Kliegman: Nelson Textbook of Pediatrics, 18th ed



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Kliegman: Nelson Textbook of Pediatrics, 18th ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 566 – Hypothyroidism

Hypothyroidism results from deficient production of thyroid hormone or a defect in thyroid hormone receptor activity ( Table 566-1 ). The disorder may be manifested from birth or acquired. When symptoms appear after a period of apparently normal thyroid function, the disorder may be truly “acquired” or may only appear so as a result of one of a variety of congenital defects in which the manifestation of the deficiency is delayed. The term cretinism, although often used synonymously with endemic iodine deficiency and congenital hypothyroidism, is to be avoided.




TABLE 566-1   -- Etiologic Classification of Congenital Hypothyroidism

CENTRAL (HYPOPITUITARY) HYPOTHYROIDISM

PIT-1 mutations

 Deficiency of thyrotropin (TSH), growth hormone, and prolactin

PROP-1 mutations

 Deficiency of TSH, growth hormone, prolactin, LH, FSH, ACTH

Thyrotropin-releasing hormone (TRH) deficiency

 Isolated?

 Multiple hypothalamic deficiencies (e.g., septo-optic dysplasia)

TRH unresponsiveness

 Mutations in TRH receptor

TSH deficiency

 Mutations in β-chain

Multiple pituitary deficiencies (e.g., craniopharyngioma)

TSH unresponsiveness

 Gsα mutation (e.g., type IA pseudohypoparathyroidism)

 Mutation in TSH receptor

PRIMARY HYPOTHYROIDISM

Defect of fetal thyroid development

 Aplasia, hypoplasia, ectopia (dysgenesis)

Defect in thyroid hormone synthesis (e.g., goitrous hypothyroidism)

 Iodide transport defect

 Thyroid peroxidase defect

  Thyroid oxidase mutations:homozygotic—permanent;heterozygotic—transient

 Thyroglobulin synthesis defect

 Deiodination defect

Defect in thyroid hormone transport

Iodine deficiency (endemic goiter)

 Neurologic type

 Myxedematous type

Maternal antibodies

 Thyrotropin receptor–blocking antibody (TRBAb, also termed thyrotropin-binding inhibitor immunoglobulin)

Maternal medications

 Radioiodine, iodides

 Propylthiouracil, methimazole

 Amiodarone




ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone.






CONGENITAL HYPOTHYROIDISM

Most cases of congenital hypothyroidism are not hereditary and result from thyroid dysgenesis. Some cases may be familial, usually caused by one of the inborn errors of thyroid hormone synthesis, and may be associated with a goiter. In many cases, the deficiency of thyroid hormone is severe, and symptoms develop in the early weeks of life. In others, lesser degrees of deficiency occur, and manifestations may be delayed for months.

EPIDEMIOLOGY.

The prevalence of congenital hypothyroidism based on nationwide programs for neonatal screening is 1/4,000 infants worldwide; prevalence is lower in black Americans (1/32,000) and higher in Hispanics and Native Americans (1/2,000). Twice as many girls as boys are affected.



ETIOLOGY

Thyroid Dysgenesis.

Some form of thyroid dysgenesis (aplasia, hypoplasia, or an ectopic gland) is the most common cause of congenital hypothyroidism, accounting for 85% of cases; 10% are caused by an inborn error of thyroxine synthesis, and 5% are the result of transplacental maternal thyrotropin-receptor blocking antibody (TRBAb). In about ⅓ of cases of dysgenesis, even sensitive radionuclide scans can find no remnants of thyroid tissue (aplasia). In the other ⅔ of infants, rudiments of thyroid tissue are found in an ectopic location, anywhere from the base of the tongue (lingual thyroid) to the normal position in the neck (hypoplasia).

The exact cause of thyroid dysgenesis is unknown in most cases. Thyroid dysgenesis occurs sporadically, but familial cases occasionally have been reported. The finding that thyroid developmental anomalies, such as thyroglossal duct cysts and hemiagenesis, are present in 8–10% of 1st-degree relatives of infants with thyroid dysgenesis supports an underlying genetic component.

Three transcription factors, TTF-1, FOXE1, and PAX-8, are important for thyroid morphogenesis and differentiation; mutations in these genes are associated with thyroid dysgenesis. In addition, genetic defects leading to absent or ineffective thyrotropin action have been described.

Another transcription factor, NKX2.1, is expressed in both the thyroid and central nervous system. Mutations in NKX2.1 have been reported to result in congenital hypothyroidism with persistent neurologic problems, including ataxia, despite early thyroid hormone treatment.

The frequent finding of thyroid dysgenesis confined to only one of a pair of monozygotic twins suggests the operation of a deleterious factor during intrauterine life. Maternal antithyroid antibodies might be that factor. Although thyroid peroxidase (TPO) antibodies have been detected in some mother-infant pairs, there is little evidence of their pathogenicity. The demonstration of thyroid growth-blocking and cytotoxic antibodies in some infants with thyroid dysgenesis, as well as in their mothers, suggests a more likely pathogenetic mechanism.

