Introduction

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 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 extract 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 thyroidstimulating hormone (TSH) and thyroxine (T4) from blood spots on filter paper, obtained for neonatal screening tests.

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 3000-4000.2,3 Some of the highest incidences (1 in 1400 to 1 in 2000) have been reported from various locations in the Middle East.4

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.5 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.6 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.

Clinical
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:
o o o o o o o o

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:
o o o o o o o o o

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:
o

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.7 Congenital hypothyroidism can be caused by any of the following:

Dysgenesis of the thyroid gland o Agenesis (ie, complete absence of thyroid gland)
o

Ectopy (lingual or sublingual thyroid gland)

Inborn errors of thyroid hormone metabolism - Dyshormonogenesis (most cases are familial and inherited as autosomal recessive conditions)

o o o o

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

o o

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
o

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.

Neonatal hypothyroidism
MedlinePlus Topics Thyroid Diseases Read More Constipation Failure to thrive Hypothyroidism Jaundice - yellow skin

Mental retardation Muscle cramps Newborn screening tests Neonatal hypothyroidism is decreased thyroid hormone production in a newborn. In very rare cases, no thyroid hormone is produced. If the baby was born with the condition, it is called congenital hypothyroidism. If it develops soon after birth, it is referred to as hypothyroidism acquired in the newborn period. Causes Hypothyroidism in the newborn may be caused by:

A missing or abnormally developed thyroid gland Pituitary gland's failure to stimulate the thyroid Defective or abnormal formation of thyroid hormones

Incomplete development of the thyroid is the most common defect and occurs in about 1 out of every 3,000 births. Girls are affected twice as often than boys. Symptoms Most affected infants have few or no symptoms, because they only have a mild decrease in thyroid hormone production. However, infants with severe hypothyroidism often have a distinctive appearance. Symptoms may include:

Puffy-appearing face Dull look Thick, protruding tongue

This appearance usually develops as the disease gets worse. The child may also have:

Dry, brittle hair Low hairline Jaundice Poor feeding Choking episodes Lack of muscle tone (floppy infant)

Constipation Sleepiness Sluggishness Short stature

Exams and Tests A physical exam may reveal:

Abnormally large fontanelles (soft spots of the skull) Broad hands with short fingers Decreased muscle tone Growth failure Hoarse-sounding cry or voice Short arms and legs Widely separated skull bones

Blood tests will be done to check thyroid function. Other tests that may be done include:

Thyroid scan X-ray of the long bones

Treatment Early diagnosis is very important. Most of the effects of hypothyroidism are easily reversible. Replacement therapy with thyroxine is the standard treatment of hypothyroidism. Once medication starts, thyroid blood tests are regularly done to make sure levels are within a normal range. Outlook (Prognosis) Very early diagnosis generally results in a good outcome. Newborns diagnosed and treated in the first month or so generally develop normal intelligence. Untreated, mild hypothyroidism can lead to severe mental retardation and growth retardation. Critical development of the nervous system takes place in the first few months after birth. Thyroid hormone deficiency may cause irreversible damage.

Possible Complications Mental retardation Growth retardation

Heart problems

When to Contact a Medical Professional Call your health care provider if:

You feel your infant shows signs or symptoms of hypothyroidism You are pregnant and have been exposed to antithyroid drugs or procedures

Prevention If a pregnant women takes radioactive iodine for thyroid cancer, the thyroid gland may be destroyed in the developing fetus. Infants whose mothers have taken such medicines should be observed carefully after birth for signs of hypothyroidism. Most states require a routine screening test to check all newborns for hypothyroidism. See also: Newborn screening tests Alternative Names Cretinism; Congenital hypothyroidism; Hypothyroidism - infants References Harris KB, Pass KA. Increase in congenital hypothyroidism in New York State and in the United States. Mol Genet Metab. 2007; 91(3):268-277. Update Date: 5/12/2009 Updated by: Robert Cooper, MD, Endocinology Specialist and Chief of Medicine, Holyoke Medical Center, Assistant Professor of Medicine, Tufts University School of Medicine, Boston MA. Review provided by VeriMed Healthcare Network. Also reviewed by Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc. Previously reviewed by Alan Greene, MD, FAAP, Department of Pediatrics, Stanford University School of Medicine, Lucile Packard Children's Hospital; Chief Medical Officer, A.D.A.M., Inc.