterations of thyroid function in newboms after prenatal and postnatal exposure to povidone iodine. J PaJiitrr. 1983;102:935-938.

20. Stubbe P, Heidemann R Schümbrand R Ulbrich R. Transient congenital hypothyroidism after amniofetograph)i EUT} Peàatt. 1 980; 1 3 5:97-99,

21. l'Allemand D, Grtiters A, Beyer R Weber B. Iodine in contrast agents and skin disinfectants is the major cause for hypothyroidism in premature infants during intensive care. Horm Ra. 1987:28:42-49.

22. Lamberg BA, Ikonen E, Teramo K, et al. Treatment of maternal hypeithyroidism with antithyroid agents and changes in TSH and thyroxine in the newborn. Acia Endocrino! ÍCopen/i). 198];97:18?-195.

23. Blizzard RM, Chandler RW, Landing BH. Petit MD. Wesr CD. Maternal auloimmunization to thyroid as a probable cause of athynrtic cretinism. N Engl } Med. l960;263:327-336.

24. Matsuura N. Yamada Y, Nohara Y, et al. Familial neonatal transient hypothyraidism due to maternal TSH-bmding inhibitory immunoglobulins. NEtigl J Med. 1980;303:738741.

25. Letarte J Dussault JH, Guyda H, Fouron J. Ciaiide J, Glorieux J. Clinical and laboratory investigation of early detected hypothyroid infants, !n: Collo R, et al, eds. Pidióme Endocrmoiug>. New York, NY: Raven Press; 1981:433.

26. Glorieux J, Desjardins M, Letarte J, Morriselte J, Dussault JH. Useful parameters to predict the eventual menial outcome of hypoihyroid children. PediarrRes. 1988;24:69.

27. Fisher IVi, Foley B. Early treatment of congenital hypolhyroidism. Pediatrics. 1989;84:785-7B9.

28. Qernichow R Vandalein JL, Hennen C. Transient neonatal hyperthyrotropinemia: a factitious syndrome due to the presence of heterophilic antibodies in the plasma of infants and their mothers. J Clin EnducrmiJ Merai?. 1 981 ;5 3: 387- 393.

29. Senecal J, Crusse MC, Vincent A, Simon J, Lefreche JN. Maturationosseuse du fétus et du nouveau ne. Arc/i Pr Pediair. 1 97 7;34:4 24-428.

30. Gertnak JA, Foley TP. Longitudinal assessment of 1-thyroxine therapy for congenital hypothyroidism J Pediotr. 1990;! 17:21 1-219.

31. l'Allemand ?, Grüters A, Beyer P. TSH erhöhung bei ausreichender Therapie der angeborenen Hypothyreose. In: Bickel H, Wachtel U, eds. Neugerwrenen Scrrniing. New York, NYi Thieme Veri Sturtgart; 1985:149.

TABLE 1

Epidemiology of Congenital Hypothyroidism

TABLE 2

Classification of Congenital Hypothyroldism

TABLE 3

Clinical Signs of Congenital Hypothyroidism That May Appear In the Neonatal Period and Beyond

TABLE 4

Recommendation for LThyroxln Therapy In Congenital Hypothyroidism

10.3928/0090-4481-19920101-06

Sign up to receive

Journal E-contents