The most common form of thyroid dysgenesis is an ectopic gland, which may be demonstrated by a thyroid scan or ultrasonographic examination. Most cases are detected by newborn screening, but in some children ectopic thyroid tissue (lingual, sublingual, subhyoid) may provide adequate amounts of thyroid hormone for many years, or it may eventually fail in early childhood. Affected children come to clinical attention because of a growing mass at the base of the tongue or in the midline of the neck, usually at the level of the hyoid. Occasionally, ectopia is associated with thyroglossal duct cysts. It may occur in siblings. Surgical removal of ectopic thyroid tissue from a euthyroid individual usually results in hypothyroidism, because most such patients have no other thyroid tissue.

Defective Synthesis of Thyroxine (Dyshormonogenesis).

A variety of defects in the biosynthesis of thyroid hormone may result in congenital hypothyroidism; these are detected in 1/30,000–50,000 live births in neonatal screening programs. These defects are transmitted in an autosomal recessive manner. A goiter is almost always present. When the defect is incomplete, compensation occurs, and onset of hypothyroidism may be delayed for years.

Defect of Iodide Transport.

This rare defect involves mutations in the sodium-iodide symporter. Among the several cases now reported, it has been found in 9 related infants of the Hutterite sect, and about ½ the cases are from Japan. Consanguinity has occurred in about ⅓ of the families.

In the past, clinical hypothyroidism, with or without a goiter, often developed in the first few months of life; the condition has been detected in neonatal screening programs. In Japan, however, untreated patients acquire goiter and hypothyroidism after 10 yr of age, perhaps because of the very high iodine content (often 19 mg/24 hr) of the Japanese diet.

The energy-dependent mechanisms for concentrating iodide are defective in the thyroid and salivary glands. In contrast to other defects of thyroid hormone synthesis, uptake of radioiodine and pertechnetate is low; a saliva to serum ratio of 123I may be required to establish the diagnosis. This condition responds to treatment with large doses of potassium iodide, but treatment with thyroxine (T4) is preferable.

Thyroid Peroxidase Defects of Organification and Coupling.

This is the most common of the T4 synthetic defects. After iodide is trapped by the thyroid, it is rapidly oxidized to reactive iodine, which is then incorporated into tyrosine units on thyroglobulin. This process requires generation of H2O2, thyroid peroxidase, and hematin (an enzyme cofactor); defects can involve each of these components, and there is considerable clinical and biochemical heterogeneity. In the Dutch neonatal screening program, 23 infants were found with a complete organification defect (1/60,000), but its prevalence in other areas is unknown. A characteristic finding in all patients with this defect is a marked decrease in thyroid radioactivity when perchlorate or thiocyanate is administered 2 hr after administration of a test dose of radioiodine. In these patients, perchlorate discharges 40–90% of radioiodine compared with less than 10% in normal individuals. Several mutations in the TPO gene have been reported in children with congenital hypothyroidism. Patients with Pendred syndrome, a disorder comprising sensorineural deafness and goiter, also have a positive perchlorate discharge. Pendred syndrome is due to a defect in a sulfate transport protein common to the thyroid gland and the cochlea.

Thyroid oxidase 2 helps generate H2O2. Bi-allelic inactivating mutations produce permanent congenital hypothyroidism, whereas single-gene lesions produce transient hypothyroidism.

Defects of Thyroglobulin Synthesis.

This heterogeneous group of disorders, characterized by goiter, elevated thyroid-stimulating hormone (TSH), low T4 levels, and absent or low levels of thyroglobulin (TG), has been reported in approximately 100 patients. Molecular defects, primarily point mutations, have been described in several patients.

Defects in Deiodination.

Monoiodotyrosine and diiodotyrosine released from thyroglobulin are normally deiodinated within the thyroid or in peripheral tissues by a deiodinase. The liberated iodine is recycled in the synthesis of thyroid hormones. Patients with a deficiency of this enzyme experience severe iodine loss from the constant urinary excretion of nondeiodinated tyrosines, leading to hormonal deficiency and goiter. The deiodination defect may be limited to thyroid tissue only or to peripheral tissue only, or it may be universal.

Defects in Thyroid Hormone Transport.

Passage of thyroid hormone into the cell is facilitated by plasma membrane transporters. A mutation in 1 such transporter gene, monocarboxylate transporter 8 (MCT8), located on the X chromosome, has been reported in 5 boys with x-linked mental retardation. The defective transporter appears to impair passage of T3 into neurons; this syndrome is characterized by elevated serum T3 levels and psychomotor retardation.

Thyrotropin Receptor–Blocking Antibody.

