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This syndrome results from inadequate thyroid hormone (TH) levels during pregnancy or in the neonatal period and during infancy. Characterized in newborns by failure to thrive and physical and mental retardation.


1:3000-4000. Eighty-five percent of cases are sporadic, with wide ethnic variations (1:4000 in Caucasians, 1:2000 in Hispanics, 1:32,000 in Blacks). Females are affected twice as often as men.

Varying etiology. Thyroid dysgenesis is occasionally autosomal recessive inherited but mostly is nonhereditary. Inborn errors of TH biosynthesis are most often autosomal recessive transmitted, except for defects in TH receptor actions that are autosomal dominant inherited.

Congenital hypothyroidism can be classified into two groups: endemic cretinism and sporadic cretinism. Endemic cretinism is caused by intrauterine and/or neonatal iodine deficiency frequently occurring in certain areas (e.g., alpine regions of Europe), whereas sporadic cretinism may be the result of basically three different mechanisms:

Thyroid dysgenesis (85% of all cases): Thyroid dysgenesis includes thyroid (hemi-)agenesis, ectopic thyroid tissue, cysts of the thyroglossal duct, and thyroid hypoplasia. In the vast majority of cases, thyroid dysgenesis is sporadic, but is familial in about 2%. The pathogenesis is largely unknown, but suggested mechanisms include mutations in the genes coding for thyroid transcription factor-1 (TTF-1), thyroid transcription factor-2 (TTF-2, which is important for thyroid morphogenesis and differentiation), and paired box 8 transcription factor (PAX-8, involved in the regulation of TH production), and mutations resulting in dysfunction of the thyrotropin (thyroid-stimulating hormone [TSH]) receptor (important for thyroid growth and function).

Inborn errors of TH biosynthesis (dyshormogenesis) (10% of patients): They are the result of a defect in any step of TH synthesis, secretion, and/or action, including mutations in the sodium/iodide symporter, defects in thyroid peroxidase, thyroglobulin, and deiodinase. In fewer than 1% of patients the cause is hypothalamic and/or pituitary failure.

Transplacental transfer of maternal antibodies (5% of patients): Maternal autoimmune thyroid disease (Graves disease, Hashimoto autoimmune thyroiditis) with transplacental passage of thyrotropin receptor-blocking antibodies (TRB Abs).

Based on the clinical findings and laboratory investigations: low levels of total and free thyroxine (T4 and fT4) and triiodothyronine (T3), altered TSH levels (depending on the etiology may be either decreased or increased), and low serum thyroglobulin concentrations can be seen. Serum, salivary, and urine iodine studies are required to confirm errors of biosynthesis, the presence of maternal and neonatal serum TRB-Abs, or low urinary iodine excretion in iodine deficiency. Imaging studies (e.g., nuclear medicine) can be used to determine the location and size of the gland, and to assess skeletal maturation (e.g., conventional radiography of the distal femur epiphysis).

Signs of hypothyroidism usually are difficult to diagnose at or immediately after birth. In severe cases, it may take a few weeks until symptoms become apparent. In milder cases, diagnosis may be delayed for months or even longer. Screening programs with measurement of ...

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