Approach to acquired goiter in children and adolescents

INTRODUCTION — Acquired goiter can present at any age. Most children and adolescents with goiter have normal thyroid function, but some are hypothyroid or hyperthyroid, depending on the cause and stage of the disorder (table 1). In the United States and other iodine-sufficient areas of the world, the most common causes of acquired goiter in children and adolescents are chronic autoimmune (Hashimoto) thyroiditis and colloid goiter. Worldwide, iodine-deficiency goiter is far more common. Once a goiter is detected, the diagnostic evaluation is aimed at identifying the underlying cause and assessing thyroid function. Both of these factors will determine management.

The causes of and clinical approach to acquired goiters in children are discussed below. Congenital goiter, which has different causes and typically presents in newborns and infants, is discussed separately. (See "Approach to congenital goiter in newborns and infants".)

Thyroid nodules and cancers, and the causes of hypothyroidism and hyperthyroidism in children, are discussed separately. (See "Thyroid nodules and cancer in children" and "Clinical manifestations and diagnosis of Graves disease in children and adolescents" and "Acquired hypothyroidism in childhood and adolescence".)

PATHOPHYSIOLOGY

Thyroid volume in healthy children and adolescents — Goiter refers to enlargement of the thyroid gland; the most accurate method to determine thyroid gland volume is by ultrasonography (table 2). The volume of each lobe is calculated from measurements of the depth (d), width (w), and length (l) of each lobe by the formula: V (mL) = d × w × l (cm) × 0.52 [1]. The thyroid volume is the sum of both lobes; the volume of the isthmus is not included. Thyroid volume should then be compared with reference ranges for age to determine if it is normal or enlarged.

Normal thyroid volume increases with age throughout childhood and also depends on iodine intake. In an extensive study of children from an iodine-sufficient area of Italy, the mean thyroid volume increased with age from 3.1 mL at 7 years to 6.3 mL at 14 years of age (table 2) [1]. Thyroid size correlates with body surface area; among children 6 to 14 years of age, the upper 95^th percentile was 6.2 mL per m² in one series [2]. The influence of iodine intake is seen in a report of 6- to 12-year-old children from Japan, where intake of iodine is relatively high (median urinary iodine 281.6 mcg/L) and thyroid volumes were smaller, increasing from 1.5 mL to 3.8 mL over this age period [3]. Clinically, we use the "rule of thumb" to evaluate thyroid size in older children: Each lobe of the normal thyroid gland is approximately the size of the terminal phalanx of the child's thumb.

Mechanisms for goiter — Goiter may be caused by several different mechanisms:

●Increased thyroid-stimulating hormone (TSH) secretion, resulting from hypothyroidism, in which TSH acts as a thyroid growth factor (table 1).

●Activation of TSH receptors, which result in thyroid hyperplasia and increased thyroid hormone secretion. This may be caused by TSH receptor-stimulating antibodies (as in Graves disease) or by genetic mutations that activate the TSH receptor. (See 'Graves disease' below.)

●TSH-independent processes, such as inflammation associated with thyroiditis, benign and malignant tumors, or infiltrative diseases.

CLINICAL PRESENTATION

●Asymptomatic – A goiter may be discovered during a routine neck examination (eg, carried out for a sports physical). In other cases, some prominence or enlargement in the neck may first be noted by a caregiver or by the child and then brought to the attention of the clinician. Most asymptomatic children with an incidentally discovered goiter are euthyroid.

●Symptomatic – Less commonly, a child presents with symptoms of hypothyroidism, hyperthyroidism, or neck tenderness. Rarely, a large goiter is associated with symptoms due to compression of nearby structures, including difficulty swallowing (dysphagia), shortness of breath (dyspnea), cough, and change in characteristics of the voice (dysphonia).

EVALUATION

History — The history should include onset and duration of goiter and change in size or characteristics, such as nodule formation. Specific questions that may help to identify a cause include:

●Ingestion of excessive iodine – High levels of iodine are found in some health food supplements (eg, kelp), drugs such as expectorants and amiodarone, topical antiseptics containing iodine (eg, povidone-iodine), and certain radiocontrast agents.

●Risk of iodine deficiency – Patients living in an area with endemic goiter, children on parenteral nutrition lacking iodine, or those who are on a very restrictive diet may develop iodine deficiency. Examples of a restrictive diet include veganism with concomitant avoidance of processed foods and iodized salt. Data and a map indicating areas of iodine deficiency worldwide are available from the Iodine Global Network website.

●Ingestion of certain drugs – Some anticonvulsants (eg, phenobarbital and phenytoin), lithium, tyrosine kinase inhibitors, and immune checkpoint inhibitors are associated with the development of hypothyroidism, which may be accompanied by a goiter.

●Family history – A family history of goiter with or without overt symptoms of hypothyroidism suggests the possibility of autoimmune thyroiditis. A family history of goiter with euthyroidism is also characteristic of colloid goiter.

●Antecedent illness – A history of an antecedent upper respiratory infection, most commonly viral, and then presenting with fever and neck pain is typically seen with subacute granulomatous thyroiditis (de Quervain disease). A febrile illness with acute onset of pharyngitis and neck pain (sometimes occurring postoperatively after neck surgery) suggests acute suppurative thyroiditis.

Physical examination — Physical examination should include a careful examination of the neck and thyroid gland, with an estimate of size of each lobe and determination of the presence or absence of nodules, tenderness or pain, and cervical adenopathy.

Vital signs such as heart rate and blood pressure may provide clues to the presence of hypo- or hyperthyroidism. Care should be taken to evaluate recent height velocity, height and weight percentiles, weight-for-height or body mass index, and pubertal development in adolescents.

