Children may be rarely afflicted with acquired or congenital diseases of thyroid hormone production, resulting in either increased or decreased hormone production and secretion. Disorders of hypothyroidism are rarely treated surgically, and may result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. The differential diagnosis of hypothyroidism in childhood is listed in Table 43-1. Moreover, a hypothyroid state may be seen in conditions of hormone unresponsiveness, such as when there is a defect in the thyroid receptor gene; in such cases, the plasma thyroxin level is elevated.

Thyroid gland dysgenesis is the most common cause of hypothyroidism diagnosed in neonatal screening programs, accounting for approximately 90% of these patients. In about one-third of these babies, no thyroid tissue is seen on radionuclide scanning. In the remaining patients, a rudimentary gland may be found in an ectopic location, such as at the base of the tongue. Often, there has been enough transplacental thyroid hormone present throughout development so even children with complete thyroid agenesis are asymptomatic at birth. In some cases, ectopically located thyroid tissue may supply a sufficient amount of thyroxin for many years or may fail in childhood. Such conditions may come to clinical attention with the development of a sublingual or midline neck mass. Surgeons should be mindful of this possibility when evaluating children with neck masses, and consideration should be given to performing radionuclide thyroid scanning prior to removing any unusual neck mass to ensure the functioning thyroid tissue is not accidentally resected.

When children are specifically surveyed for abnormalities of the thyroid gland, a goiter is found in about 3% of population (1). This prevalence rate has decreased markedly with the increased use of iodized table salt. Indeed, early in the twentieth century, the incidence of thyroid enlargement was as high as 70% in children living in iodide-poor regions of the United States. Goiters may be classified as either diffusely enlarged or nodular, and they may be associated with increased hormone secretion (thyrotoxicosis) or the patient may be euthyroid. Physiologically, diffuse goiters may be related to autoimmune diseases or as a response to a nonautoimmune inflammatory condition, or the enlargement may be a compensation for some defect in hormone production. The differential diagnosis of diffuse thyroid enlargement is listed in Table 43-2. It should be noted that most children with goiters are euthyroid, and surgical resection is rarely indicated.

In a study of 5,462 Croatian schoolchildren, 152 subjects (2.78%) had thyromegaly (4). The various etiologies of thyroid enlargement in this population are presented in Table 43-3. As in other studies of populations with adequate dietary iodine intake, most of these patients had simple colloid goiter, which is frequently called adolescent goiter or nontoxic goiter. More recent studies have suggested that this disease may be part of the spectrum of autoimmune thyroid diseases, and in as many as 90% of patients,
there may be circulating thyroid-stimulating antibodies present (5). Currently, the measurement of such antibodies is not particularly useful in making the diagnosis of simple colloid goiter; rather, the diagnosis is established by excluding the other known causes of thyroid enlargement.

The laboratory evaluation of thyroid enlargement should start with a plasma-free T₄ and TSH level to determine if the patient is euthyroid. Normal levels of TSH and thyroid hormone should be documented, and the diffuse nature of the goiter may be documented scintigraphically or by ultrasound. Usually, no specific treatment is recommended for simple colloid goiter. The natural history of the condition is not well known, but one study in which adolescents with diffuse colloid goiter were reevaluated some 20 years later, nearly 60% of the glands were judged to be normal in size (1). This spontaneous rate of colloid goiter resolution was not significantly different than the response rate in children treated with exogenous thyroid hormone. Thus, simple colloid goiters should generally not undergo any specific treatment. In rare cases, a trial of thyroid hormone may be made. Surgical resection of the gland may infrequently be indicated if there are symptoms related to the size of the goiter, if there is a suspicion of neoplasia, or for cosmetic reasons.

Another common cause of diffusely enlarged thyroid glands in children is chronic lymphocytic thyroiditis, also know as Hashimoto’s thyroiditis. Occurring most frequently in adolescent females, this condition is part of the spectrum of autoimmune thyroid disorders. Indeed, the condition is associated with the presence of other autoimmune disorders such as juvenile rheumatoid arthritis, Addison’s disease, and type I diabetes mellitus. Patients are usually euthyroid and slowly progress to become hypothyroid. However, approximately 10% of these patients are hyperthyroid; this condition has been termed Hashitoxicosis. Patients with chronic lymphocytic thyroiditis are characterized by high titers of the circulating antithyroglobulin and antimicrosomal autoantibodies, which are presumably responsible for the B-lymphocytic infiltrate found in the thyroid gland on histologic evaluation.

Children with chronic lymphocytic thyroiditis generally come to clinical evaluation because of thyroid gland enlargement. On palpation, the gland is generally pebbly or granular in texture, and may be mildly tender. Diagnosis generally no longer requires a thyroid biopsy and may be established by the discovery of high-titer antithyroid antibodies, in association with the proper clinical and laboratory circumstances. Plasma thyroid hormone levels are generally not very useful, but the TSH level may be elevated in 70% of patients. Thyroid ultrasound demonstrates a diffuse hypoechogenicity, and scintigraphy shows a patchy uptake of the tracer. In rare cases, autoantibodies cannot be detected, and fine needle aspirate of the gland may be needed to pathologically confirm the diagnosis. Treatment is usually expectant. As many as one-third of adolescent patients with chronic lymphocytic thyroiditis will resolve spontaneously, with normalization of gland size and disappearance of the antithyroid antibodies. Administration of thyroid hormone to euthyroid patients has been shown to be ineffective in reducing the size of the goiter and is thus probably not indicated (6). Thyroid function studies should be obtained every 6 months, and exogenous hormone should be administered if hypothyroidism develops.

