Congenital hypothyroidism is inadequate thyroid hormone production in newborn infants.

This can occur because of an anatomic defect in the gland, an inborn error of thyroid metabolism, or iodine deficiency. The term endemic cretinism is used to describe clusters of infants with goiter and hypothyroidism in a defined geographic area. Such areas were discovered to be low in iodine, and the cause of endemic cretinism was determined to be iodine deficiency. In the 1920s, adequate dietary intake of iodine was found to prevent endemic goiter and cretinism.[1] Endemic goiter and cretinism are still observed in some areas, such as regions of Bangladesh, Chad, China, Indonesia, Nepal, Peru, and Zaire. The term sporadic cretinism was initially used to describe the random occurrence of cretinism in nonendemic areas. The cause of these abnormalities was identified as nonfunctioning or absent thyroid glands. This led to replacement of the descriptive term sporadic cretinism with the etiologic term congenital hypothyroidism. Treatment with thyroid replacement therapy was found to elicit some improvement in these infants (see the images below), although many remained impaired.

An infant shown a few months after starting thyroid hormone

replacement. replacement.

Infant a few months after starting thyroid hormone

The morbidity from congenital hypothyroidism can be reduced to a minimum by early diagnosis and treatment.[2] Although initial preliminary studies were performed using thyroidstimulating hormone (TSH) levels in cord blood,[3, 4] mass screening was made feasible by the development of radioimmunoassay for TSH and thyroxine (T4) from blood spots on filter paper, obtained for neonatal screening tests.[5, 6]

Pathophysiology
The thyroid gland develops from the buccopharyngeal cavity between 4 and 10 weeks' gestation. The thyroid arises from the fourth branchial pouches and ultimately ends up as a bilobed organ in the neck. Errors in the formation or migration of thyroid tissue can result in thyroid aplasia, dysplasia, or ectopy. By 10-11 weeks' gestation, the fetal thyroid is capable

of producing thyroid hormone. By 18-20 weeks' gestation, blood levels of T4 have reached term levels. The fetal pituitary-thyroid axis is believed to function independently of the maternal pituitary-thyroid axis. The thyroid gland uses tyrosine and iodine to manufacture T4 and triiodothyronine (T3). Iodide is taken into the thyroid follicular cells by an active transport system and then oxidized to iodine by thyroid peroxidase. Organification occurs when iodine is attached to tyrosine molecules attached to thyroglobulin, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). The coupling of 2 molecules of DIT forms tetraiodothyronine (ie, T4). The coupling of one molecule of MIT and one molecule of DIT forms T3. Thyroglobulin, with T4 and T3 attached, is stored in the follicular lumen. TSH activates the enzymes needed to cleave T4 and T3 from thyroglobulin. In most situations, T4 is the primary hormone produced by and released from the thyroid gland. Inborn errors of thyroid metabolism can result in congenital hypothyroidism in children with anatomically normal thyroid glands. T4 is the primary thyronine produced by the thyroid gland. Only 10-40% of circulating T3 is released from the thyroid gland. The remainder is produced by monodeiodination of T4 in peripheral tissues. T3 is the primary mediator of the biologic effects of thyroid hormone and does so by interacting with a specific nuclear receptor. Receptor abnormalities can result in thyroid hormone resistance. The major carrier proteins for circulating thyroid hormones are thyroid-binding globulin (TBG), thyroid-binding prealbumin (TBPA), and albumin. Unbound, or free, T4 accounts for only about 0.03% of circulating T4 and is the portion that is metabolically active. Infants born with low levels of TBG, as in congenital TBG deficiency, have low total T4 levels but are physiologically normal. Familial congenital TBG deficiency can occur as an X-linked recessive or autosomal recessive condition. The contributions of maternal thyroid hormone levels to the fetus are thought to be minimal, but maternal thyroid disease can have a substantial influence on fetal and neonatal thyroid function. Immunoglobulin G (IgG) autoantibodies, as observed in autoimmune thyroiditis, can cross the placenta and inhibit thyroid function. Thioamides used to treat maternal hyperthyroidism can also block fetal thyroid hormone synthesis. Most of these effects are transient. Radioactive iodine administered to a pregnant woman can ablate the fetus's thyroid gland permanently. The importance of thyroid hormone to brain growth and development is demonstrated by comparing treated and untreated children with congenital hypothyroidism. Thyroid hormone is necessary for normal brain growth and myelination and for normal neuronal connections. The most critical period for the effect of thyroid hormone on brain development is the first few months of life.[2]

