Etiology and Pathogenesis

Congenital hypothyroidism (CH) is one of the most common causes of preventable mental retardation (Figure 68-2). Fortunately, early identification and rapid treatment lead to normal neurocognitive development. Although approximately 10% of cases of CH are transient and caused by factors such as iodine exposure, prematurity, or maternal transfer of antithyroid antibodies, in most cases, hypothyroidism is permanent. Worldwide, iodine deficiency is the most common cause of CH. However, in areas of the world where iodine deficiency is uncommon, CH most commonly results from thyroid dysgenesis (≈75% of cases); thyroid dyshormonogenesis (≈10%), TSH deficiency (5%), and genetic defects in the TSH receptor are much less common. The incidence of CH is approximately one in 3000 to 4000 births. In most cases, CH is sporadic, but mutations in genes encoding transcription factors that are required for normal development of the thyroid gland are present in about 10% to 15% of cases. Circulating levels of TSH are elevated and thyroid hormone levels are low in those with CH.

Figure 68-2 Congenital hypothyroidism.

A clinical picture that is similar to CH can occur in children who have genetic defects in the thyroid hormone receptor or in the MCT8 protein required to transport thyroid hormone into cells. Unlike CH, however, these patients have elevated serum levels of both TSH and thyroid hormones.

Clinical Presentation

Although there may be few obvious symptoms of CH in the first few weeks of life, a prolonged period of hypothyroidism during infancy can have profound neurocognitive consequences. Therefore, newborn screening (NBS) programs have been established in many countries to identify newborns with CH who require prompt treatment. Infants with untreated CH have an enlarged posterior fontanelle, prolonged jaundice, macroglossia, hoarse cry, distended abdomen, umbilical hernia, hypotonia, poor growth, weight gain, pericardial edema, or delayed development.

Long-term studies in adults with a history of CH indicate that when treatment is initiated before 2 months of age, there are only minor differences in intelligence, school achievement, and performance on neuropsychologic tests by comparison with control groups of classmates and siblings. Residual deficits in these patients may include visuospatial processing, selective memory, and sensorimotor defects. The prognosis for mental and neurologic performance in children with CH identified after 2 months of age is uncertain. Infants with CH who were not identified by the NBS but whose treatment was initiated between 2 and 3 months of age may manifest nonspecific developmental delays, including impaired arithmetic ability, speech, or fine motor coordination later in life. Long-term untreated CH can result in severe mental retardation and impaired growth.

Evaluation (Figure 68-3)

NBS for CH is based on collection of a blood sample from the newborn between 48 hours and 4 days of life. Earlier measurement may lead to erroneous results because of the normal physiologic surge in TSH that occurs soon after birth. NBS programs use blood spots collected on filter paper and use one of two strategies to identify infants with CH: a primary TSH with backup T4 or a primary T4 with a backup TSH method. An abnormal result should be further evaluated immediately using serum-based assays for TSH and T4 or free T4. Premature or ill infants may have false-negative or false-positive results and should be retested by 7 days of age. Any infant with a TSH level above 40 mU/L with low T4 is considered to have primary hypothyroidism. In addition to T4 and TSH measurements, a thyroglobulin (TG) level may be helpful because elevation suggests dyshormonogenesis.

Figure 68-3 Evaluation of congenital hypothyroidism.

AB, antibody; CH, congenital hypothyroidism; TBG, thyroid-binding globulin; TH, thyroid hormone; TSH, thyroid-stimulating hormone.

When there is history of maternal autoimmune thyroid disease, measurement of TSH–receptor binding antibodies in the infant or the mother may identify transient CH. Other diagnostic tests include thyroid ultrasonography and technetium or iodine (I-123) scans to identify functional thyroid tissue, as well as the perchlorate washout test to detect iodine organification defects that might indicate Pendred’s syndrome. Treatment with levothyroxine (L-T4) should not be delayed to perform imaging.

Treatment

To avoid neurocognitive deficit, newborns with CH must be treated promptly with L-T4 and monitored closely by a pediatric endocrinologist. L-T4 is instituted at a dosage of 10 to 17 µg/kg/d initially, with a goal to normalize the serum T4 level within 2 weeks (fT4 >2 ng/dL) and serum TSH by 1 month of age. There are no suitable liquid preparations of L-T4, so tablets must be used. Tablets should be crushed and mixed with a few milliliters of formula, breast milk, or water. Soy-based formula, fiber, or iron may reduce absorption of L-T4 and should be given separately.