Hyperthyroidism in Infants and Children

In infants, hyperthyroidism is rare (1 to 5% of infants born to mothers with Graves disease) but potentially life-threatening (1). 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 most common cause of hyperthyroidism (2). It is not common before 5 years of age. Incidence of Graves disease increases during puberty, with peak incidence between 10 years and 15 years of age (3). 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. (See also Overview of Thyroid Function.)

Other causes of hyperthyroidism in children and adolescents include autonomously functioning toxic nodules, transient hyperthyroidism during the early phase of Hashimoto thyroiditis followed by eventual hypothyroidism (hashitoxicosis), or adverse drug effects (eg, amiodarone-induced hyperthyroidism). Occasionally, transient hyperthyroidism can be caused by infections, including bacterial (acute thyroiditis) and viral (followed by eventual hypothyroidism (hashitoxicosis), or adverse drug effects (eg, amiodarone-induced hyperthyroidism). Occasionally, transient hyperthyroidism can be caused by infections, including bacterial (acute thyroiditis) and viral (subacute thyroiditis) infections. Bacterial causes include Staphylococcus aureus, S. epidermis, Streptococcus pyogenes, S. pneumoniae, Escherichia coli, and Clostridium septicum. Predisposing factors for acute suppurative thyroiditis in children include congenital anomalies (eg, persistent pyriform sinus fistula) and immunocompromised status (4).

In the fetus, hyperthyroidism is rare (1). 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 medications. 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 12%.

In infants, symptoms and signs of hyperthyroidism include irritability, feeding problems, hypertension, tachycardia, exophthalmos, goiter, frontal bossing, and microcephaly. Other early findings are growth and weight faltering (failure to thrive), vomiting, and diarrhea. Affected infants generally recover within 6 months (2); the course is rarely longer. The onset and severity of symptoms also vary depending on whether the mother is taking antithyroid medications. If the mother is not taking antithyroid medications, infants are hyperthyroid at birth; if the mother is taking antithyroid medications, infants may not become hyperthyroid until the medications are metabolized at approximately 3 to 7 days. Most children with hyperthyroidism 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 40% of children (3). 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 of puberty are usually not affected by hyperthyroidism, with the exception of oligomenorrhea or amenorrhea 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. Approximately 10% of patients with acute thyroiditis present with transient 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, heart failure, and delirium, with progression to coma and death.

• Thyroid function tests

• Sometimes thyroid ultrasound or radionuclide scanning

Thyroid function tests include thyroid stimulating hormone (TSH), free thyroxine (T4), and triiodothyronine (T3). In contrast to the evaluation of hypothyroidism, measurement of T3 is essential because early in Graves disease, T3 may rise before T4 levels increase.

Antibodies directed against the TSH receptor include thyroid-stimulating immunoglobulins (TSI) and TSH receptor antibodies (TRAb). The TSI test is a functional assay that measures only stimulatory antibodies and is typically the first study obtained to confirm Graves disease in children outside of infancy. The TRAb test is a competitive assay that measures both stimulating, blocking, and neutral antibodies to the TSH receptor but does not distinguish between them. TRAb can be measured in patients with symptoms and signs of thyrotoxicosis but a negative test for TSI.

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 (TSI or TSH receptor antibodies [TRAb]). During pregnancy, TRAb is considered the first-line test and is measured early in pregnancy in women with current Graves disease, a history of Graves disease even if now euthyroid, or a history of radioablation or thyroidectomy, as TRAb can remain elevated for years after definitive therapy. In women with elevated TRAb in the first trimester who are taking antithyroid medications or in whom there is concern for fetal thyroid dysfunction, serum TRAb should be measured again at 18 to 22 weeks and 30 to 34 weeks of gestation (1). For infants born to mothers with positive TRAb, cord blood samples can be obtained to measure TRAb, free T4, T3, and TSH.