Important clues include:

●Diffuse thyroid enlargement – The most common cause of childhood goiter, chronic autoimmune (Hashimoto) thyroiditis, is characterized by diffuse thyroid enlargement with a bosselated (bumpy), nontender gland on palpation. (See 'Chronic autoimmune thyroiditis' below.)

●Thyroid nodules or masses – Goiter with multiple nodules is most commonly associated with autoimmune thyroiditis or toxic multinodular goiter. Thyroid cancer most commonly presents as a solitary nodule without goiter, though most solitary nodules are benign. Nodules discovered by palpation should undergo ultrasound examination, both to better establish the size and echo characteristics of the nodule and to evaluate for other nonpalpable nodules. Individuals with low TSH (suggesting a hyperfunctioning nodule) should be evaluated with thyroid scintigraphy in addition to thyroid ultrasound [4]. Patients with large nodules (>1 cm) or with risk factors for thyroid cancer should undergo fine-needle aspiration (FNA) to evaluate for thyroid cancer. (See 'Further evaluation of nodules or cysts' below.)

●Thyroid tenderness – Most types of goiter in children are nontender to palpation, although slight tenderness may be associated with the most common cause, which is chronic autoimmune thyroiditis. Marked tenderness on palpation is a hallmark of subacute granulomatous thyroiditis (de Quervain disease) and of acute suppurative thyroiditis. (See 'Chronic autoimmune thyroiditis (Hashimoto)' below and 'Subacute granulomatous thyroiditis (early)' below and 'Acute suppurative thyroiditis' below.)

●Compressive symptoms – Some children with very large goiters may develop compressive symptoms, including difficulty swallowing (dysphagia), shortness of breath (dyspnea), cough, and change in characteristics of the voice (dysphonia).

●Signs and symptoms of hypothyroidism – Overt hypothyroidism in children is characterized by decreased height velocity and, if the hypothyroidism is prolonged, short stature. Adolescents may present with delayed pubertal development. Less commonly, some children will have an associated "pseudoprecocious puberty," characterized by breast development and vaginal bleeding in females and macro-orchidism in males. Other manifestations tend to be nonspecific, such as weight gain, fatigue, and constipation. (See "Acquired hypothyroidism in childhood and adolescence".)

●Signs and symptoms of hyperthyroidism – Common clinical manifestations of hyperthyroidism include emotional lability, increased sweating, heat intolerance, increased frequency of bowel movements, sleep disturbances, deterioration in school performance, some acceleration of linear growth, tachycardia, hyperreflexia, and failure to gain weight despite an increase in appetite. Children with hyperthyroidism caused by Graves disease may have associated features of Graves ophthalmopathy, which include exophthalmos, decreased extraocular movements, excessive retraction of the eyelids causing lid lag and stare, and conjunctival chemosis. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

Initial testing — Laboratory testing of thyroid function should be performed in all children and adolescents discovered to have a goiter, regardless of whether clinical manifestations of hypo- or hyperthyroidism are present. All children should also have tests for thyroid antibodies. Thyroid ultrasonography should be performed in children with palpable thyroid nodules, asymmetry of the gland, or suspicious cervical adenopathy [4]. We also suggest ultrasonography for baseline evaluation of children with positive thyroid antibodies but without these features, although practice varies on this point.

Thyroid function tests — Initial testing should include measurement of serum thyroid-stimulating hormone (TSH) and free thyroxine (T4). If there is a clinical suspicion of hyperthyroidism, measurement of serum total triiodothyronine (T3) should be included because it may be the first thyroid hormone to be elevated and often it is proportionally more elevated than the free T4. It is important to compare thyroid test results with age-appropriate reference intervals.

Thyroid antibody tests — For all patients with goiter who are likely euthyroid or with a clinical suspicion of hypothyroidism, we suggest including measurement of antithyroid peroxidase (TPO) and antithyroglobulin (Tg) antibodies in the initial blood draw. These tests evaluate for autoimmune thyroiditis, which is the most common cause of goiter in children and adolescents. Most patients with autoimmune thyroiditis are euthyroid, but some are hypothyroid. (See 'Chronic autoimmune thyroiditis (Hashimoto)' below.)

Specific antibody testing is directed by clinical evidence of hypo- or hyperthyroidism:

●Confirmed hypothyroidism – If the anti-TPO and/or anti-Tg antibody tests are negative and thyroid function tests confirm hypothyroidism, we suggest measurement of thyrotropin receptor antibodies (TRAb or TSHR-Ab) using a thyrotropin-binding inhibitory immunoglobulin (TBII) assay. This assay measures both blocking and stimulating antibodies and if positive in the setting of hypothyroidism, suggests the mechanism of the hypothyroidism may be TSH receptor-blocking antibodies. (See 'Chronic autoimmune thyroiditis (Hashimoto)' below.)

●Suspected or confirmed hyperthyroidism – For patients with suspected or confirmed hyperthyroidism (low TSH), we recommend measurement of TRAb using either a thyroid-stimulating immunoglobulin (TSI) assay or a TBII assay. A positive result in a patient with hyperthyroidism confirms the diagnosis of Graves disease. (See 'Graves disease' below.)

Ultrasonography — Although practice varies on this point, we obtain a thyroid ultrasound for most children with a goiter discovered by physical examination; the primary purpose is to obtain accurate baseline dimensions (transverse, depth, and longitudinal diameters are used to calculate volume). Sonography characteristics may also provide clues to the underlying etiology. As examples, chronic autoimmune (Hashimoto) thyroiditis typically shows a "moth-eaten" pattern of scattered hypo- or hyperechogenicity (image 1) and the presence of colloid cysts on ultrasonography supports the diagnosis of colloid goiter. We do not routinely do thyroid ultrasound on children with a goiter and a diagnosis of Graves hyperthyroidism. We also suggest ultrasonography for baseline evaluation of children with positive thyroid antibodies but without detection of goiter on examination, although, again, practice varies on this point. (See 'Chronic autoimmune thyroiditis (Hashimoto)' below and 'Colloid goiter' below.)

