Congenital hypothyroidism

Congenital hypothyroidism also known as neonatal hypothyroidism, is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). If the condition is not found and treated, it can result in irreversible neurological problems and poor growth. The good news is that early diagnosis and proper treatment can prevent these problems. In most cases, congenital hypothyroidism is permanent and your child will need lifelong treatment.

The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.

Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.

Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.

Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.

About 1 in every 2,000 to 4,000 babies is born with congenital hypothyroidism. For reasons that remain unclear, congenital hypothyroidism affects more than twice as many females as males.

Congenital hypothyroidism causes

Congenital hypothyroidism can be caused by a variety of factors, only some of which are genetic. The most common cause of congenital hypothyroidism worldwide is a shortage of iodine in the diet of the mother and the affected infant. Iodine is essential for the production of thyroid hormones. Genetic causes account for about 15 to 20 percent of cases of congenital hypothyroidism.

The most common causes of congenital hypothyroidism are:

• An underdeveloped thyroid gland
• A thyroid gland that’s not located where it should be (in the neck below the voice box or larynx)
• A missing thyroid gland

The majority (85 to 90%) of cases of permanent congenital hypothyroidism in North America, Western Europe, and Japan are due to an abnormality of thyroid gland development (thyroid dysgenesis) ¹. Thyroid dysgenesis may result in the complete absence of thyroid tissue (agenesis, 20-30%) owing to a defect in survival of the thyroid follicular cells precursors) or it may be partial (hypoplasia); the latter often is accompanied by a failure to descend into the neck (ectopy) mostly located in a sublingual position as a result of a premature arrest of its migratory process. Females are affected twice as often as males. In the United States, thyroid dysgenesis, is less frequent among African Americans and more common among Hispanics and Asians. Babies with congenital hypothyroidism have an increased incidence of cardiac anomalies, particularly atrial and ventricular septal defects. An increased prevalence of renal and urinary tract anomalies has also been reported. These abnormalities are not inherited from the parents. Most cases of thyroid dysgenesis are sporadic, which means they occur in people with no history of the disorder in their family. Studies suggest that 2 to 5 percent of cases are inherited. Two of the genes involved in this form of the condition are PAX8 and TSHR. These genes play roles in the proper growth and development of the thyroid gland. Mutations in these genes prevent or disrupt normal development of the gland. The abnormal or missing gland cannot produce normal amounts of thyroid hormones.

Inborn errors of thyroid hormonogenesis (thyroid dyshormonogenesis) are responsible for most of the remaining cases (15%) of hypothyroidism in newborn ¹. Thyroid dyshormonogenesis results from mutations in one of several genes involved in the production of thyroid hormones. These genes include DUOX2, SLC5A5, TG, and TPO. Mutations in each of these genes disrupt a step in thyroid hormone synthesis, leading to abnormally low levels of these hormones. Unlike thyroid dysgenesis, inborn errors of thyroid hormonogenesis are commonly associated with an autosomal recessive form of inheritance, consistent with a single gene abnormality. DUOX2 mutations can be transmitted in autosomal dominant way. Mutations in the TSHB gene disrupt the synthesis of thyroid hormones by impairing the stimulation of hormone production. Changes in this gene are the primary cause of central hypothyroidism. The resulting shortage of thyroid hormones disrupts normal growth, brain development, and metabolism, leading to the features of congenital hypothyroidism. Goiter can be present in utero or at birth. A number of different defects have been characterized based on radioiodine uptake and perchlorate test and include: 1) Iodide transport defect that shows failure to concentrate iodide, with low or absent radioiodine uptake; 2) Iodide organification defects due to thyroid peroxidase mutations (TPO), Dual Oxidase 2 (DUOX2), Dual Oxidase Maturation Factor 2 mutations (DUOX2A), SLC26A4, and pendrin defects that have normal radioiodine uptake and altered perchlorate discharge test; and 3) Forms with normal radioiodine uptake and a normal perchlorate test due to thyroglobulin TG mutations, iodide recycling defects, and iodothyrosine deiodinase mutations.