Epidemiology

Frequency United States

The incidence of congenital hypothyroidism, as detected through newborn screening, is approximately 1 per 4000 births.[7] An increase in the diagnosis of primary congenital hypothyroidism has been reported in New York.[8] This trend has also been observed in some other states,[9] although not all. Possible explanations include changing demographics of the birth population, including changes in race, ethnicity, and the incidence of low birth weight.[9] Changes in laboratory and screening methodology may also play a role in this reported rise in incidence.[10] Some infants identified as having primary congenital hypothyroidism may have transient disease and not permanent congenital hypothyroidism.[11]
Twins

An increased incidence of congenital hypothyroidism is observed in twins.[12, 13, 14] Twin births are approximately 12 times as likely to have congenital hypothyroidism as singletons.[15] Usually, only one twin is hypothyroid, but a common in-utero exposure can cause hypothyroidism in both.[16]
International

In central Africa, where iodine deficiency occurs along with excess dietary cyanate from cassava (Manihot esculenta),[17] as many as 10% of newborns may have both low cord blood T4 concentration and TSH concentrations over 100 mU/L.[18] Data from most countries with well-established newborn screening programs indicate an incidence of congenital hypothyroidism of about 1 per 3000-4000.[19, 20] Some of the highest incidences (1 in 1400 to 1 in 2000) have been reported from various locations in the Middle East.[21] Although percentages of specific etiologies vary from country to country, ranges are as follows:

Ectopic thyroid - 25-50% Thyroid agenesis - 20-50% Dyshormonogenesis - 4-15% Hypothalamic-pituitary dysfunction - 10-15%

Mortality/Morbidity

Profound mental retardation is the most serious effect of untreated congenital hypothyroidism. Severe impairment of linear growth and bone maturation also occurs. Affected infants whose treatment is delayed can have neurologic problems such as spasticity and gait abnormalities, dysarthria or mutism, and autistic behavior.

Race

Congenital hypothyroidism is observed in all populations. The prevalence at birth is increased in Hispanics, particularly in Hispanic females, who have a birth prevalence of 1 in 1886 births.[22] Black infants have about one third the prevalence rate of white infants.
Sex

Most studies of congenital hypothyroidism suggest a female-to-male ratio of a 2:1. Devos et al showed that much of the discrepancy is accounted for by infants with thyroid ectopy.[23] The sex ratio for Hispanics is more striking, with a 3:1 female-to-male ratio. The ratio is lower among Black infants.
Age

By definition, congenital hypothyroidism is present at, or before, birth. Children who develop primary hypothyroidism when aged 2 years or older have poor growth and slow mentation but generally do not exhibit the profound and incompletely reversible neurologic abnormalities observed in untreated congenital hypothyroidism.

History
In regions of iodide deficiency and a known prevalence of endemic cretinism, the diagnosis may be straightforward. Infants with congenital hypothyroidism are usually born at term or after term. Symptoms and signs include the following:

Decreased activity Large anterior fontanelle Poor feeding and weight gain Small stature or poor growth Jaundice Decreased stooling or constipation Hypotonia Hoarse cry

Often, they are described as "good babies" because they rarely cry and sleep most of the time. Family history should be carefully reviewed for information about similarly affected infants or family members with unexplained mental retardation. Maternal history of a thyroid disorder and mode of treatment, whether before or during pregnancy, can occasionally provide the etiology of the infant's problem. Congenital hypothyroidism is more common in infants with birthweights less than 2,000 g or more than 4,500 g.[24, 13]

Congenital hypothyroidism is more common in multiple births, with a low concordance rate.[1

Physical
The physical findings of hypothyroidism may or may not be present at birth (see the image below).

An infant with cretinism. Note the hypotonic posture, coarse facial features, and umbilical hernia. Signs include the following:

Coarse facial features

Macroglossia (See the image below.) Large fontanelles Umbilical hernia Mottled, cool, and dry skin Developmental delay Pallor Myxedema Goiter

Note the macroglossia.