Ultrasonography is also useful to identify thyroid nodules or cysts not found on neck examination prompted by discovery of a goiter. In one single-center experience, thyroid nodules were detected by ultrasound examination in 15 percent of children with goiter [5]. Thyroid cysts are uncommon in children and may be either simple cysts or mixed solid and cystic nodules. Simple cysts are benign and do not require further evaluation. Mixed solid/cystic nodules are usually the result of hemorrhagic degeneration of a thyroid adenoma and may warrant further evaluation by FNA. FNA is also appropriate for some solid nodules with characteristics suggesting cancer risk (table 3). (See 'Further evaluation of nodules or cysts' below.)

Subsequent testing for selected patients

Tests of iodine status — Tests of iodine status should be performed if excessive iodine exposure is suspected from the history and may be performed if the child has otherwise unexplained hypothyroidism. The most accurate test to assess iodine status is measurement of 24-hour urinary iodine and creatinine. Measurement of a spot urine iodine and creatinine, yielding an iodine-to-creatinine ratio, or measurement of serum iodine levels may also be used to assess for iodine excess or deficiency.

Radionuclide uptake and scan — A radionuclide study is not indicated for most children and adolescents at discovery of a goiter. It may be indicated in selected hyperthyroid children, including those suspected to have Graves disease who present with a suppressed TSH level but with negative TRAb (TSI and/or TBII), and in all children with suspected autonomously functioning "hot" nodules or toxic multinodular goiter. We recommend iodine-123 (I-123) for diagnostic studies because it allows a quantitative measure of uptake, typically performed at 4 and 24 hours after administration (as opposed to iodine-131, which is used to treat certain forms of thyroid cancer). A precise quantitative measure of uptake is not possible if technetium-99m pertechnetate is used, because this isotope is not "organified," ie, does not attach to tyrosine residues on thyroglobulin.

The radionuclide uptake and scan helps to identify certain disorders:

●Nil or decreased radionuclide uptake – This result in a hyperthyroid patient suggests a "destructive thyroiditis" with autonomous release of stored thyroid hormones. This may occur in the hyperthyroid phase of chronic autoimmune (Hashimoto) thyroiditis (termed painless or silent thyroiditis) or the early phase of subacute granulomatous thyroiditis (de Quervain disease). Decreased radioactive iodine uptake also occurs in the late phase of Hashitoxicosis, as the gland undergoes destruction by the autoimmune thyroiditis [6]. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents", section on 'Destructive thyroiditis with thyrotoxic phase' and 'Subacute granulomatous thyroiditis (early)' below.)

●Elevated (or normal) radionuclide uptake with diffuse hyperplasia – This result in a hyperthyroid patient is consistent with Graves disease and supports that diagnosis even if TSI and/or TBII are negative. An elevated uptake also is reported in the early phases of Hashitoxicosis [6]; however, often this diagnosis is only apparent in hindsight as the thyroid function evolves from hyperthyroidism to hypothyroidism over a few months, owing to the destruction of the gland by the autoimmune process. (See 'Graves disease' below.)

●Focal radionuclide uptake – The finding of radionuclide uptake within a focal area ("hot nodule") with reduced or no uptake in the remainder of the gland is diagnostic of an autonomously functioning adenoma. More than one area of focal uptake is seen with toxic multinodular goiter.

Further evaluation of nodules or cysts — If a nodule or cyst is detected on ultrasonography that was performed because of the presence of a goiter, further steps (eg, observation versus FNA) depend on the size and ultrasound characteristics of the lesion. (See "Thyroid nodules and cancer in children", section on 'Evaluation of thyroid nodules'.)

We do not recommend FNA of simple cysts for diagnostic purposes. Aspiration of the cyst may be done for therapeutic purposes; the cyst may disappear completely if emptied, but the fluid often reaccumulates.

ESTABLISHING THE CAUSE — For diagnostic purposes, it is helpful to categorize the causes of acquired goiter depending on whether the patient is euthyroid (normal thyroid-stimulating hormone [TSH]), hypothyroid (elevated TSH), or hyperthyroid (low TSH) (table 1). However, for some disorders, thyroid function varies depending on the severity or stage of the disease. The results of the tests for antithyroid antibodies (antithyroid peroxidase [TPO] or antithyroglobulin [Tg]) and anti-TSH receptor antibodies (thyroid-stimulating immunoglobulin [TSI] or thyrotropin-binding inhibitory immunoglobulins [TBII]) can confirm the diagnosis in most cases.

Euthyroid goiter (normal TSH and free T4) — Among the causes of acquired goiter in children and adolescents, chronic autoimmune (Hashimoto) thyroiditis and colloid goiter are the most common in the United States. These disorders usually can be distinguished by measurement of antithyroid antibodies and ultrasonography.

Chronic autoimmune thyroiditis (Hashimoto) — Chronic autoimmune thyroiditis (also known as Hashimoto thyroiditis or chronic lymphocytic thyroiditis) is the most common cause of goiter in children in the United States and other iodine-sufficient populations. In certain parts of the world, eg, Southeast Asia, Africa, and the Western Pacific, iodine deficiency is a more common cause.