Maternal thyrotropin receptor–blocking antibody (TRBAb) (often measured as thyrotropin-binding inhibitor immunoglobulin), is an unusual cause of transitory congenital hypothyroidism. Transplacental passage of maternal TRBAb inhibits binding of TSH to its receptor in the neonate. The frequency is approximately 1/50,000–100,000 infants. It should be suspected whenever there is a history of maternal autoimmune thyroid disease, including Hashimoto thyroiditis, Graves disease, hypothyroidism while the patient is receiving replacement therapy, or recurrent congenital hypothyroidism of a transient nature in subsequent siblings. In these situations, maternal levels of TRBAb should be measured during pregnancy. Affected infants and their mothers may also have thyrotropin receptor–stimulating antibodies (TRSAbs) and TPO antibodies. Technetium pertechnetate and 125I scans may fail to detect any thyroid tissue, mimicking thyroid agenesis, but ultrasonography will show a thyroid gland. After the condition remits, a normal thyroid gland is demonstrable by scanning following discontinuation of replacement treatment. The half-life of the antibody is 21 days, and remission of the hypothyroidism occurs in about 3–6 mo. Correct diagnosis of this cause of congenital hypothyroidism prevents unnecessary protracted treatment, alerts the clinician to possible recurrences in future pregnancies, and allows a favorable prognosis.

Radioiodine Administration.

Hypothyroidism may occur as a result of inadvertent administration of radioiodine during pregnancy for treatment of Graves disease or cancer of the thyroid. The fetal thyroid is capable of trapping iodide by 70–75 days. Whenever radioiodine is administered to a woman of childbearing age, a pregnancy test must be performed before a therapeutic dose of 131I is given, regardless of the menstrual history or putative history of contraception. Administration of radioactive iodine to lactating women also is contraindicated because it is readily excreted in milk.

Thyrotropin Deficiency.

Deficiency of TSH and hypothyroidism may occur in any of the conditions associated with developmental defects of the pituitary or hypothalamus (see Chapter 558 ). More often in these conditions, the deficiency of TSH is secondary to a deficiency of thyrotropin-releasing hormone (TRH). TSH-deficient hypothyroidism is found in 1/30,000–50,000 infants; most screening programs are designed to detect primary hypothyroidism, so most of these cases are not detected by neonatal thyroid screening. The majority of affected infants have multiple pituitary deficiencies and present with hypoglycemia, persistent jaundice, and micropenis in association with septo-optic dysplasia, midline cleft lip, midface hypoplasia, and other midline facial anomalies.

Pit-1 mutations are a recessive cause of central hypothyroidism secondary to TSH deficiency. Affected children also have deficiency of growth hormone and prolactin. Pit-1, a gene transcription factor, is essential to differentiation, maintenance, and proliferation of somatotrophs, lactotrophs, and thyrotrophs. Examination of prolactin and TSH responses to TRH stimulation can detect these patients. Failure of the prolactin response to TRH should prompt examination of the Pit-1 gene.

PROP-1 is another transcription factor important in pituitary development and hormone production. Infants with a mutation in the PROP-1 gene (“prophet” of Pit-1) are reported to have not only TSH, GH, and prolactin deficiency but also LH and FSH deficiency and variable ACTH deficiency.

Isolated deficiency of TSH is a rare autosomal recessive disorder that has been reported in several sibships. DNA studies in 2 Japanese children and in 3 children in 2 related Greek families have revealed different point mutations in the TSH β subunit gene; studies in 2 German siblings revealed a mutation causing a stop codon due to a frame shift, and studies in 2 Turkish families revealed splice site mutations.

Thyrotropin Hormone Unresponsiveness.

A mutation in the TSH-receptor gene has been reported in 3 siblings with elevated levels of TSH and normal levels of T4; 2 of them had been detected during neonatal screening. Despite persistent resistance to TSH through childhood, they remained euthyroid without treatment. Patients in 3 other reports of presumed TSH-receptor gene mutations had severe hypothyroidism that required treatment. The disorder is inherited in an autosomal recessive fashion. Both homozygous and compound heterozygous mutations in the TSH receptor gene have been reported.

Mild congenital hypothyroidism has been detected in newborn infants who subsequently proved to have type Ia pseudohypoparathyroidism. The molecular cause of resistance to TSH in these patients is the generalized impairment of cyclic adenosine monophosphate activation caused by genetic deficiency of the α subunit of the guanine nucleotide regulatory protein Gs (see Chapter 573 ).

Thyrotropin-Releasing Hormone Receptor Abnormality.

A patient with a TRH receptor abnormality resulting in isolated TSH deficiency and hypothyroidism has been reported. This condition was suspected because of failure of both TSH and prolactin to respond to TRH stimulation. Investigations disclosed a compound heterozygote mutation in the gene coding for the TRH receptor, resulting in inability of the receptor to bind TRH.