A small but significant number (3-7%) of infants with congenital hypothyroidism have other birth defects, mainly atrial and ventricular septal defects.[25] Newborn screening involves the following:

Infants with congenital hypothyroidism are usually identified within the first 2-3 weeks of life. These infants should be carefully examined for signs of hypothyroidism, and the diagnosis should be confirmed by repeat testing.

Infants with obvious findings of hypothyroidism (eg, macroglossia, enlarged fontanelle, hypotonia) at the time of diagnosis have intelligence quotients (IQs) 10-20 points lower than infants without such findings.

Anemia may occur, due to decreased oxygen carrying requirement.

Causes
Endemic cretinism is caused by iodine deficiency, and is occasionally exacerbated by naturally occurring goitrogens.[26] Dysgenesis of the thyroid gland, including agenesis (ie, complete absence of thyroid gland) and ectopy (lingual or sublingual thyroid gland) may be a cause. Inborn errors of thyroid hormone metabolism include dyshormonogenesis. Most cases are familial and inherited as autosomal recessive conditions. These may also include the following:

Thyroid-stimulating hormone (TSH) unresponsiveness (ie, TSH receptor abnormalities)[27] Impaired ability to uptake iodide Peroxidase, or organification, defect (ie, inability to convert iodide to iodine) Pendred syndrome, a familial organification defect associated with congenital deafness Thyroglobulin defect (ie, inability to form or degrade thyroglobulin) Deiodinase defect

Thyroid hormone resistance (ie, thyroid hormone receptor abnormalities) may also be a cause.[27] In maternal autoimmune disease, transplacental passage of antibodies cause transient or permanent hypothyroidism.[28, 29] Radioactive iodine therapy of pregnant women may cause permanent congenital hypothyroidism. Iodine in contrast agents or skin disinfectants can cause hypothyroidism or hyperthyrotropinemia in premature neonates.[30] TSH or thyrotropin-releasing hormone (TRH) deficiencies are also noted. Hypothyroidism can also occur in TSH or TRH deficiencies, either as an isolated problem or in conjunction with other pituitary deficiencies (eg, hypopituitarism). If present with these deficiencies, hypothyroidism is usually milder and is not associated with the significant neurologic morbidity observed in primary hypothyroidism.

Diagnostic Considerations
Neonatal hypothyroxinemia Premature and sick infants have lower levels of thyroid hormone than term infants but usually do not have elevated thyroid-stimulating hormone (TSH) levels.[31, 32] Reference ranges

appropriate to the infant's gestational age should be used to avoid confusing this with hypothyroidism. A meta-analysis suggests that treatment of these neonates with thyroxine is futile.[33] Transient neonatal hypothyroidism and hyperthyrotropinemia Ingestion of excessive amounts of iodine,[34] or of goitrogens such as lithium,[35] thioamides,[36, 16] or amiodarone,[37, 38] can cause a temporary hypothyroid state. Maternal antibodies to the TSH receptor can also cause temporary hypothyroidism.[28, 29, 39] This may require treatment with levothyroxine for a period of days to months. The etiology of transient hypothyroidism is often unclear.[40, 11]

Differentials

Beckwith-Wiedemann Syndrome Goiter Hypopituitarism Iodine Deficiency Panhypopituitarism Thyroxine-Binding Globulin Deficiency

Laboratory Studies
Diagnosis of primary hypothyroidism is confirmed by demonstrating decreased levels of serum thyroid hormone (total or free T4) and elevated levels of thyroid-stimulating hormone (TSH). If maternal antibodymediated hypothyroidism is suspected, maternal and neonatal antithyroid antibodies may confirm the diagnosis.[28] Such antibodies are an uncommon cause of congenital hypothyroidism.[39] Low or low-normal serum total T4 levels in the setting of a serum TSH within the reference range suggests TBG deficiency. This congenital disorder causes no pathologic consequence; however, it should be recognized to avoid unnecessary thyroid hormone administration. Thyroid-binding globulin (TBG) deficiency affects 1 individual per 3000 population; therefore, occurrence is nearly as frequent as that in congenital hypothyroidism. TBG deficiency results in low serum total T4 levels; however, serum TSH and serum-free T4 concentrations are normal. Assessment of the serum TBG concentration, preferably with simultaneous serum free and serum total T4 concentrations, confirms the diagnosis. TBG levels can be measured in infants with suspected TBG deficiency. This condition does not require treatment, but appropriate diagnosis and parental counseling can avoid later confusion and misdiagnosis. Routine laboratory testing in patients with TBG deficiency shows a low total T4 level and a TSH level within the reference range. Free T4 and T3 levels are within the reference range. Congenital nephrotic syndrome is a rare cause of TBG deficiency or congenital hypothyroidism.[41, 42]

Laboratory results similar to infants with TBG deficiency can be found in infants who have hypopituitarism or hypothalamic disease, but these children have normal TBG levels.

