Treatment and prognosis of Graves disease in children and adolescents

INTRODUCTION — Hyperthyroidism in children and adolescents has unique effects on growth and development, in addition to causing many of the same symptoms that it does in adults. Graves disease is by far the most common cause of hyperthyroidism in this age group, accounting for more than 95 percent of cases [1]. Nearly all children with Graves disease have a diffuse goiter; Graves ophthalmopathy also may be present but is less severe than in adults.

The treatment and prognosis of Graves disease in childhood and adolescence will be discussed here. The clinical manifestations and diagnosis are presented separately. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

Rarely, conditions other than Graves disease may cause hyperthyroidism in children. These include autoimmune thyroiditis (also known as chronic lymphocytic or Hashimoto thyroiditis); subacute granulomatous thyroiditis (de Quervain disease); solitary hyperfunctioning thyroid nodules or toxic multinodular goiter; pituitary thyroid-stimulating hormone (TSH)-secreting adenoma; and hyperthyroidism induced by iodine, neck trauma, or radiation. Treatment of these conditions is similar to that for adults, except that children with nodular goiters are generally treated with surgery rather than radioactive iodine (RAI). (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

SELECTION OF TREATMENT

Children and adolescents with Graves hyperthyroidism can be treated with an antithyroid drug, radioactive iodine (RAI), or thyroidectomy. The choice of therapy is determined by individual consideration of the risks and benefits of the three treatment modalities (table 1). Regardless of the choice of treatment, all patients will require lifelong monitoring. An overview of treatment is shown in the algorithm (algorithm 1).

Most pediatric endocrinologists recommend antithyroid drug therapy as initial treatment, in the hope that the patient will have a remission of the Graves disease and therefore will remain euthyroid after treatment is discontinued. RAI therapy is generally used for children who do not achieve a permanent remission after a period of treatment with an antithyroid drug or for those who experience serious adverse effects necessitating discontinuation of antithyroid drug treatment. RAI also may be used as initial treatment for children older than 10 years [2]. Surgical near-total thyroidectomy is an equally effective and safe treatment.

The primary considerations for each of these therapies are:

●Antithyroid drugs are the best-established treatment in the pediatric age group and provide a chance of permanent remission with euthyroidism. Improvement is gradual, the course of treatment is long, and patients must be monitored for potential side effects.

●RAI (if given in a sufficiently high dose) permanently cures hyperthyroidism, replacing it with hypothyroidism, which requires lifelong thyroid hormone replacement therapy. Although there are general concerns about the radiation exposure, small studies in children have not shown increased long-term risks of thyroid cancer or other cancers.

●Surgery provides the most rapid resolution of hyperthyroidism and avoids the theoretical risk of radiation exposure. The patient is exposed to modest surgical risks, is rendered hypothyroid, and requires lifelong thyroid hormone replacement therapy.

Details about each of these treatments are discussed in the following sections.

ANTITHYROID DRUGS — Most children and adolescents with Graves hyperthyroidism respond well to an antithyroid drug, with 87 to 100 percent becoming euthyroid within a few weeks to a few months [2-6]. We recommend using methimazole (MMI; 0.25 to 1.0 mg/kg per day). Propylthiouracil (PTU; 5 to 10 mg/kg per day) is also effective but has more frequent and severe side effects, including a small risk of severe hepatotoxicity [7,8]. Because of these safety concerns, the Endocrine Society (ES) and the American Thyroid Association (ATA) and European Thyroid Association (ETA) recommend against the use of PTU as first-line treatment for Graves disease in children [9-11] and the US Food and Drug Administration (FDA) has issued a boxed warning [12]. (See 'Side effects' below and "Thionamides: Side effects and toxicities" and "Thionamides in the treatment of Graves' disease".)

Initiating and adjusting therapy — Before initiating therapy, we perform laboratory screening with a white blood cell (WBC) count and differential, along with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) concentrations [13]. The goal is to determine whether there are baseline abnormalities prior to beginning therapy, such as the modest decreases in WBC and elevations in liver enzymes that can be caused by hyperthyroidism itself.