Subacute (de Quervain’s) thyroiditis is rarely seen in children. This condition is caused by a viral infection and is characterized by tender, painful swelling of the gland. Typically, there is mild thyrotoxicosis owing to injury to the thyroid follicles with leakage of thyroid hormone into the circulation. This may be reflected by elevated T₃ and T₄ levels, with a decreased TSH. Radioactive iodine uptake is decreased, as a result of thyroid follicular cell dysfunction. This finding distinguishes subacute thyroiditis from Graves’ disease. Histologically, granulomas and epithelioid cells may be seen. Treatment is symptomatic, and generally consists of nonsteroidal antiinflammatory agents or steroids. The disease usually lasts 2 to 9 months, and complete recovery may be expected.

Acute suppurative thyroiditis is caused by a bacterial infection of the gland. On examination, the patient may have evidence of sepsis, with an acutely inflamed thyroid
gland. Patients are usually euthyroid. The offending organisms are usually staphylococci or mixed aerobic and anaerobic flora. There may be a congenital pharyngeal sinus tract predisposing to infection. Treatment consists of antibiotics; if an abscess develops, incision and drainage may be necessary. The thyroid gland may be expected to recover completely.

With rare exceptions, hyperthyroidism of childhood is caused by Graves’ disease, or diffuse toxic goiter. Other possible etiologies of this condition are listed in Table 43-4. The McCune-Albright syndrome is the association of bony fibrous dysplasia, skin pigmentation abnormalities, and abnormally increased hormone secretion by the endocrine organs, including the thyroid, parathyroid, and adrenal glands. Hyperthyroidism may occur congenitally in about 1% of babies born to women with active Graves’ disease. In these patients, the onset of the condition may be delayed until 2 to 3 weeks after birth.

Graves’ disease is seen in girls about five times more commonly than boys, and the incidence steadily increases throughout childhood and peaks in the adolescent years. The onset is usually insidious, and the condition develops over several months. Initial symptoms include nervousness, emotional lability, and declining school performance. Then, weight loss will become manifest, and increased sweating, palpitations, heat intolerance, and malaise may develop. True exophthalmos is an unusual finding in children, but a conspicuous stare is commonly seen. A goiter is evident on physical examination in more than 95% of cases. The thyroid gland is smooth, firm, and nontender. A bruit may be heard on auscultation. Laboratory evaluation generally reveals elevated free T₄ and a decreased TSH. In 10% to 20% of patients, there is only elevation of T₃, a condition known as T₃ toxicosis. The diagnosis of Graves’ disease is further supported by the presence of TSH-stimulating immunoglobulins.

Graves’ disease is an autoimmune disease caused by the presence of TSH receptor antibodies. These autoantibodies stimulate the thyroid follicles to increase iodide uptake and cyclic adenosine monophosphate production, inducing the production and secretion of increased thyroid hormone. As with many other autoimmune diseases, the inciting event to elicit the antibody response against the TSH receptor is unknown. More recent reports have suggested that the TSH-binding proteins are present in a number of gram-positive and gram-negative bacteria. It is possible that infection with such organisms may elicit an antibody response that could react with the TSH receptor (7). In addition, an infectious etiology for Graves’ disease is further supported by some epidemiologic reports of disease clustering (8).

The currently used methods for treating Graves’ disease include antithyroid medications, or thyroid gland ablation using either radioactive ¹³¹I or surgical resection (9). Most pediatric endocrinologists begin therapy with antithyroid medications, although there is increasing use of radioablation as the first line of treatment (10). The most commonly used antithyroid medications are methimazole or propylthiouracil, which act principally by inhibiting follicle cell organification of iodide and the coupling of iodotyrosines to reduce thyroid hormone production. Further, there may be some immunosuppressive activity because there is usually a reduction in antithyroid antibodies. Because of its longer half-life and increased potency, methimazole is usually preferred. The initial dose is 30 mg once daily, which should be reduced if the patient is younger than the usual adolescent. The TSH should be monitored carefully because rising TSH levels signal overtreatment and may cause further increase in the goiter size. When the patient is euthyroid, as determined by normal T₃ and T₄ levels, the dose of methimazole should be reduced to 10 mg and maintained at a level to ensure normal thyroid hormone levels.

Side effects of methimazole are unusual, and include nausea, minor skin reactions, urticaria, arthralgias, arthritis, and fevers. The most serious reaction is an idiosyncratic agranulocytosis. This can occur at any time during the course of treatment or even during a second course of the drug. The onset of a sore throat with fever should raise concern, and a neutrophil count should be obtained. Typically, the granulocyte count will rise 2 to 3 weeks after stopping the drug, but in rare cases, fatal opportunistic infections have been reported. Treatment with parenteral antibiotics during the recovery period has been recommended.

