Early Detection Reduces Risk of Intellectual Disabilities

Late Friday afternoon you are contacted by the newborn nursery due to abnormal newborn screening results in an apparently healthy child who had been released home earlier in the week. The newborn screen identified a TSH of 52 milliunits/liter and a T4 of 2.5 mcg/dL. You then consider the next most reasonable steps in managing the child.

Discussion: Congenital hypothyroidism (CH) is a relatively common disorder, affecting up to 1 in 3000 newborns in the United States. It represents one of the most important preventable causes of intellectual disabilities in the world today.

The most common world-wide cause of CH is severe maternal iodine deficiency, resulting in hypothyroidism during fetal development and severe intellectual disabilities. Without the necessary substrate for thyroid hormone synthesis, it is impossible for the gland to produce adequate amounts of hormone. This is typified by an elevated TSH, a low T4, and, variably, a goiter.

The common etiologies of CH in North America are sporadic and include thyroid agenesis, dysgenesis, and ectopic thyroid gland development. Thyroid dyshormonogenesis is the most common genetically inheritable form and follows an autosomal recessive pattern of transmission. Thyroid dysgenesis is the most common cause of CH and results from failure of gland differentiation. Ectopic thyroid gland development results from failure of normal migration of the thyroid gland from the foramen cecum to the mid-anterior neck. Ectopic glands usually exhibit mild dysfunction which may not become evident until the child grows older. Thyroid dyshormonogensis results from mutations in the enzymes required to synthesize thyroid hormone.

Newborn screening strategies vary, but the most common practice is to measure the serum T4 level first, and subsequently measure the TSH if the T4 is abnormal. Because both TSH and T4 values are higher in the first few days of life, age-appropriate cut-offs are selected. TSH values greater than 20 milliunits/liter beyond the second day of life are more likely to represent true hypothyroidism.

Once an abnormal newborn screen is identified, confirmatory lab evaluation incorporating a TSH, total T4, and free T4 should be repeated as soon as possible. While the confirmatory results are pending, the infant may be started on levothyroxine replacement at 10 to 15 mcg/kg/day via crushed tablets.

Once CH is confirmed, imaging studies of the thyroid may be helpful. Thyroid ultrasound has a relatively high sensitivity at detecting dysgenetic or ectopic glands. 123I or 99Tc-labeled nuclear scans may also be considered to help identify the location of an ectopic thyroid gland, but these must be performed while the TSH is still elevated. Ectopic thyroid tissue may enlarge over time if the TSH is not normalized and this may cause symptoms and result in a significant health impact later in life. If pursued, imaging should not delay the initiation of therapy.

Children with CH should be referred to a pediatric endocrinologist for long-term care. With early identification of disease, normalization of thyroid function within the first 2 to 4 weeks of life, compliance with treatment and regular monitoring, the future is very bright.

References and Suggested Readings

American Academy of Pediatrics, Rose SR; and the Section of Endocrinology and Committee on Genetics, American Thyroid Association, Brown, RS; and the Public Health Committee, and Lawson Wilkins Pediatric Endocrine Society, Foley T. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics. 2006;117:2290-2303.