The Laboratory Features of Congenital Hypothyroidism and Approach to Therapy

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Most infants with CH are healthy at birth because of a small amount of placental transfer of maternal T4. In addition, intracerebral T4 to T3 conversion is increased, leading to availability of brain T3, despite low serum concentrations of T4. (11) T4 has a half-life of 7 to 10 days, so the signs and symptoms of CH become more apparent as maternal T4 is metabolized. However, when both maternal and fetal hypothyroidism are present, there are significant neurointellectual delays despite adequate diagnosis and treatment. This may occur in the setting of severe iodine deficiency or potent blocking TSH receptor antibodies (TRAbs). (10)

The American Academy of Pediatrics (AAP) guidelines from 2006 dictate that “infants with low T4 and elevated TSH concentrations have CH until proven otherwise. All infants with hypothyroidism, with or without goiter, should be rendered euthyroid as promptly as possible by replacement therapy with TH (thyroid hormone).” (14)

Neonates with primary CH have an elevated TSH, with low T4, T3, and free T4 (FT4) values. In iodine-sufficient areas, 95% of cases of CH are primary, meaning they result from abnormalities of the thyroid gland. Although some cases are transient, such as with the presence of TRAbs, treatment should be started until the underlying etiology disappears and should not be delayed for diagnosis. Thyroid dysgenesis, failure of the thyroid gland to appropriately develop, accounts for 85% of primary CH. (15) Thyroid ectopy is usually sporadic and accounts for two-thirds of the cases of thyroid dysgenesis. It is more common in females, with a lingual thyroid representing 90% of cases. Thyroid agenesis and thyroid hypoplasia cause the other one-third of cases of thyroid dysgenesis. (15)(16) Mutations have been reported in some transcription factor genes that regulate thyroid gland development, but a genetic mutation is only found in 2% to 5% of cases of thyroid dysgenesis. (17) Thyroid dyshormonogenesis, because of a defect in the enzymes or transporters involved in thyroid hormone production, accounts for up to 10% to 15% of cases and is typically inherited in an autosomal recessive pattern. (18) Mutations in the thyroid peroxidase gene are the most prevalent form of inherited CH. Other causes include defects in peripheral thyroid hormone transport, metabolism, or action. (16) Neonatal hyperthyrotropinemia occurs when patients have a normal T4 and FT4 and mildly elevated TSH. These newborns require close follow-up until their TSH value normalizes, but may not require treatment.

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Neonates with central CH have a low-normal TSH with low T4, T3, and FT4 values. Central hypothyroidism is caused by deficient TSH production in the setting of a normal thyroid gland. The incidence of central hypothyroidism is 1 in 25,000 to 50,000 live births. (15) Central hypothyroidism is more challenging to diagnose, because human chorionic gonadotropin stimulates the normal fetal thyroid gland and thyrotrope function is not completely absent in most cases. It can be caused by various disorders affecting the hypothalamus or pituitary gland. Genes leading to TSH deficiency can be isolated or result in multiple pituitary hormone deficiencies (such as deficiency of adrenocorticotropin, growth hormone, and gonadotropins). (19) If there are signs of multiple pituitary deficiencies (micropenis and undescended testicles from luteinizing hormone deficiency and hypoglycemia from cortisol and/or growth hormone deficiency) or midline facial defects, brain magnetic resonance imaging (MRI) should be performed to assess for an absent or hypoplastic pituitary gland or abnormalities in the pituitary stalk. Septo-optic dysplasia can manifest with CH and should be considered in the presence of pituitary deficiencies, visual defects and/or blindness, congenital nystagmus, and midline brain defects. Multiple pituitary abnormalities may reflect a genetic defect in pituitary formation, such as PROP1, LHX3, or Pou1F1 mutations. (16) If isolated, central hypothyroidism typically results from a mutation in the beta subunit of the TSH gene or TRH receptor gene. (15) Brain trauma, asphyxia, and excessive treatment of maternal hyperthyroidism can also lead to central hypothyroidism. Neonates with central hypothyroidism may have similar laboratory values as neonates who are premature, critically ill, or have thyroxine-binding globulin (TBG) deficiency.

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Preterm and critically ill infants have a smaller rise in TSH, T4, T3, and FT4 at birth compared with healthy term infants, because of immaturity of the HPT axis and non-thyroidal illness (sick euthyroid syndrome). The reference range for thyroid hormones varies by gestational and post-natal age. Preterm infants may also have lower concentrations of TBG. During the first week after birth, there is a decline in T4 levels, which is greater in very-low-birthweight and more premature infants. Preterm or critically ill infants with low T3 and T4 levels and normal TSH levels on initial evaluation typically have normalization of the thyroid function by 6 to 10 weeks after birth without needing treatment. Van Wassenaer et al showed that neonates who were treated with T4 at less than 27 weeks’ gestation had improvement in mental development scores at 2 years of age and motor development outcomes at 10.5 years of age; however, when T4 was administered to neonates at 27 weeks’ gestation or later, treated infants had worse neurodevelopmental outcomes than those who received a placebo. (20)(21) Currently, there is insufficient evidence to recommend treating preterm infants with abnormal thyroid function. However, preterm and critically ill infants require close monitoring because there may be a delay in the appropriate TSH elevation in cases of transient or permanent primary hypothyroidism, thus leading to a delay in diagnosis and treatment of CH. (22)

A low total T4 with normal TSH and FT4 levels in a healthy infant may indicate TBG deficiency. This is an X-linked disorder with an incidence of 1 in 4,000 males. There is no true deficiency, so treatment is not needed. (15) Rarely, a neonate may have primary hypothyroidism and TBG deficiency. In these cases, the TSH will be useful in determining the accurate diagnosis.

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Transient hypothyroidism can be seen with maternal blocking TRAbs, exposure to maternal antithyroid medications, iodine deficiency or excess, and large congenital hepatic hemangiomas (increased type 3 deiodinase activity). (15) TRAbs, as seen in maternal Graves’ disease, cross the placenta and can block or mimic the function of TSH. Neonatal Graves’ disease (also called neonatal autoimmune hyperthyroidism) occurs in about 2% of neonates born to mothers with Graves’ disease and may be associated with serious neonatal adverse events, including goiter, intrauterine growth restriction, oligohydramnios, prematurity, tachy-cardia and heart failure, hepatomegaly, and death. (23) Alternatively, hypothyroidism from maternal Graves’ disease has an incidence of 1 in 180,000. The antibodies typically disappear from the serum of the affected infant by 3 to 5 months of age. (24)

In developing countries, iodine deficiency continues to be a significant cause of preventable cognitive deficits. Selenium and iron deficiencies may have an effect on neurologic development and thyroid response to iodine. (14) Iodine exposure with surgery and procedures can increase the risk of hypothyroidism secondary to iodine overload. This is usually transient but short-term therapy may be needed. (15)

Patients with Down syndrome have a mild increase in TSH concentration, with lower mean FT4 values than the general population. Down syndrome is associated with higher rates of thyroid dysfunction, most commonly subclinical hypothyroidism and thyroid autoimmunity. The AAP recommends routine newborn screening at birth and then serum thyroid screening at 6 months, 1 year, and then annually in children with Down syndrome. (25)


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