Chronic autoimmune thyroiditis typically presents as a firm, bosselated (bumpy), nontender goiter discovered incidentally by a parent or during a routine clinical examination [7]. The goiter is usually diffuse but may be irregular or even nodular. Most of these children are euthyroid, but some have subclinical or overt hypothyroidism [8] and, even less commonly, a few are hyperthyroid at presentation [6]. The most common manifestations of hypothyroidism in childhood are decreased height velocity, short stature, and delayed pubertal development. Autoimmune thyroiditis can also cause thyroid atrophy rather than goiter.

●Diagnosis – Chronic autoimmune thyroiditis is distinguished by the presence of antithyroid antibodies (TPO and/or Tg). Approximately 10 to 15 percent of children with this disorder have negative anti-TPO and anti-Tg antibodies [9] ("antibody-negative" autoimmune thyroiditis). If autoimmune thyroiditis is suspected in a child with goiter despite negative antithyroid antibodies, eg, with a family history of autoimmune thyroiditis, or a finding of acquired hypothyroidism, ultrasonography may help establish this diagnosis.

Ultrasonography typically shows scattered hypo- or hyperechogenicity, giving a "moth-eaten" or "Swiss cheese-like" appearance. If the initial ultrasound is normal, approximately one-half of these children will show typical ultrasound changes within seven months [10]. The ultrasound also helps to obtain baseline dimensions and check for nodules. Thyroid nodules were reported in 15 percent of children with goiter who underwent ultrasonography [5]. If any large nodules (>1 cm) are detected on ultrasonography, these should be further evaluated for thyroid cancer, regardless of the presence or absence of antithyroid antibodies. (See 'Further evaluation of nodules or cysts' above and 'Thyroid adenomas or carcinomas' below.)

Routine evaluation with a radionuclide uptake and scan generally is not indicated in these children [11]. If this test is performed during a hyperthyroid phase, iodine-123 (I-123) uptake typically will be reduced. (See 'Radionuclide uptake and scan' above.)

●Epidemiology – Approximately 1 to 2 percent of school-aged children have clinical manifestations of chronic autoimmune thyroiditis [7,12] and 5 to 6 percent have serologic evidence [13]. It is more common in females than males and more common in White children than in Black children. The disorder is especially common in children with certain chromosomal disorders, including trisomy 21 (Down syndrome) [14], Turner syndrome, and perhaps Klinefelter syndrome, and is an integral component of the autoimmune polyglandular syndromes. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Autoimmune thyroiditis'.)

●Management – Management of patients with chronic autoimmune thyroiditis depends upon thyroid function.

•Euthyroid patients – Treatment with levothyroxine is not routinely indicated for patients with autoimmune thyroiditis and normal thyroid function (normal TSH, thyroxine [T4], and free T4). However, thyroid function tests should be monitored, initially six months after diagnosis and then annually and treatment initiated if abnormalities develop, as outlined below.

•Overt hypothyroidism – Treatment with levothyroxine is indicated in children with a goiter and overt hypothyroidism, evidenced by elevated serum TSH (generally >10 mU/L) and low serum T4 or free T4. The purpose is to treat the hypothyroidism, but the treatment also tends to reduce goiter size [15]. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

•Subclinical hypothyroidism – Management is less clear for children with goiter and subclinical hypothyroidism, indicated by elevated TSH (often mild) and normal serum T4 or free T4. These patients are clinically euthyroid, but some (although, not all) progress to hypothyroidism. Practice varies regarding whether to initiate levothyroxine treatment for these patients. Most experts treat patients with TSH >10 mU/L. Initiating treatment ensures that the child maintains normal thyroid hormone levels during the critical period of growth and pubertal development and may also reduce goiter size. Many experts also treat patients with mild elevations (TSH 6 to 10 mU/L), while others will simply monitor thyroid function tests without initiating treatment. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

If levothyroxine treatment is initiated, we generally continue therapy until growth and pubertal development are complete, then do a trial off of treatment and recheck serum TSH and free T4 one month later to distinguish transient from permanent cases.

•Hyperthyroid patients – Occasionally, patients with chronic autoimmune thyroiditis present with hyperthyroidism characterized by thyrotoxic symptoms and low radioiodine uptake; this may represent a destructive thyroiditis, termed "painless" or "silent" thyroiditis. As described above, low uptake may also occur later in Hashitoxicosis with autoimmune destruction of the gland. Antithyroid drug treatment is not effective or indicated. Treatment with beta-adrenergic receptor blockers improves thyrotoxic clinical manifestations until the destructive thyroiditis resolves, generally within three months. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents", section on 'Destructive thyroiditis with thyrotoxic phase'.)

●Effect of levothyroxine on goiter – The primary purpose of levothyroxine treatment in patients is to treat hypothyroidism, if present. A few studies have examined the effect of treatment on goiter size.

The evidence for an effect on goiter size includes an observational study of children with chronic autoimmune thyroiditis and goiter (as defined by thyroid volume >2.0 standard deviation score [SDS] for age) that found that treatment with thyroid hormone (levothyroxine) for a median 2.8 years was associated with a significant decrease in goiter size [15]. A greater decrease was seen in hypothyroid children (-1.6 SDS), but thyroid volume also decreased in euthyroid children (-0.9 SDS). However, a direct effect of the drug is uncertain because it is impossible to separate treatment effects from the natural history of chronic autoimmune thyroiditis. A randomized study suggests that levothyroxine treatment may prevent development of goiter during the course of the disease. This study enrolled 50 children in Greece with chronic autoimmune thyroiditis but without goiter [16]. In the group randomized to thyroid hormone treatment for two years, thyroid volume decreased (baseline 1.1 SDS, after treatment 0.6 SDS), while in the control group, thyroid volume increased (baseline 0.9 SDS, after two years 2.0 SDS). Further studies are needed before a treatment recommendation can be made for this indication.