Imaging Studies
Thyroid scanning (using technetium-99m or iodine-123) may be useful in defining the cause of hypothyroidism and may aid in genetic counseling. It can aid in distinguishing congenital hypothyroidism from transient hyperthyrotropinemia.[43, 11] The absence of radionuclide uptake suggests sporadic athyreotic hypothyroidism but can also be seen when uptake is blocked by excess iodide or thyroid receptor blocking antibodies. If no uptake is found on isotope scanning, thyroid ultrasonography may demonstrate thyroid tissue in these patients.[11, 44] One study of 210 scanned infants stated a preference for using iodine-123 over pertechnetate.[45] Thyroid scans can also demonstrate the presence of an ectopic thyroid, such as a lingual or sublingual gland, which is also sporadic. The presence of a bilobed thyroid in the appropriate position or a goiter would suggest either an inborn error of thyroid hormone production or transient hypothyroidism or transient hyperthyrotropinemia. Thyroid scanning is not required to make or confirm the diagnosis of congenital hypothyroidism, but can provide important information about the etiology. Ultrasonography may be a reasonable alternative or addition to scintigraphy but may fail to reveal some ectopic glands.[46] A lateral radiograph of the knee may be obtained to look for the distal femoral epiphysis. This ossification center appears at about 36 weeks' gestation. Its absence in a term or postterm infant indicates prenatal effects of hypothyroidism, and prior to the introduction of hormone measurements, was used as a diagnostic test for congenital hypothyroidism.[47] Early studies of outcome suggested that infants without a distal femoral epiphysis did less well than those with one, although both groups had results in the normal range.[48] The author of this study was later unable to demonstrate an effect of bone age at diagnosis on outcome.[49] Another study was unable to demonstrate any difference in outcome in infants with or without a distal femoral epiphysis.[50]

Other Tests
Neonatal hypothyroidism screening, using TSH levels, has proven helpful in countries with mild to no iodine deficiency. It has not been found useful in countries with moderate-tosevere levels of iodine deficiency disorders (IDD) because resources are insufficient to deal with the problem, and efforts here should be made to supply sufficient iodine to the population as a whole. In infants with suspected dyshormonogenesis, radioactive iodine uptake (iodine-123) and perchlorate flush testing (KCIO2) can be performed to determine the presence of an iodide uptake or organification defect.

Medical Care

The mainstay in the treatment of congenital hypothyroidism is early diagnosis and thyroid hormone replacement. One study suggested that optimal care includes diagnosis before age 13 days and normalization of thyroid hormone blood levels by age 3 weeks.[51]

Consultations
The treatment of hypothyroidism is straightforward. However, because of the potential for serious morbidity with inadequate treatment or overtreatment, primary physicians should consult a pediatric endocrinologist. Appropriate psychological, developmental, and educational evaluations should also be considered.

Diet
Dietary iodide supplementation in iodine-deficient areas can prevent endemic cretinism but does not have a major effect on sporadic congenital hypothyroidism. Dietary iodine deficiency is the most common preventable cause of brain damage worldwide.[52] Soy-based formulas may decrease the absorption of levothyroxine.[53] This is not a contraindication to their use, even in infants with congenital hypothyroidism. Switching an infant from a milk-based formula to a soy-based formula may increase the dose of thyroid hormone needed to maintain a euthyroid status.[54]

Activity
Activity should be encouraged in children with congenital hypothyroidism, because activity should be encouraged in all children.

