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Chapter 559 Hypothyroidism

Hypothyroidism results from deficient production of thyroid hormone, either from a defect in the gland itself (primary hypothyroidism) or a result of reduced thyroid-stimulating hormone (TSH) stimulation (central or hypopituitary hypothyroidism; Table 559-1). The disorder may be manifested from birth (congenital) or acquired. When symptoms appear after a period of apparently normal thyroid function, the disorder may be truly acquired or might 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.




ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone, TRH, thyroid-releasing hormone; TSH, thyroid-stimulating hormone.

Congenital Hypothyroidism

Most cases of congenital hypothyroidism are not hereditary and result from thyroid dysgenesis. Some cases are familial; these are usually caused by one of the inborn errors of thyroid hormone synthesis and may be associated with a goiter. Most infants with congenital hypothyroidism are detected by newborn screening programs in the first few weeks after birth, before obvious clinical symptoms and signs develop. In infants born in areas with no screening program, severe cases manifest features in the first few weeks of life, but in cases of lesser deficiency, manifestations may be delayed for months.


Thyroid Dysgenesis

Some form of thyroid dysgenesis (aplasia, hypoplasia, or an ectopic gland) is the most common cause of congenital hypothyroidism, accounting for 80-85% of cases; 15% are caused by an inborn error of thyroxine synthesis (dyshormonogeneses), and 2% are the result of transplacental maternal thyrotropin-receptor blocking antibody (TRBAb). In about 33% of cases of dysgenesis, even sensitive radionuclide scans can find no remnants of thyroid tissue (aplasia). In the other 66% 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 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.

Mutations in several transcription factors important for thyroid morphogenesis and differentiation (including TTF-1/NKX2.1, TTF-2 [also termed FOXE1] and PAX8) are monogenic causes of about 2% of the cases of thyroid dysgenesis. In addition, genetic defects leading to absent or ineffective thyrotropin action have been described.

The transcription factor TTF-1/NKX2.1 is expressed in the thyroid, lung, and central nervous system. Mutations in TTF-1/NKX2.1 have been reported to result in congenital hypothyroidism, respiratory distress, and persistent neurologic problems, including chorea and ataxia, despite early thyroid hormone treatment. NKX2.5 is expressed in the thyroid and heart. Mutations in NKX2.5 are associated with congenital hypothyroidism and cardiac malformations. PAX-8 is expressed in the thyroid and kidney. Mutations in PAX-8 are associated with congenital hypothyroidism and kidney and ureteral malformations.

The common 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.

Thyroid Peroxidase Defects of Organification and Coupling

Thyroid peroxidase defects of organification and coupling are 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 “discharge” of 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 <10% in normal persons. Several mutations in the TPO gene have been reported in children with congenital hypothyroidism.

Dual oxidase maturation factor 2 (DUOXA2) is required to express DUOX2 enzymatic activity, which is required for H2O2 generation, a crucial step in iodide oxidation. Biallelic DUOXA2 mutations produce permanent congenital hypothyroidism, whereas monoallelic mutations are associated with transient hypothyroidism. DUOX2 mutations can also cause permanent or transient congenital hypothyroidism. DUOX2 mutations are relatively common, present in 30% of cases of apparent dyshormonogenesis, whereas DUOXA2 are relatively rare, present in 2% of such cases.

Patients with Pendred syndrome, an autosomal recessive disorder comprising sensorineural deafness and goiter, also have impaired iodide organification and a positive perchlorate discharge. Pendred syndrome is due to a mutation in the chloride-iodide transport protein common to the thyroid gland and the cochlea.

Thyrotropin and Thyrotropin-Releasing Hormone Deficiency

Deficiency of TSH and hypothyroidism can occur in any of the conditions associated with developmental defects of the pituitary or hypothalamus (Chapter 551). 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.

Mutations in genes coding for transcription factors essential to pituitary development, cell type differentiation, and hormone synthesis are associated with congenital TSH deficiency. PIT-1 mutations include TSH deficiency associated with growth hormone (GH) and prolactin deficiency. Patients with PROP-1 mutations (“prophet of pit-1”) have not only TSH, GH, and prolactin deficiency but also LH and follicle-stimulating hormone (FSH) deficiency and variable ACTH deficiency. HESX1 mutations are associated with TSH, GH, prolactin, and ACTH deficiencies and is found in some patients with optic nerve hypoplasia (septo-optic dysplasia syndrome).

Isolated deficiency of TSH is a rare autosomal recessive disorder that has been reported in several sibships. DNA studies in affected family members reveal defects in the TSH β subunit gene, including point mutations, frame shifts causing a stop codon, and splice site mutations. The diagnosis is usually delayed because the serum TSH level is not elevated, and so such patients are not detected by newborn screening programs.

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 can 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 because patients 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. 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 patients with generalized or isolated pituitary resistance, even in different members 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 of them. The resistance appears to be more severe in this form of the entity.

On rare occasions, resistance to thyroid hormone selectively affects 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