With advances in clinical research and molecular medicine in children with newborn screening, clinicians have greatly expanded their understanding and classification of congenital hypothyroidism (CH). However, because of the complex and diverse etiology of CH and the extremely limited time available for treatment, an accurate diagnosis is more important than a clear etiology in clinical management. Studies have shown that clinical signs and symptoms are often not helpful in the early diagnosis of CH. Only about 5% of newborns with CH are diagnosed with clinical information. Early clinical signs include prolonged hyperbilirubinemia, abdominal bulging, hoarseness, umbilical hernia, hypotonia, large posterior fontanelle, macroglossia, and goiter. The diagnosis of primary CH can be confirmed by combining positive screening results with serologic testing. Definitive etiology of CH during the neonatal period is unlikely, as immediate treatment is required to ensure optimal IQ. In most cases, the differential diagnosis is delayed until 2-3 years of age, when thyroid hormone can be safely discontinued for 1 to 2 months for confirmatory testing. The choice of radioactive iodine scan for newborns can reduce radiation exposure. Lack of isotope uptake indicates an underdeveloped thyroid, and some infants may have low isotope uptake and a scan that does not detect the thyroid due to defects in the TSH receptor and iodine pumping mechanisms or the presence of maternal TSH receptor blocking antibodies (TBA). Clinical studies have shown that it is possible to diagnose thyroid dysgenesis in the neonatal period if isotopic and ultrasound examinations are available. In addition, measurement of serum Tg is helpful in infants with lack of uptake or normal scans. Elevated serum Tg concentrations in infants with hypothyroidism are related to the amount of residual thyroid tissue and the intensity of stimulation, but mostly do not exceed 1000 pmol/L. Serum calcitonin concentrations are reduced in infants with hypothyroidism, but are not superior to Tg measurements for diagnosis. Measurement of bone age (knee and foot X-rays) may be an indication of intrauterine hypothyroidism. Hypothalamic-pituitary hypothyroidism is generally more difficult to diagnose and cannot be detected with elevated TSH as the only screening test. A careful physical examination should be performed to look for evidence of hypothyroidism, and a subnormal TSH response to TRH may confirm hypopituitarism. Treatment of affected infants Infants diagnosed with CH should be evaluated quickly and early, not later than 2 to 5 days. When scans and ultrasonography are not available, treatment should be initiated as early as possible after diagnosis and specimens collected for in vitro laboratory testing. The goal of thyroid screening in newborns is to start adequate thyroid hormone replacement therapy as early as possible. The most critical time for brain development to depend on thyroid hormones is between 2 and 3 years of age, with the most important time being the first 6 months of life when IQ may be reduced by 30 or more points in the absence of thyroid hormones. The key hormone for brain development is T3, and approximately 70% of cortical T3 is derived from local T4 deiodination. Therefore, levothyroxine sodium is the ideal replacement therapy. To ensure that all children receive adequate hormones, serum T4 must be maintained above the median normal value during treatment. The mean value should remain above the physiologic amount for several weeks or months, and serum TSH should be suppressed in the normal range for 2 to 3 weeks. Treatment requires routine monitoring of T4 and/or free T4 and TSH to ensure that hormone levels are above the median normal and that replacement doses maintain normal growth and skeletal maturation.