THYROID HORMONE UNRESPONSIVENESS.

This autosomal dominant disorder is caused by mutations in the thyroid hormone receptor. Most patients have a goiter, and levels of T4, T3, free T4, and free T3 are elevated. These findings often have led to the erroneous diagnosis of Graves disease although most affected patients are clinically euthyroid. The unresponsiveness may vary among tissues. There may be subtle clinical features of hypothyroidism, including mild mental retardation, growth retardation, and delayed skeletal maturation. On the other hand, there may be clinical features compatible with hyperthyroidism, such as tachycardia and hyperreflexia. It is presumed that these patients have varying tissue resistance to thyroid hormone. One neurologic manifestation is an increased association of attention-deficit hyperactivity disorder; the converse is not true, however, because individuals with attention-deficit hyperactivity disorder do not have an increased risk of thyroid hormone resistance.

TSH levels are diagnostic in that they are not suppressed as in Graves disease but instead are moderately elevated or normal but inappropriate for the levels of T4 and T3 when measured by a sensitive TSH assay. A TSH response to TRH occurs in these patients, unlike the situation in Graves disease. The failure of TSH suppression indicates that the resistance is generalized and affects the pituitary gland as well as peripheral tissues. More than 40 distinct point mutations in the hormone-binding domain of the β–thyroid receptor have been identified. Different phenotypes do not correlate with genotypes. The same mutation has been observed in individuals with generalized or isolated pituitary resistance, even in different individuals of the same family. A child homozygous for the receptor mutation showed unusually severe resistance. These cases support the dominant negative effect of mutant receptors, in which the mutant receptor protein inhibits normal receptor action in heterozygotes. Elevated levels of T4 on neonatal thyroid screening should suggest the possibility of this diagnosis. No treatment is usually required unless growth and skeletal retardation are present.

Two infants of consanguineous matings are known to have an autosomal recessive form of thyroid resistance. These infants had manifestations of hypothyroidism early in life, and genetic studies revealed a major deletion of the β–thyroid receptor in 1 individual. The resistance appears to be more severe in this form of the entity.

On rare occasions, resistance to thyroid hormone may selectively affect the pituitary gland. Because the peripheral tissues are not resistant to thyroid hormones, the patient has a goiter and manifestations of hyperthyroidism. The laboratory findings are the same as those seen with generalized thyroid hormone resistance. This condition must be differentiated from a pituitary TSH-secreting tumor. Different treatments, including d-thyroxine, TRIAC (triiodothyroacetic acid), and TETRAC (tetraiodothyroacetic acid) have been reported to be successful in some patients. Bromocriptine administration, which interferes with TSH secretion, was reported to be successful in another patient.

Iodine Exposure.

Congenital hypothyroidism may result from fetal exposure to excessive iodides. Perinatal exposure may occur with the use of iodine antiseptic to prepare the skin for cesarian section or painting of the cervix prior to delivery. It has also been reported in infants born to mothers in Japan who consumed large quantities of iodine-rich seaweed. These conditions are transitory and must not be mistaken for the other forms of hypothyroidism. In the neonate, topical iodine-containing antiseptics used in nurseries and by surgeons can also cause transient congenital hypothyroidism, especially in low-birthweight infants, and can lead to abnormal results on neonatal screening tests. In older children, the usual sources of iodides are proprietary preparations used to treat asthma. In a few instances, the cause of hypothyroidism was amiodarone, an antiarrhythmic drug with high iodine content. In most of these instances, goiter is present (see Chapter 568.3 ).

Iodine-Deficiency Endemic Goiter.

Essentially unseen in the United States, iodine deficiency or endemic goiter is the most common cause of congenital hypothyroidism worldwide. Borderline iodine deficiency is more likely to cause problems in preterm infants who depend on a maternal source of iodine for normal thyroid hormone production.

THYROID FUNCTION IN PRETERM BABIES.

Postnatal thyroid function in preterm babies is qualitatively similar but quantitatively reduced compared with that of term infants. The cord serum T4 is decreased in proportion to gestational age and birthweight. The postnatal TSH surge is reduced, and infants with complications of prematurity, such as respiratory distress syndrome, actually experience a decrease in serum T4 in the 1st wk of life. As these complications resolve, the serum T4 gradually increases so that generally by 6 wk of life it enters the T4 range seen in term infants. Serum free T4 concentrations seem less affected, and when measured by equilibrium dialysis, these levels are often normal. Preterm babies also have a higher frequency of transient TSH elevations and apparent transient primary hypothyroidism. Premature infants less than 28 wk of gestation may have problems resulting from a combination of immaturity of the hypothalamic-pituitary-thyroid axis and loss of the maternal contribution of thyroid hormone and so may be candidates for temporary thyroid hormone replacement; further studies are needed.


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