In summary, there is equivocal evidence that levothyroxine treatment may reduce goiter size in euthyroid children with chronic autoimmune thyroiditis. In general, it is not our practice to treat such children. If the decision is made to try levothyroxine treatment for this purpose, it is important to prevent overtreatment. Thyroid function tests should be monitored every three to six months and the levothyroxine dose adjusted as indicated to maintain normal TSH and free T4 levels.

In addition, we do not initiate levothyroxine for euthyroid children without antibody evidence for autoimmune thyroiditis and with no clear underlying etiology. We recommend observation with monitoring of thyroid function tests every three to six months.

Colloid goiter — Colloid goiter is characterized by negative antithyroid antibodies (TPO and Tg), normal TSH, and colloid cysts on ultrasonography. Although the thyroid gland is usually diffusely enlarged, it can be asymmetric or nodular.

Colloid goiters usually occur in adolescent females. The disorder may be familial, with an autosomal dominant pattern of inheritance. In a study of female twins in Denmark, for example, the cumulative concordance rates for goiter in monozygotic and dizygotic twins were 53 percent and 20 percent, respectively [17].

The cause of colloid goiter in children is not known. Histologic examination reveals flattened epithelium, variable follicular size, and dense colloid. These goiters usually gradually decrease in size over several years. As these patients are consistently euthyroid, levothyroxine therapy is not recommended.

Thyroid adenomas or carcinomas — If any large nodules (>1 cm) are detected on ultrasonography, these should be further evaluated for thyroid cancer, regardless of the presence or absence of antithyroid antibodies (see 'Further evaluation of nodules or cysts' above). In a report of 365 children with autoimmune thyroiditis, 115 (31.5 percent) had nodules [18]. Fine-needle aspiration (FNA) biopsy led to discovery of papillary thyroid cancer in 11 patients (3 percent).

Thyroid adenomas and carcinomas are uncommon and typically present as a solitary nodule or mass within a normal-sized thyroid gland, though they may be associated with a goiter. Multinodular goiter has been reported as the presenting feature in children with PTEN hamartoma tumor syndrome (Cowden syndrome) resulting from PTEN mutations and children with a DICER1 mutation, a familial condition that also predisposes to cysts or tumors in the lungs, kidneys, and gonads [19,20]. (See "Thyroid nodules and cancer in children".)

Thyroid cysts

●Thyroglossal duct cysts – These are congenital cysts of the thyroglossal duct. The cyst may be recognized at birth, but more often, it appears during childhood or later. (See "Approach to congenital goiter in newborns and infants", section on 'Thyroglossal duct cysts'.)

●Other cysts – Thyroid cysts are uncommon in children and may present as a neck mass or be identified incidentally on ultrasonography performed for goiter. Cysts may be simple or mixed solid and cystic nodules, which can be distinguished by ultrasonography. Simple cysts are benign. Complex cystic/solid nodules are usually the result of hemorrhagic degeneration of a thyroid adenoma. They warrant further evaluation by FNA if ≥1 cm in size or if they have other risk factors based on clinical context and/or ultrasound features. (See 'Ultrasonography' above and 'Further evaluation of nodules or cysts' above.)

Acute suppurative thyroiditis — Acute suppurative thyroiditis should be suspected in children with abrupt onset of painful, tender swelling of one lobe of the thyroid accompanied by fever, chills, sore throat, hoarseness, or dysphagia. Affected patients have negative TRAb (TSI and/or TBII), excluding Graves disease. TSH is normal in the majority; rarely, it is transiently suppressed due to destructive thyroiditis [21]. In those with suppressed TSH, if radionuclide uptake scanning is performed, I-123 uptake is low. (See 'Radionuclide uptake and scan' above.)

This disorder is caused by acute bacterial infection resulting in an abscess of the thyroid. The left lobe is more commonly involved (90 percent of cases) and a pyriform sinus fistula is usually present; this can be detected by barium swallow, computed tomography (CT), or magnetic resonance imaging (MRI) of the neck and, less frequently, by ultrasonography. Culture of aspirated material (eg, as from an abscess) may identify specific bacteria and guide antibiotic therapy. (See "Suppurative thyroiditis in children and adolescents".)

Hypothyroid goiter (elevated TSH, low or normal free T4)

Chronic autoimmune thyroiditis — The presence of antithyroid antibodies (TPO or Tg) indicates a diagnosis of chronic autoimmune (Hashimoto) thyroiditis. Although most patients with this disorder are euthyroid, it is also the most common cause of hypothyroid goiter in children and adolescents in the United States. Hypothyroidism is more common late in the disease course, a result of destruction and atrophy of the gland, but also occurs among the subset of patients who have TSH receptor-blocking antibodies. (See 'Chronic autoimmune thyroiditis (Hashimoto)' above.)

As noted above, this diagnosis is further supported by the characteristic finding of a "moth-eaten" appearance on ultrasonography; ultrasonography is also useful to establish baseline measurements and check for nodules to exclude the possibility of thyroid cancer. If radionuclide scanning is performed, I-123 uptake is variable and typically matches the TSH level: If the serum TSH is normal, the uptake is usually normal, whereas if the TSH is elevated, the uptake will be high-normal or slightly elevated (table 1). The scan picture will match the ultrasound image, with heterogeneous uptake.

Patients with overt hypothyroidism should be treated with levothyroxine according to standard protocols. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

Excess iodine or other goitrogens — In hypothyroid patients, the possibility of iodine excess may be suspected from the history and further evaluated by tests of iodine status. (See 'Tests of iodine status' above.)

