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.

Defective Synthesis of Thyroxine (Dyshormonogenesis)

A variety of defects in the biosynthesis of thyroid hormone can result in congenital hypothyroidism; these account for 15% of cases detected by neonatal screening programs (1/30,000-1/50,000 live births). 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

Defect of iodide transport is rare and 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 50% of the cases are from Japan. Consanguinity is a factor in about 30% 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 will 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

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.

Defects of Thyroglobulin Synthesis

Defects of thyroglobulin synthesis is a heterogeneous group of disorders characterized by goiter, elevated TSH, low T₄ levels, and absent or low levels of thyroglobulin (TG). It 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. The DEHAL1 gene encodes iodotyrosine deiodinase in the thyroid. DEHAL1 mutations are relatively rare; patients with deiodinase deficiency 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 one 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, low T₄ levels, normal or mildly elevated TSH 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 incidence 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 or Graves disease, maternal hypothyroidism on 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 can also have thyrotropin receptor–stimulating antibodies (TRSAbs) and TPO antibodies. Technetium pertechnetate and ¹²⁵I scans might 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 can 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 of gestation. 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 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.

Thyrotropin Hormone Unresponsiveness

A mutation in the TSH-receptor gene is a relatively uncommon autosomal recessive cause of congenital hypothyroidism. Both homozygous and compound heterozygous mutations in the TSH receptor gene have been reported. Infants with a severe defect have elevated TSH levels and will be detected by newborn screening, whereas other patients with a mild defect remain euthyroid without treatment. A study of infants with congenital hypothyroidism detected by newborn screening from Tokyo reported TSH-receptor mutations in 4.3% of patients (1/118,000), with a founder mutation (p.R450H) accounting for 70% of gene defects.

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 G_s (Chapter 566).

Thyrotropin-Releasing Hormone Receptor Abnormality

Mutations in the TRH receptor gene, a rare cause of congenital hypothyroidism, have now been reported in a few families. This condition, which results in isolated TSH deficiency and hypothyroidism, was suspected because of failure of both TSH and prolactin to respond to TRH stimulation.