Measurement of cord blood TRAb can help stratify risk of neonatal Graves disease If the TRAb in cord blood is negative, monitoring the newborn is not required. If TRAb in cord blood is positive, thyroid function should be obtained shortly after birth; if TRAb status in cord blood is unknown, thyroid function tests and TRAb should be measured in the newborn. For infants with TRAb positive status or unknown status, serial thyroid function tests should be obtained at 3 to 5 days of life and again at 10 to 14. 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 of hyperthyroidism (2, 3).

Algorithm for the Management of Neonates Born to Mothers With Graves Disease

T4 = thyroxine; TSH = thyroid-stimulating hormone. Data from van der Kaay DC, Wasserman JD, Palmert MR. Management of Neonates Born to Mothers With Graves' Disease. Pediatrics. 2016;137(4):e20151878. doi:10.1542/peds.2015-1878.

Diagnosis in older children and adolescents is similar to that in adults and also includes thyroid function tests (see also diagnosis of hyperthyroidism in adults) and measurement of antibodies directed against the TSH receptor (either TSI or TRAb). Positive TSI in patients with symptoms and signs of thyrotoxicosis confirms the diagnosis of Graves disease. TSI is a functional assay that measures only stimulatory antibodies and is typically the first antibody measured to confirm Graves disease in older children. 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. In contrast to the evaluation of hypothyroidism, measurement of T3 is essential because early in Graves disease, T3 may rise before T4 levels increase. Positive TSI in patients with symptoms and signs of thyrotoxicosis confirms the diagnosis of Graves disease. Measurement of other thyroid antibodies, such as thyroid peroxidase and thyroglobulin, can help evaluate for possible hyperthyroid phase of autoimmune thyroiditis (hashitoxicosis). Biotin is a common over-the-counter supplement used for hair and nails that can interfere with some thyroid assays and should be stopped for at least 2 days before laboratory tests are performed. Most commonly, biotin can result in falsely high levels of T4 and T3 and falsely low levels of TSH and can lead to an inappropriate diagnosis of hyperthyroidism (4).

Many clinicians do thyroid ultrasound in older children with hyperthyroidism and thyroid gland asymmetry, negative TSI/TRAb, or a palpable nodule. Ultrasound 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 performed if the TSI/TRAb level is not elevated, to exclude an autonomously functioning toxic nodule ("hot" nodule), toxic multinodular goiter, differentiated thyroid cancer, or other anatomic abnormality. 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 medications

• Sometimes beta-blockers

• Sometimes radioactive iodine or surgery

Infants are given an antithyroid medication, typically methimazole or carbimazole (outside of the United States) orally in divided doses 3 times a day, sometimes with an oral beta-blocker to treat symptoms. Treatment of hyperthyroidism must be monitored closely and stopped as soon as the disease has run its course. Care must be taken to avoid iatrogenic hypothyroidism in infants treated with antithyroid medications. (See also are given an antithyroid medication, typically methimazole or carbimazole (outside of the United States) orally in divided doses 3 times a day, sometimes with an oral beta-blocker to treat symptoms. Treatment of hyperthyroidism must be monitored closely and stopped as soon as the disease has run its course. Care must be taken to avoid iatrogenic hypothyroidism in infants treated with antithyroid medications. (See alsotreatment of Graves disease during pregnancy.)

For older children, treatment is similar to treatment of hyperthyroidism in adults and includes antithyroid medications and sometimes definitive therapy with thyroid ablation using radioactive iodine or surgery (1, 2). Beta-blockers, such as atenolol or propranolol, may be used to control hypertension and tachycardia. Serious adverse effects of methimazole may include agranulocytosis; if patients taking ). Beta-blockers, such as atenolol or propranolol, may be used to control hypertension and tachycardia. Serious adverse effects of methimazole may include agranulocytosis; if patients takingmethimazole develop febrile illness, they should have a complete blood count with differential. The low blood count usually occurs early in treatment with methimazole and at higher doses and, if detected, is a contraindication to continuation of antithyroid medications.

