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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 ofthyroid metabolism, oriodine 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 intakeof 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 andcretinism 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 absentthyroid 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 thyroid-

stimulating hormone (TSH) and thyroxine (T4) from blood spots on filter paper, obtained forneonatal 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 thyroidhormone. 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 iodineby 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 moleculeof 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.

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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 isreleased 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 doesso 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 lowlevels 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, butmaternal 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. Radioactiveiodine 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 isnecessary 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, isapproximately 1 per 4000 births.1

International

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

Data from most countries with well-established newborn screening programs indicate anincidence 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

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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 whosetreatment 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 fromproteinaceous 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 insymptoms 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 thyroidectopy.6The sex ratio for Hispanics is more striking, with a 3:1 female-to-male ratio. The ratio is

lower among black infants.

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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 butgenerally do not exhibit the profound and incompletely reversible neurologic abnormalitiesobserved 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 Decreased activity

o Large anterior fontanelle

o Poor feeding and weight gain

o Small stature or poor growth

o Jaundice

o Decreased stooling or constipation

o Hypotonia

o 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

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The physical findings of hypothyroidism may or may not be present at birth.

Signs include the following:

o Coarse facial features

o Macroglossia

o Large fontanelles

o Umbilical hernia

o Mottled, cool, and dry skin

o Developmental delay

o Pallor

o Myxedema

o Goiter

A small but significant number (3-7%) of infants with congenital hypothyroidism have

other birth defects, mainly atrialand ventricular septal defects.

Newborn screening involves the following:

o Infants with congenital hypothyroidism are usually identified within the first 2-3

weeks of life.

o These infants should be carefully examined for signs of hypothyroidism, and the

diagnosis should be confirmed by repeat testing.

o 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.7Congenital 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)

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o TSH unresponsiveness (ie, TSH receptor abnormalities)

o Impaired ability to uptake iodide

o Peroxidase, or organification, defect (ie, inability to convert iodide to iodine)

o Pendred syndrome, a familial organification defect associated with congenitaldeafness

o Thyroglobulin defect (ie, inability to form or degrade thyroglobulin)

o 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

o Hypothyroidism can also occur in TSH or TRH deficiencies, either as an isolated

problem or in conjunction with other pituitary deficiencies (eg, hypopituitarism).

o 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 MoreConstipation

Failure to thrive

Hypothyroidism

Jaundice - yellow skin

http://www.nlm.nih.gov/medlineplus/thyroiddiseases.htmlhttp://www.nlm.nih.gov/medlineplus/ency/article/003125.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000991.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000991.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000353.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/003243.htmhttp://www.nlm.nih.gov/medlineplus/thyroiddiseases.htmlhttp://www.nlm.nih.gov/medlineplus/ency/article/003125.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000991.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/000353.htmhttp://www.nlm.nih.gov/medlineplus/ency/article/003243.htm

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Mental retardation

Muscle cramps

Newborn screening tests

Neonatal hypothyroidism is decreased thyroid hormone production in a newborn. In very rarecases, 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 ofevery 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 adistinctive 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)

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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 thefirst 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.

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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 beobserved 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, HolyokeMedical 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, LucilePackard Children's Hospital; Chief Medical Officer, A.D.A.M., Inc.

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