AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

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 cretinism in defined geographic areas. These areas were discovered to be low in iodine, and the cause of endemic cretinism was determined to be hypothyroidism secondary to iodine deficiency. In the 1930s, adequate dietary intake of iodine was found to prevent this goiter and cretinism. Thus, the wholesale iodization of salt was established. Despite its efforts, the World Health Organization (WHO) has not been able to completely eliminate iodine deficiency throughout the world. As a result, 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 animal thyroid extracts was found to elicit some improvement in these infants, although many remained impaired.

The morbidity from congenital hypothyroidism can be reduced to a minimum by early diagnosis and treatment, which was made feasible by the development of radioimmunoassay for thyroid-stimulating hormone (TSH) and thyroxine (T4) from blood spots for neonatal screening.

Pathophysiology

The thyroid gland develops from the buccopharyngeal cavity between 4 and 10 weeks' gestation. The thyroid arises from the fourth brachial 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.

Frequency

United States

The incidence of congenital hypothyroidism, as detected through newborn screening, is approximately 1 per 4000 births.¹

International

In areas of iodine deficiency, the prevalence of goiter is reported to range from 5-15% of the population, with a lower incidence of hypothyroidism.

Data from most countries with well-established newborn screening programs indicate an incidence of congenital hypothyroidism of about 1 per 3000-4000. Some of the highest incidences (1 in 1400 to 1 in 2000) have been reported from various locations in the Middle East.

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.

Two clinical forms of endemic cretinism are described, with considerable overlap between them. The neurologic form is characterized by mental retardation, spasticity, ataxia, and defects in speech and hearing to the point of deaf-mutism. Thyroid function and stature are usually normal. Iodine deficiency in early fetal life is thought to be the cause. In the myxedematous form, marked growth delay, myxedema (a doughy edema of the skin and subcutaneous tissue from proteinaceous fluid), and mental retardation without other neurologic features are present. Considerable geographic variation among the predominant forms and findings is noted.

Race

Congenital hypothyroidism is observed in all populations. The racial differences observed in endemic cretinism are probably related more to geographic location and socioeconomic status than to any particular racial predilection. Some researchers have observed variability in symptoms and signs when comparing groups from one part of the world to another. The explanation for these differences is unclear.

• The prevalence at birth is increased in Hispanics, particularly in Hispanic females, who have a birth prevalence of 1 in 1886 births.²
• Black infants have about one third the prevalence rate of white infants.
• Twin births are approximately 12 times as likely to have congenital hypothyroidism as singletons.

Sex

Most studies of congenital hypothyroidism suggest a female-to-male ratio of a 2:1. In 1999, Devos et al showed that much of the discrepancy is accounted for by infants with thyroid ectopy.³ The sex ratio for Hispanics is more striking, with a 3:1 female-to-male ratio.² 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.

CLINICAL

Section 3 of 11  

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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.

Physical

• The physical findings of hypothyroidism may or may not be present at birth.
• Signs include the following:
• • Coarse facial features
  • Macroglossia
  • Large fontanelles
  • Umbilical hernia
  • Mottled, cool, and dry skin
  • Developmental delay
  • Pallor
  • Myxedema
  • Goiter
• A small but significant number (3-7%) of infants with congenital hypothyroidism have other birth defects, mainly atrial and ventricular septal defects.
• 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 is 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, occasionally exacerbated by naturally occurring goitrogens. Congenital hypothyroidism can be caused by any of the following:

• Dysgenesis of the thyroid gland
• • Agenesis (ie, complete absence of thyroid gland)
  • Ectopy (lingual or sublingual thyroid gland)
• Inborn errors of thyroid hormone metabolism - Dyshormonogenesis (most cases are familial and inherited as autosomal recessive conditions)
• • TSH unresponsiveness (ie, TSH receptor abnormalities)
  • 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)
• Maternal autoimmune disease (transient or permanent)
• Iatrogenic causes - Maternal use of thioamides, iodine excess, radioactive iodine therapy
• TSH or thyrotropin-releasing hormone (TRH) deficiencies
• • 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. 

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Endemic cretinism
Goiter
Iodide deficiency
Pendred syndrome
TBG deficiency

WORKUP

Section 5 of 11  

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Lab Studies

• Diagnosis of primary hypothyroidism is confirmed by demonstrating decreased levels of serum thyroid hormone (total or free T4) and elevated levels of TSH.
• If maternal antibody–mediated hypothyroidism is suspected, maternal or neonatal antithyroid antibodies may confirm 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.

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. No radionuclide uptake suggests sporadic athyrotic hypothyroidism. Such 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 would suggest an inborn error of thyroid hormone production.
• Ultrasonography may be a reasonable alternative to scintigraphy but may fail to reveal some ectopic glands.
• 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, which is a poor prognostic sign.

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-to-severe 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. The results of these tests rarely alter the treatment of the patient, and the tests are generally not recommended.

TREATMENT

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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.⁴

Endemic cretinism can be prevented by appropriate iodine supplementation. 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.

Consultations

The treatment of hypothyroidism is straightforward. However, because of the potential for serious morbidity with inadequate treatment or overtreatment, physicians without experience dealing with infants with congenital hypothyroidism should consult a pediatric endocrinologist. Appropriate assistance for psychological, developmental, and educational evaluations should also be solicited.

Diet

• Dietary iodide supplementation, especially in endemic areas, can prevent endemic cretinism.
• Soy-based formulas may decrease the absorption of levothyroxine. 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.

Activity

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

MEDICATION

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Only levothyroxine is recommended for treatment and has been established as safe, effective, inexpensive, easily administered, and easily monitored. No liquid preparations are commercially available in the United States. 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 very inconsistent. Children have been harmed by this approach.

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. Toddlers readily chew the tablets without problems or complaints.

Drug Category: Thyroid hormones

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. Desiccated thyroid is an obsolete medication made from pooled animal tissue. Desiccated thyroid should not be used because of unknown risks from potential viral or prion contamination.

FOLLOW-UP

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• Follow-up
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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.
• Thyroid hormone replacement and medical monitoring are required for life.

Deterrence/Prevention

• Dietary iodide supplementation can prevent endemic goiter and cretinism, but not sporadic congenital hypothyroidism.
• 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. 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.
• 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.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to diagnose and treat early any patient with congenital hypothyroidism to prevent severe mental retardation and other neurologic complications

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  An infant with cretinism. Note the hypotonic posture, coarse facial features, and umbilical hernia.
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Media file 2:  Close-up of the face of the infant shown in Media file 1. Note the macroglossia.
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Media file 3:  The infant shown in Media files 1-2 a few months after starting thyroid hormone replacement.
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Media file 4:  Close-up of the infant in Media files 1-3 a few months after starting thyroid hormone replacement.
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Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Nov 19, 2007