The most common goitrogen ingested by children is iodine, most often in the form of iodine-containing expectorants for chronic reactive airway disease or cystic fibrosis, from drugs such as amiodarone, from "health food supplements" containing iodine, or from topical iodine antiseptics, such as povidone-iodine. Children living in a region with a high content of iodine in the drinking water (>300 ug/L) are at risk for goiter development [22]. Another source of iodine is kelp. Within these populations, most children with iodine-induced goiters probably have chronic autoimmune thyroiditis, and they develop a goiter because the damaged thyroid cannot adapt to a high iodine intake. Such patients have positive antithyroid antibodies (anti-TPO or anti-Tg) as well as laboratory evidence of iodine excess.

Similarly, the possibility of other goitrogens may be suspected from the history. As an example, lithium carbonate may cause hypothyroidism and goiter in children as well as in adults [23]. Interferon treatment, tyrosine kinase inhibitors, and immune checkpoint inhibitors may be associated with the development of thyroiditis and disturbances of thyroid function (hypo- or hyperthyroidism) and, in a few patients, the development of a goiter [24].

Certain foods (cassava and millet) contain goitrogenic substances. Consumed alone, these substances are unlikely to cause goiter, but they can contribute to goiter formation when iodine intake is marginal.

Cessation of the offending drug or food supplement should result in restoration of normal thyroid function and diminution of the goiter. Thyroid function generally recovers to normal within a few weeks after discontinuation of excess iodine without treatment. If the iodine-containing drugs or expectorants need to be continued for medical reasons, levothyroxine treatment is indicated. (See "Disorders that cause hypothyroidism", section on 'Drugs' and "Lithium and the thyroid", section on 'Goiter'.)

Iodine-deficiency goiter — In children with goitrous hypothyroidism who are from a geographical area with low iodine availability, children on parental nutrition lacking iodine, or those who are on a very restrictive diet, the goiter may be caused by iodine deficiency. Children with moderate or severe iodine deficiency and goiter have subclinical or overt (mild) hypothyroidism, but their serum triiodothyronine (T3) concentrations may be normal or high because of preferential thyroidal T3 secretion. The diagnosis can be confirmed by tests of iodine status in urine (or in blood). Other common causes of goiter should also be excluded with thyroid antibody tests and ultrasonography, although these tests may not be necessary in populations with high prevalence of iodine deficiency. (See 'Tests of iodine status' above.)

Approximately 1.88 billion people worldwide are at risk for iodine deficiency and, therefore, for iodine-deficiency (endemic) goiter. Data and a map indicating areas of iodine deficiency worldwide are available from the Iodine Global Network website. Iodine supplementation, primarily through iodized salt, has eradicated iodine-deficiency goiter in the United States. However, median urinary iodine excretion in adults decreased by approximately 50 percent in the United States from the 1970s to the 1990s (from 320 to 145 mcg/L [2.6 to 1.2 micromol/L]), indicative of a substantial decline in iodine intake [25]. Values less than 50 mcg/L (0.4 micromol/L) are associated with goiter, raising the possibility of recrudescence of endemic goiter. It appears that this decrease has stabilized as a more recent survey (2011 to 2014) reports median urinary iodine excretion of 133 mcg/L [26]. Eradication of endemic iodine-deficiency goiter can take up to a decade after initiation of iodine prophylaxis in a geographic region [27]. In children with severe iodine deficiency, concomitant vitamin A deficiency may increase TSH stimulation, which increases the odds for goiter formation and reduces the risk for hypothyroidism [28]. (See "Iodine deficiency disorders".)

Even in iodine-sufficient countries, a food-restricted diet low in iodine has been reported to cause goiter and hypothyroidism, as in a report of a four-year-old child [29].

Patients with iodine deficiency can be treated with either iodine or levothyroxine.

Iodine-deficiency goiter can occur in neonates, but it is rare. Many neonates and infants with endemic iodine deficiency are hypothyroid but do not have a goiter. (See "Approach to congenital goiter in newborns and infants", section on 'Iodine excess'.)

Thyroid infiltrative disease — The possibility of thyroid infiltrative disease should be suspected in children with euthyroid or hypothyroid goiter and a history of Langerhans cell histiocytosis or cystinosis. These diseases may involve the thyroid, with histiocytic infiltration [30] and cystine crystal deposition, respectively. This may result in goiter and, if severe enough, hypothyroidism. Children known to have these conditions should have periodic (annual) measurements of serum TSH and free T4. If hypothyroidism develops, they should be treated with levothyroxine according to standard protocols. (see "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'). Histiocytosis also can cause central hypothyroidism. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis" and "Cystinosis".)

Subacute granulomatous thyroiditis (late) — Subacute granulomatous thyroiditis, also known as de Quervain disease, may be associated with elevated TSH late in the disease course, reflecting hypothyroidism. Typically associated with a viral infection, subacute thyroiditis has been reported in an adolescent following a coronavirus disease 2019 (COVID-19) infection [31,32]. Patients have a history of painful goiter, and antithyroid antibodies (TRAb [TSI and/or TBII]) are negative. Earlier in the disease course, TSH tends to be low, often with symptoms of thyrotoxicosis, then progresses to euthyroidism and then, in some cases, to hypothyroidism. If hypothyroidism develops, the patient should be treated with levothyroxine according to standard protocols. Since most recover to euthyroidism, patients can be trialed off of treatment after a few months, with measurement of TSH and free T4 approximately one month later. (See 'Subacute granulomatous thyroiditis (early)' below and "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

Hyperthyroid goiter (suppressed TSH, elevated free T4 and total T3) — Most children with goiter and hyperthyroidism have Graves disease, which can be diagnosed by specific thyroid autoantibody testing. Less common causes are toxic adenoma or multinodular goiter, which are identified by radioactive iodine uptake.