Mutations in other genes that have not been as well characterized can also cause congenital hypothyroidism. Still other genes are involved in syndromic forms of the disorder.

Other possible causes include:

• Defective production of thyroid hormone (an inherited condition)
• Problems with the pituitary gland (located at the base of the brain), which tells the thyroid to make thyroid hormone
• Less commonly, a mother’s thyroid disease or medicines taken during pregnancy can cause congenital hypothyroidism.

Thyroid hormone resistance (ie, thyroid hormone receptor abnormalities) may also be a cause ².

In maternal autoimmune disease, transplacental passage of antibodies cause transient or permanent hypothyroidism ³.

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 ⁴.

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.

Congenital hypothyroidism symptoms

Many babies with congenital hypothyroidism appear normal at birth or for several months after birth. But others may have these signs and symptoms:

• Jaundice (yellowing of the skin and eyes)
• Constipation
• Poor muscle tone
• Sluggishness
• A hoarse cry
• Feeding problems
• A thick, large tongue
• A puffy-looking face
• A swollen abdomen, sometimes with “outpouching” of the belly button
• Large soft spots of the skull

Thyroid hormone deficiency can also occur in older babies or young children, even if test results at birth were normal. If your child shows signs and symptoms of hypothyroidism, contact your doctor right away.

Congenital hypothyroidism diagnosis

Most newborns in the United States are tested a few days after birth for congenital hypothyroidism as part of standard screening tests. These tests detect almost all cases of congenital hypothyroidism. Doctors check blood levels of:

• Thyroxine (T4), one of the thyroid hormones
• Thyroid-stimulating hormone (TSH), a hormone produced by the pituitary gland that tells the thyroid gland to make thyroid hormone

Low levels of T4 and high levels of TSH suggest a diagnosis of congenital hypothyroidism. Doctors also might do a thyroid scan or an ultrasound exam to look at the size and location of the thyroid or to find out if it is missing altogether.

Congenital hypothyroidism treatment

The mainstay in the treatment of congenital hypothyroidism is early diagnosis and thyroid hormone replacement. Optimal care includes diagnosis before age 10-13 days and normalization of thyroid hormone blood levels by age 3 weeks ⁵. Only levothyroxine is recommended for treatment ⁶. It has been established as safe, effective, inexpensive, easily administered, and easily monitored. Optimum dosage regimens and follow-up laboratory monitoring have not yet been determined ⁷. Initial dosages of 10-15 mcg/kg/day, equivalent to a starting dose of 50 mcg in many newborns, have been recommended ⁸. However, in up to 43% of infants and 10% of older children with congenital hypothyroidism, TSH elevation fails to normalize despite appropriate levothyroxine treatment ⁹. Every day, you will give a replacement form of thyroid hormone to your baby to substitute the missing thyroid hormone. You”ll crush the hormone pill and mix it with a small amount of water, breast milk, or formula. Do not mix it with soy protein-based formulas, because they interfere with absorption of thyroid hormone. Then you’ll give it to your baby by mouth, using a medicine dropper, syringe, or open nipple. Treatment begins as soon after birth as possible. In most cases, your child will need to take daily thyroid hormone throughout life.

Talk with your doctor about how often to have follow-ups. The doctor will recommend blood tests to check your child’s hormone levels regularly, including one month after any dose change, to make sure your child is getting the right amount of hormone. The doctor also will check your child’s growth and brain development.

Congenital hypothyroidism prognosis

Congenital hypothyroidism does not affect the all-cause standardized mortality ratio in treated patients ¹⁰. 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.

Early diagnosis and treatment of congenital hypothyroidism prevents severe mental retardation and other neurologic complications ¹¹. 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 normal thyroid peers ¹².

Infants with delayed 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.

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 ¹³. The author of this study was later unable to demonstrate an effect of bone age at diagnosis on outcome ¹⁴. Another study was unable to demonstrate any difference in outcome in infants with or without a distal femoral epiphysis ¹⁵.

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