The length of medical treatment is controversial, but the goal is to treat long enough to allow for resolution of the disease. In general, treatment should be continued for 3 to 4 years. Remission of Graves’ disease is approximately 25% if medication is discontinued after 2 years of treatment, and the continuing remission rate is about 25% every 2 years. In most children, the remission of Graves’ disease will occur within 6 months of discontinuing antithyroid therapy. The resolution rate is decreased in children who have persistence of their TSH receptor antibodies during and after treatment. In patients with Graves’
disease resistant to treatment with antithyroid medications, or if there is a severe reaction to the medication, then the thyroid gland must undergo definitive ablation. Current methods of definitively treating Graves’ disease include either surgical resection or ablation with radioactive ¹³¹I. Neither of these modalities is without complications. Although ¹³¹I therapy is effective and the disease remission rate is low, patients have a 50% to 80% incidence of long-term hypothyroidism following treatment (11). In some cases, fixed doses of radioiodine have been administered to destroy the entire gland and to induce an easily managed state of permanent hypothyroidism (10). Despite a lack of evidence, concerns have been raised over the possibility of teratogenic or carcinogenic effects of ¹³¹I therapy in these younger patients; however, more recent studies have suggested such concerns are without merit (12,13).

In rare cases, surgical treatment may be recommended for pediatric patients with Graves’ disease refractory to medical treatment. Subtotal thyroidectomy is the surgical procedure of choice for the treatment of Graves’ disease, and is appropriate treatment for patients who refuse radioiodine treatment, fail medical management, or if the thyroid is so large that there are symptoms related to compression. Patients should be rendered euthyroid before undergoing surgery. Methimazole should be used to decrease T₃ and T₄ levels into the normal range. Alternatively, β-blocking agents such as propranolol may be used to ameliorate the adrenergic symptoms of hyperthyroidism. Finally, iodine in the form of Lugol’s solution, 5 to 10 drops per day, should be administered for 4 to 7 days before surgery to reduce the vascularity of the gland. In large studies of adults treated with a subtotal thyroidectomy for Graves’ disease, the rate of recurrent hyperthyroidism is approximately 6% to 10% at 10 years’ follow-up (11). Patients continue to relapse even later, and 30% of patients will exhibit recurrent hyperthyroidism 25 years after their subtotal thyroidectomy (9). There is also a significant risk of permanent hypothyroidism in these patients, affecting approximately 5% of patients 1 year after surgery, increasing to as high as 50% of patients who are followed for 25 years. The incidence of hyperthyroidism or hypothyroidism is even higher when abnormal TSH levels are considered, which are indicative of subclinical abnormalities in hormone production. These findings underscore the importance of carefully following such patients postoperatively to monitor thyroid status.

Although thyroid nodules are uncommon in children, their importance stems from a relatively high likelihood of associated cancer. In more recent pediatric studies, the incidence of malignancy in thyroid nodules has been 20% or less (14,15,16,17). This is a much lower incidence of cancer than was reported in previous decades and is believed to reflect the decreased number of children who have been exposed to neck radiation for trivial reasons. Proper evaluation and treatment of these lesions is essential because the cancer may be at an easily curable stage. A summary of pathologic results of several large series of children who underwent surgery for thyroid nodules is presented in Table 43-5.

The differential diagnosis of solitary thyroid nodules is listed in Table 43-6. In most large pediatric series, females having nodules outnumber males approximately 2 to 1 (16). The majority of patients will come to clinical attention because of the mass in their neck; it is unusual to have an abnormal hormone level in the setting of a single thyroid nodule. A careful neck examination should be performed, with special attention directed to determine if there are enlarged cervical lymph nodes. Such a finding is suspicious for locally advanced carcinoma, but may also be found in patients with benign disease. In general, it is impossible to differentiate benign from malignant lesions on clinical grounds. The serum TSH level should be measured to identify patients with unsuspected thryotoxicosis resulting from an autonomously functioning nodule. Although imaging studies are often performed early in the evaluation process, they are unreliable at distinguishing benign from malignant nodules. Malignant nodules may be either functioning or nonfunctioning on thyroid scintiscan. Similarly, ultrasonography is usually nondiagnostic; malignant nodules may be either solid or cystic. Thus, such imaging studies should be deferred in the evaluation of thyroid nodules in pediatric patients. A therapeutic trial of exogenous thyroid hormone to induce nodule regression, as is often prescribed in adults, is not recommended for children.

The use of needle aspiration cytology to evaluate thyroid nodules is well established in adults, and the use of the technique has significantly decreased the incidence of thyroidectomy for benign conditions. Further, this has doubled the number of surgical patients whose pathologic evaluation reveals carcinoma (18). The overall reduction in surgery has resulted from the practice of observing benign lesions, rather than removing them. Whereas this practice has been shown to be safe in adults, the incidence of false-negative cytology with an attendant delay in the diagnosis of thyroid cancer is approximately 1% to 6%. In adult patients, this rare delay in diagnosis of thyroid cancer has not resulted in a discernible decrease in survival.