Graves disease — Graves disease is the most common cause of hyperthyroid goiter in children and adolescents. The diagnosis should be suspected in a patient presenting with diffuse goiter and evidence of hyperthyroidism or Graves ophthalmopathy on physical examination (see 'Physical examination' above). The diagnosis is established by the presence of autoantibodies that bind to and stimulate the TSH receptor (TSI and/or thyrotropin binding inhibitor immunoglobulin [TBII]).

Graves disease occurs in approximately 0.02 percent of children (1:5000), mostly in adolescent females. As in adults, the onset is usually insidious, but, over time, clinical manifestations of hyperthyroidism become obvious [33]. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

If TRAb (TSI and/or TBII) is negative but Graves disease is still suspected clinically, the next step is to undertake I-123 uptake and scan. Most children with Graves disease will have elevated uptake at 4 and 24 hours following administration of I-123, but even quantitatively, "normal" uptake in the setting of a low TSH indicates abnormal thyroid autonomy consistent with Graves disease. The scan picture will show diffuse uptake throughout the thyroid gland. (See 'Radionuclide uptake and scan' above.)

Management of Graves disease is discussed separately. (See "Treatment and prognosis of Graves disease in children and adolescents".)

Toxic adenoma or multinodular goiter — The possibility of an autonomously functioning thyroid adenoma or multinodular goiter should be suspected in patients with hyperthyroidism and negative TRAb. Autonomous nodules are usually large enough to be palpable by the time they cause hyperthyroidism [34]. The diagnosis is established by an I-123 uptake and scan. An autonomously functioning nodule appears as an area of increased uptake within the nodule and decreased or absent uptake in the remainder of the gland. Children with toxic multinodular goiter will show discrete areas of increased uptake throughout the gland. (See 'Radionuclide uptake and scan' above.)

●In some cases, the multinodular goiter is part of McCune-Albright syndrome, which is caused by somatic activation of the guanine nucleotide-binding protein (G protein) stimulatory alpha subunit that activates adenylyl cyclase [35]. These mutations result in thyroid hyperplasia or formation of nodules and, ultimately, in toxic nodular goiter, typically presenting in childhood [36]. Affected patients also may present with precocious puberty and features of fibrous dysplasia. (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

●Other children with toxic adenoma or multinodular goiter have germline mutations of the TSH receptor gene [37].

The hyperthyroidism associated with these conditions is permanent. Patients respond to antithyroid drug treatment but will eventually require more definitive treatment, such as radioactive iodine ablation or thyroidectomy. Treatment options for these conditions are discussed separately. (See "Treatment and prognosis of Graves disease in children and adolescents".)

Chronic autoimmune thyroiditis with thyrotoxic phase ("painless" or "silent" thyroiditis) — Approximately five percent of children with autoimmune thyroiditis have an associated thyrotoxic phase. Most commonly, this is a "destructive" thyroiditis with unregulated release of preformed, stored thyroid hormone (so-called painless or silent thyroiditis). It typically occurs at the initial presentation of autoimmune thyroiditis, though it can manifest later in the disease course. At presentation, patients have clinical features of thyrotoxicosis, with a nontender (or mildly tender) goiter to palpation and without features of Graves ophthalmopathy. Laboratory testing shows a suppressed serum TSH, elevated free T4 and T3, positive anti-TPO and/or anti-Tg antibodies, and negative TRAb. The diagnosis is confirmed by decreased I-123 uptake. (See 'Radionuclide uptake and scan' above.)

The thyrotoxic phase is transient, typically lasting several weeks to three months.

Antithyroid drug treatment is not indicated or effective for painless thyroiditis. Symptomatic patients may be treated with a beta-adrenergic receptor blocker until the thyrotoxic phase resolves. Patients should have thyroid function tests monitored at approximately monthly intervals since some patients recover to euthyroidism, but others will become hypothyroid. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents", section on 'Destructive thyroiditis with thyrotoxic phase'.)

Hashitoxicosis — The term "Hashitoxicosis" was originally coined in the 1960s and 1970s, with a report of adult patients with coexistent Hashimoto thyroiditis and Graves disease [38]. These patients presented with hyperthyroidism and elevated radioactive iodine uptake and were responsive to antithyroid drug treatment; most had evidence of Graves eye disease. Over a few months, the hyperthyroidism transitioned to hypothyroidism due to autoimmune destruction of the thyroid gland.

In children, Hashitoxicosis is also difficult to distinguish from Graves disease initially. Affected children present with goiter, thyrotoxicosis (suppressed TSH), and positive anti-TPO and anti-Tg antibodies [6]. If radioactive iodine uptake is elevated, the thyrotoxicosis is due to thyroid hormone overproduction. By contrast, low or nil uptake on the scan indicates destructive thyroiditis. (See 'Radionuclide uptake and scan' above and 'Subacute granulomatous thyroiditis (early)' below.)

Most patients with elevated radioactive iodine uptake will respond well to antithyroid drugs (see "Treatment and prognosis of Graves disease in children and adolescents"). The diagnosis of Hashitoxicosis becomes apparent only when autoimmune hypothyroidism develops. Children with low or nil uptake are typically managed with beta adrenergic receptor blocker drugs alone. Patients should have thyroid function tests monitored at approximately monthly intervals since some patients recover to euthyroidism but others will become hypothyroid.