Propylthiouracil, another antithyroid medication, has been found to sometimes cause severe liver failure (Propylthiouracil, another antithyroid medication, has been found to sometimes cause severe liver failure (3), but it may be used in special situations such as thyroid storm. In thyroid storm, Lugol solution (potassium iodide) can be added orally 3 times a day, with the first dose given 1 hour after the first . In thyroid storm, Lugol solution (potassium iodide) can be added orally 3 times a day, with the first dose given 1 hour after the firstmethimazole dose, especially for disease refractory to methimazole and beta-blocker treatment. Hydrocortisone or prednisolone orally can also be considered, particularly in critically ill patients. and beta-blocker treatment. Hydrocortisone or prednisolone orally can also be considered, particularly in critically ill patients.

Children treated with antithyroid medications 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 medications may be stopped if patients require only a low dose of methimazole to maintain a euthyroid state and/or have negative TSI. When these medications 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 medications have a 20 to 30% likelihood of remission after 2 years of treatment, up to 50% after 10 years of treatment (1, 4, 5, 6), which is lower than that in adults (50%) (7), and is defined as the lack of recurrence ≥ 12 months after antithyroid medications have been stopped. Long-term treatment with antithyroid medications is safe and seems to improve the remission rate in children.

Characteristics associated with lower likelihood of remission after medical therapy include younger age at onset (eg, prepubertal vs pubertal), higher thyroid hormone levels at initial presentation, larger thyroid gland (> 2.5 times normal size for age), and persistent elevation in TSH receptor antibody titers (8, 9). For patients without these risk factors, antithyroid medication can potentially be continued for 5 years or longer without pursuing definitive therapy with radioactive iodine or surgery. However, definitive therapy, may be needed for patients outside the neonatal period who do not achieve remission with 24 to 36 months of antithyroid medication therapy, who have adverse drug effects, or who are nonadherent.

Both radioactive iodine and surgery are reliable options for definitive therapy, with the goal of producing hypothyroidism. However, radioactive iodine is usually not used in children who are under age 10 years (and is absolutely contraindicated under age 5 years) (1, 10). It is often not effective in larger thyroid glands. Therefore, surgery may be preferable for children and adolescents who have these factors. Following definitive therapy, patients are started on levothyroxine. Doses may need to be adjusted based on weight gain or pubertal status.). It is often not effective in larger thyroid glands. Therefore, surgery may be preferable for children and adolescents who have these factors. Following definitive therapy, patients are started on levothyroxine. Doses may need to be adjusted based on weight gain or pubertal status.

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

Treatment of acute thyroiditis involves oral or IV antibiotics (typically amoxicillin/clavulanic acid or cephalosporins for patients allergic to penicillin but ideally based on antibiotic sensitivities obtained from culture of a fine-needle aspiration biopsy specimen). Surgical treatment may be needed (eg, to drain an abscess or repair a fistula). Subacute thyroiditis is self-limiting, and nonsteroidal anti-inflammatory drugs are given for pain control. Antithyroid medications are not indicated, but beta-blockers can be used if patients are symptomatic. involves oral or IV antibiotics (typically amoxicillin/clavulanic acid or cephalosporins for patients allergic to penicillin but ideally based on antibiotic sensitivities obtained from culture of a fine-needle aspiration biopsy specimen). Surgical treatment may be needed (eg, to drain an abscess or repair a fistula). Subacute thyroiditis is self-limiting, and nonsteroidal anti-inflammatory drugs are given for pain control. Antithyroid medications are not indicated, but beta-blockers can be used if patients are symptomatic.

Treatment of thyroid eye disease in Graves disease is typically conservative (1). Patients may require artificial tears and only rarely require glucocorticoids in more severe cases (). Patients may require artificial tears and only rarely require glucocorticoids in more severe cases (5). Patients are advised to avoid smoking and/or exposure to secondhand smoke. Improvement of Graves' orbitopathy with normalization of thyroid function is often reported, and few patients may need surgery, which is typically performed after the skull as fully grown. Teprotumumab, an ). Patients are advised to avoid smoking and/or exposure to secondhand smoke. Improvement of Graves' orbitopathy with normalization of thyroid function is often reported, and few patients may need surgery, which is typically performed after the skull as fully grown. Teprotumumab, aninsulin-like growth factor 1 monoclonal blocking antibody, is not used in children due to growth-related side effects (11).