Hyperthyroidism in Early Infancy: Pathogenesis, Clinical Features and Diagnosis with a Focus on Neonatal Hyperthyroidism

Neonatal hyperthyroidism has mostly been described in the context of maternal Graves' disease. It has been estimated that about 0.2% of pregnant women have Graves' disease; however only 1% of the children born to these women are described as having hyperthyroidism. In most of the cases, the disease is due to maternal antibodies transferred from the mother into the fetal compartment, which stimulate the fetal thyroid by binding to the thyrotropin (TSH) receptor. In this form of neonatal hyperthyroidism, thyrotoxicosis disappears with the clearance of the maternal antibodies and usually signs disappear during the first 4 months of life. Rare forms of persistent, nonimmune neonatal hyperthyroidism are explained by molecular abnormalities of the TSH receptor. Prematurity is frequent, as well as hypotrophia. Tachycardia, goiter, hyperexcitability, poor weight gain, hepatomegaly and/or splenomegaly, stare and/or eyelid retraction are among the most frequent neonatal thyrotoxicosis clinical signs. Diagnosis is based on the determination of the blood level of thyroxine (T4), triiodothyronine (T3), and TSH. Even if these levels are normal in the cord blood, tests should be repeated 3 to 10 days later to detect possible delayed appearance of the disorder. These parameters should be interpreted according to the age of the neonate. To confirm the immune nature of this hyperthyroidism, thyroid-stimulating immunoglobulins (TSI) should be determined. The TSI determination is crucial in identifying nonimmune causes of neonatal hyperthyroidism: in this neonatal hyperthyroidism, TSI are not detected, either by radioreceptor assay and/or by functional assay, and molecular studies are needed to identify the mutation. Mutation of the TSH receptor leading to its constitutive activation and to neonatal hyperthyroidism have been described. Germline mutations are found in hereditary hyperthyroidism; de novo germline mutations can cause sporadic congenital hyperthyroidism.