Hyperthyroidism in Infants and Children

In infants, hyperthyroidism is rare but potentially life-threatening. It develops in fetuses of women with current or prior Graves disease. In Graves disease, maternal autoantibodies against the thyroid receptor for thyroid-stimulating hormone (TSH) overstimulate thyroid hormone production by binding to TSH receptors in the thyroid gland. These antibodies cross the placenta and cause thyroid hyperfunction in the fetus (intrauterine Graves disease), which can result in fetal death or preterm birth due to fetal hyperactivity or tachycardia. Because infants clear the antibodies after birth, neonatal Graves disease is usually transient. However, because the clearance rate varies, duration of neonatal Graves disease varies.

In children and adolescents, Graves disease is the cause of hyperthyroidism in > 90% of cases. There is an increased incidence of Graves disease during puberty, with 80% of cases occurring after 11 years of age. The primary mechanism is stimulating antibodies for the TSH receptor. Other antibodies block the TSH receptor, and the balance between stimulating and blocking determines the severity of Graves disease. Many children with Graves disease have a family history of autoimmune thyroid disease or other autoimmune conditions. Children with trisomy 21 are at increased risk of Graves disease.

Less common causes of hyperthyroidism in children and adolescents include autonomously functioning toxic nodules, transient hyperthyroidism during the early phase of Hashimoto thyroiditissubacute thyroiditis) infections; bacterial causes include Staphylococcus aureus, S. epidermis, Streptococcus pyogenes, S. pneumoniae, Escherichia coli, and Clostridium septicum. Predisposing factors for acute thyroiditis in children include congenital anomalies (eg, persistent pyriform sinus fistula) and immunocompromised status.

In the fetus, hyperthyroidism is rare. Signs of hyperthyroidism (eg, poor intrauterine growth, fetal tachycardia [> 160 beats/minute], goiter) may be detected as early as the second trimester. Fetal hyperthyroidism may cause preterm labor. If fetal thyrotoxicosis is noted, the mother can be treated with antithyroid drugs. If fetal hyperthyroidism is not detected until the neonatal period, the infant may be severely affected; possible manifestations include craniosynostosis (premature fusion of the cranial sutures), impaired intellect, growth failure, and short stature. Mortality rate may reach 10 to 15%.

In infants, symptoms and signs of hyperthyroidism include irritability, feeding problems, hypertension, tachycardia, exophthalmos, goiter ( see Congenital Goiter), frontal bossing, and microcephaly. Other early findings are failure to thrive, vomiting, and diarrhea. Affected infants almost always recover within 6 months; the course is rarely longer. The onset and severity of symptoms also vary depending on whether the mother is taking antithyroid drugs. If the mother is not taking drugs, infants are hyperthyroid at birth; if the mother is taking drugs, infants may not become hyperthyroid until the drugs are metabolized at about 3 to 7 days. More than 95% of children born to mothers with Graves disease present with symptoms within the first month of life; rarely, presentation is delayed into the second month.

In children and adolescents, symptoms of acquired Graves disease may include sleep difficulties, hyperactivity, emotional lability, marked decrease in concentration and school performance, heat intolerance, diaphoresis, fatigue, weight loss, increased frequency of bowel movements, tremor, and palpitations. Signs include diffuse goiter, tachycardia, and hypertension. Graves ophthalmopathy occurs in up to one third of children. Although eye findings are less dramatic than in adults, children may have eyelid lag or red or prominent eyes, sometimes with proptosis (exophthalmos). Children and adolescents may present with alterations in growth, including growth acceleration and advanced bone age. The onset and progression through puberty are usually not affected by hyperthyroidism, with the exception of oligomenorrhea or amenorrhea noted in some girls.

Acute thyroiditis may occur at any age and manifests with sudden onset of symptoms of hyperthyroidism, tenderness over the thyroid gland, and fever. About 10% of patients with acute thyroiditis have hyperthyroidism. Many have leukocytosis with a left shift. In subacute thyroiditis these manifestations are present but less severe and may have been preceded by a viral illness; fever may last for several weeks.

Thyroid storm, a rare, severe complication in children with hyperthyroidism, may manifest with extreme tachycardia, hyperthermia, hypertension, congestive heart failure, and delirium, with progression to coma and death.

• Thyroid function tests

• Sometimes thyroid ultrasonography or radionuclide scanning

In infants, hyperthyroidism is suspected if the mother has active Graves disease or a history of Graves disease and high titers of antibodies directed against the TSH receptor (thyroid-stimulating immunoglobulins [TSI] or TSH receptor antibodies [TRAb])

Hyperthyroidism is confirmed in the infant by measuring serum free thyroxine (T4), triiodothyronine (T3), and TSH. TSI is a functional assay that measures only stimulatory antibodies and is typically the first antibody measured to confirm Graves disease. TRAb is a competitive assay that measures both stimulating and blocking antibodies to the TSH receptor, but it does not distinguish between the different antibodies. TRAb may be measured in patients with symptoms and signs of thyrotoxicosis but with negative TSI. Because symptoms of hyperthyroidism may be nonspecific, neonates born to mothers with Graves disease are at risk of hyperthyroidism and should be monitored by measuring free T4 and TSH levels at 3 to 5 days of life and again at 10 to 14 days of life. If no biochemical abnormalities are noted, infants should be followed clinically until 2 to 3 months of life to identify those few with delayed presentation (1, 2).

Diagnosis in older children and adolescents is similar to that in adults and also includes thyroid function tests (see diagnosis of hyperthyroidism

Many clinicians do thyroid ultrasonography in older children with hyperthyroidism and thyroid gland asymmetry, negative TSI, or a palpable nodule. Ultrasonography or CT can also help localize an abscess or identify a congenital anomaly. Radionuclide scanning (with either technetium-99m pertechnetate or iodine-123) can also be done if the TSI level is not elevated to exclude an autonomously functioning toxic nodule or differentiated thyroid cancer. Radionuclide scanning shows diffuse uptake throughout the gland in Graves disease but shows increased uptake in the location of an autonomous nodule with reduced or absent uptake in the rest of the gland.

If a thyroid nodule is confirmed, fine-needle aspiration (FNA) biopsy should be considered. FNA biopsy can also help differentiate acute from subacute thyroiditis and provide a tissue sample for culture to allow testing of bacterial sensitivities for proper antibiotic coverage.

• Antithyroid drugs

• Sometimes radioactive iodine or surgery

Infants see Graves disease.)

For children age 11 or older and adolescents (11 or older), treatment is similar to treatment of hyperthyroidism in adultsmethimazole develop febrile illness, they should have a complete blood count with differential. This usually occurs early in treatment with methimazole and at higher doses and, if detected, would be a contraindication to continuation of antithyroid drugs.

Children treated with antithyroid drugs are regularly monitored with thyroid function tests, typically every 4 to 6 weeks until a stable regimen is achieved and then every 3 to 4 months. Antithyroid drugs may be stopped if patients require only a low dose of methimazole to maintain a euthyroid state and/or have negative TSI. When these drugs are stopped, thyroid function tests should be repeated at regular intervals (4 to 6 weeks later then every 3 to 4 months throughout the next year). Children treated with antithyroid drugs have a 35% likelihood of remission, which is lower than that in adults (50%), and is defined as the lack of recurrence ≥ 12 months after antithyroid drugs have been stopped.

If an autonomously functioning toxic nodule is detected, surgical excision is recommended in children and adolescents.

Treatment of acute thyroiditis