Medication Summary
Only levothyroxine is recommended for treatment.[55] It has been established as safe, effective, inexpensive, easily administered, and easily monitored. No liquid preparations are commercially available in the United States, but they are licensed elsewhere.[56] Pharmacies should be discouraged from dispensing suspensions prepared in-house by crushing tablets and mixing with various agents. The T4 in these preparations is very difficult to keep in suspension, and the delivery of drug is inconsistent. Parents should be provided the hormone in pill form and taught proper administration. The pills can be crushed in a spoon; dissolved with a small amount of breast milk, water, or other liquid immediately before administration, and administered to the child with a syringe or dropper. The pills should not be mixed in a full bottle of formula. Toddlers readily chew the tablets without problems or complaints. Optimum dosage regimens and follow-up laboratory monitoring have not yet been determined.[57, 58, 59] Initial dosages of 10-15 mcg/kg/d, equivalent to a starting dose of 50 mcg in many newborns, have been recommended.[60] Equally good developmental results, but with higher thyroid-stimulating hormone (TSH) levels, have been reported with half this starting dose (25 mcg/d).[61]

Thyroid Hormones
Class Summary

These agents are administered to supplement thyroid hormone in patients with hypothyroidism. Levothyroxine is the preferred form of thyroid hormone replacement in all patients with hypothyroidism.[62] Desiccated thyroid is an obsolete medication made from pooled animal tissue. Desiccated thyroid should not be used.
View full drug information Levothyroxine (Levothroid, Levoxyl, Synthroid)

Also known as L-thyroxine, T4, and thyroxine. A thyroid hormone with proven record of safety, efficacy, and ease of use. In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development.

Further Outpatient Care

Children with congenital hypothyroidism should be monitored clinically and biochemically. Clinical parameters should include linear growth, weight gain, developmental progression, and overall well-being. Laboratory measurements of T4 (total or free T4) and TSH should be repeated 4-6 weeks after initiation of therapy, then every 1-3 months during the first year of life and every 2-4 months during the second and third years. In children aged 3 years and older, the time interval between measurements may be increased, depending on the reliability of the patient's caretakers. As dosage changes are made, testing should be more frequent. Formal developmental and psychoneurological evaluations should be considered in all infants with congenital hypothyroidism. Such evaluations are especially important in children whose treatment was delayed or inadequate. As mentioned above, infants diagnosed early who have detectable signs of hypothyroidism at the time of diagnosis are also at increased risk of developmental problems. As with any child, school progression should be monitored and parents encouraged to seek early evaluations and interventions as soon as problems are recognized.[63] Unless an anatomic defect of the thyroid was found at diagnosis, reevaluation after withdrawing treatment should be considered at about age 3 years.[64] If the child remains hypothyroid at age 3 years, thyroid hormone replacement and medical monitoring are usually required for life.

Deterrence/Prevention
Dietary iodide supplementation can prevent endemic goiter and cretinism, but not sporadic congenital hypothyroidism. Iodization of salt is the usual method, but cooking oil, flour, and drinking water have also been iodinated for this purpose. Long-acting intramuscular

injections of iodized oil (Lipiodol) have been used in some areas, and oral lipiodol[65, 66] can also be effective. Properly administered newborn screening programs have made diagnosis of infants with congenital hypothyroidism possible within the first 3 weeks of life. With early and adequate treatment, the sequelae can be eliminated in most and minimized in the rest. Methods of prenatal diagnosis and treatment are being evaluated.

Prognosis
Early diagnosis and treatment of congenital hypothyroidism prevents severe mental retardation and other neurologic complications.[67] Even with early treatment, some children demonstrate mild delays in areas such as reading comprehension and arithmetic in third grade. Some of these delays improve by sixth grade. Despite treatment, individuals diagnosed by newborn screening as a group do not do as well as their euthyroid peers.[68] As might be expected, infants with delayed bone age at diagnosis or a longer time to normalize thyroid hormone levels have poorer outcomes. Although continued improvement in IQ has been documented in treated patients through adolescence, some cognitive problems may persist. These may include problems in visuospatial, language, and fine motor function. Defects in memory and attention may also be present.

Patient Education
Parents should be educated regarding their child's disorder, the potential problems associated with no treatment or inadequate treatment, and the benefits of early and appropriate treatment. This should include instructions on the proper administration of the medication and how and when to follow up with the physician. Because learning problems are possible, even with early diagnosis and treatment, parents should be advised when to seek psychomotor and educational evaluations and interventions. Early childhood intervention programs, if available, should be encouraged. When inborn errors of thyroid hormone production are suspected, genetic counseling should be provided. For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.