Subacute granulomatous thyroiditis (early) — Subacute granulomatous thyroiditis, also known as de Quervain disease, is uncommon in children. It should be suspected in any child with a viral prodrome followed by a painful, tender goiter with hyperthyroidism (suppressed serum TSH) and negative TRAb (TSI and/or TBII). The diagnosis can be confirmed by radionuclide uptake and scan, in which I-123 uptake is decreased. (See 'Radionuclide uptake and scan' above.)

The course of this disorder in children is similar to that in adults, with an early, painful hyperthyroid phase, followed by euthyroid and then hypothyroid phases (see 'Subacute granulomatous thyroiditis (late)' above) and finally recovery. The thyrotoxicosis in the early phase is a result of release of preformed thyroid hormone due to "destructive thyroiditis" (rather than the increased thyroid hormone production seen with Graves disease).

Treatment consists of a nonsteroidal antiinflammatory drug or, in very symptomatic patients, prednisone. Antithyroid drug treatment is not effective or indicated. If patients have symptoms of hyperthyroidism with a suppressed serum TSH level, they may be treated with a beta-adrenergic receptor blocker until the destructive thyroiditis resolves, generally within three months. During the hypothyroid phase, patients may require thyroid hormone replacement. (See "Subacute thyroiditis".)

Goitrogens/drugs — Certain drugs, including lithium, tyrosine kinase inhibitors, immune checkpoint inhibitors, and amiodarone (from iodine excess), may be associated with thyroid dysfunction. As noted above, these drugs most commonly are associated with hypothyroidism (see 'Excess iodine or other goitrogens' above), though they may also be associated with hyperthyroidism resulting from "destructive thyroiditis" and release of stored thyroid hormone. Clinically thyrotoxic patients may be managed with a beta-adrenergic receptor blockade.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypothyroidism" and "Society guideline links: Hyperthyroidism" and "Society guideline links: Pediatric thyroid disorders".)

SUMMARY AND RECOMMENDATIONS

●Common causes of goiter – In the United States and other iodine-sufficient areas of the world, the most common causes of acquired goiter are chronic autoimmune (Hashimoto) thyroiditis and colloid goiter. Worldwide, goiter due to iodine deficiency is far more common.

●Initial laboratory tests and diagnostic implications – For diagnostic purposes, it is helpful to categorize the causes of acquired goiter depending on whether the patient is euthyroid (normal thyroid-stimulating hormone [TSH]), hypothyroid (elevated TSH), or hyperthyroid (low TSH) (table 1). However, for some disorders, thyroid function varies depending on the severity or stage of the disease. (See 'Establishing the cause' above.)

Common causes of acquired goiter are:

•Autoimmune thyroiditis – Children with autoimmune thyroiditis usually are euthyroid and present with a firm, nontender goiter discovered incidentally by a parent or during a routine physical examination. Some children have subclinical or overt hypothyroidism or, less commonly, hyperthyroidism. The diagnosis is confirmed by the presence of antithyroid antibodies (antithyroid peroxidase [TPO] or antithyroglobulin [Tg]), but 10 to 15 percent of patients with this disorder have negative antibody testing. Management depends on thyroid function; patients who are hypothyroid should be treated with levothyroxine according to standard protocols. (See 'Chronic autoimmune thyroiditis' above and 'Thyroid antibody tests' above.)

•Colloid goiter – Children with colloid goiters have normal thyroid function and undetectable/very low serum antithyroid antibody titers. These are diffuse goiters, usually occurring in adolescent females. They may be familial, but their cause is unknown. These goiters usually gradually decrease in size over several years, without treatment. (See 'Colloid goiter' above.)

•Graves disease – Children who present with a goiter and hyperthyroidism most likely have Graves disease; less commonly, they may have chronic autoimmune thyroiditis with a thyrotoxic phase ("Hashitoxicosis" or painless thyroiditis), a toxic adenoma, or toxic multinodular goiter. (See 'Graves disease' above and 'Toxic adenoma or multinodular goiter' above.)

●Ultrasonography and further steps – In our practice, we perform ultrasonography in most children with goiter discovered by physical examination to obtain accurate baseline dimensions. Sonographic characteristics also may help identify the underlying etiology.

•Indications – Ultrasonography should be performed for children with palpable thyroid nodules, asymmetry of the gland, or suspicious cervical adenopathy. In addition, we obtain a thyroid ultrasound for most children with a goiter, although practice varies on this point.

If autoimmune thyroiditis is suspected despite negative antithyroid antibodies (eg, due to goiter and acquired hypothyroidism), ultrasound may help establish this diagnosis (image 1). (See 'Ultrasonography' above and 'Chronic autoimmune thyroiditis (Hashimoto)' above.)

•Next steps – If a nodule or cyst is detected on ultrasonography that was performed because of the presence of a goiter, further steps (eg, observation versus fine-needle aspiration [FNA]) depend on the size and ultrasound characteristics of the lesion. (See 'Ultrasonography' above and "Thyroid nodules and cancer in children".)

Thyroid cysts are uncommon in children; they are typically discovered on examination and confirmed by ultrasonography. Simple cysts are benign, but mixed solid/cystic nodules may require further evaluation. (See 'Thyroid cysts' above and 'Further evaluation of nodules or cysts' above.)

●Radionuclide uptake and scan – While performance of a radionuclide uptake and scan is not necessary for management of most children with a goiter, it is indicated in a few situations. In children who present with a goiter and hyperthyroidism with low serum TSH, and who have undetectable TSHR-stimulating antibodies, high I-123 uptake is likely diagnostic of Graves disease, while low or absent uptake is diagnostic of some form of destructive thyroiditis. Uptake in a localized nodule or in multiple areas of the thyroid is diagnostic of an autonomous "hot" nodule or toxic multinodular goiter, respectively. (See 'Radionuclide uptake and scan' above.)