●Dosing – We choose an initial MMI dose between 0.25 and 1.0 mg/kg/day (given once daily or in two divided doses), based on clinical severity, size of goiter, and biochemical severity. Patients with mild features of hyperthyroidism, a small goiter, and milder elevations of serum free T4 (thyroxine) and T3 (triiodothyronine) are started at the lower end of the dose range (around 0.25 mg/kg/day). Patients with more severe clinical features of hyperthyroidism, a large goiter, and more severe elevations of serum free T4 and T3 are started at the higher end of the dose range (0.5 to 1.0 mg/kg/day). Children younger than seven years of age typically also require this higher dose [14]. Since MMI is available as 5 mg or 10 mg tablets, for practical purposes, we round off the dose so that whole or one-half tablets can be used.

Subsequently, we adjust the MMI dose based on serial measurements of serum free T4 and total T3. We measure these every four to six weeks initially. We measure total T3 rather than free T3 because assays for free T3 are less accurate, and age-reference ranges for children are still being established. If these values remain elevated, then we increase the dose of MMI by approximately 0.25 mg/kg increments (again rounding the dose to whole or one-half tablets) until thyroid function is normal. Serum thyroid-stimulating hormone (TSH) typically remains suppressed until thyroid function normalizes, and it may remain suppressed for several months even after a patient becomes euthyroid. For this reason, we do not measure it until a patient becomes euthyroid, but some clinicians prefer to measure TSH with all monitoring blood draws. After thyroid function has normalized, follow-up visits, with measurement of serum free T4, T3, and TSH, can be scheduled at three- to four-month intervals. If the free T4 and total T3 levels show a downward trend and fall below the normal range, typically associated with an elevated TSH level, the dose is titrated down.

●Monitoring – If a patient develops a febrile illness or pharyngitis, antithyroid drug treatment (usually MMI) should be stopped immediately and WBC and differential measured. We recommend giving patients and parents or caregivers written instructions that describe these guidelines. If the granulocyte count is normal, antithyroid drug treatment may be restarted. This is important because a potential complication of antithyroid drug treatment is a drop in WBC; rarely, agranulocytosis or even pancytopenia develop, which can be life-threatening if not detected promptly [15]. If the granulocyte count is low (<1500/mm³) but not meeting criteria for agranulocytosis (ie, <500/mm³), we hold the MMI, monitoring the WBC twice weekly; these counts usually recover spontaneously within one to two weeks [16]. Once the granulocyte count is >1500/mm³, we restart MMI. Agranulocytosis (<500/mm³) is a contraindication to future antithyroid drug treatment [10]. Routine (rather than symptom-driven) monitoring of WBC is not recommended, because of the rarity of agranulocytosis and its sudden onset, which is generally associated with symptoms [10].

Similarly, we remeasure liver enzymes and serum bilirubin only if we note any clinical evidence of liver disease, such as jaundice, and not on a routine basis. (See "Thionamides: Side effects and toxicities" and "Drug-induced neutropenia and agranulocytosis".)

Side effects — MMI and PTU are associated with similar types of side effects. However, side effects tend to be more frequent and more severe with PTU [17]. Because of these safety concerns, we recommend against the use of PTU as first-line treatment for Graves disease in children, consistent with positions of the ES, ATA, FDA, and ETA [9-11]. PTU may be reserved for children who experience a minor side effect with MMI that is not a contraindication to continued antithyroid drug use and for whom RAI or surgery are not treatment options [10].

Minor adverse effects include papular or urticarial skin rashes, arthralgias, nausea, and abnormal taste sensation and are more common with PTU than with MMI (30 versus 13 percent in one series) [17]. In a series of 100 patients treated with MMI, the following minor side effects were reported: pruritus and hives (8 percent), diffuse arthralgia (3 percent), neutropenia (2 percent), and Stevens-Johnson syndrome and cholestatic jaundice (1 percent each) [18]. In patients who have one of these minor side effects, we discontinue the drug for a few days until the symptom subsides and then resume it, with monitoring for recurrence.

Major adverse effects include agranulocytosis (granulocyte count <500/mm³), vasculitis (lupus-like syndrome), hepatitis, and liver failure:

●Agranulocytosis occurs in 0.1 to 0.5 percent of patients treated with either PTU or MMI, although the risk appears to be dose-related for MMI but not for PTU [15,17]. If agranulocytosis occurs, it usually develops within the first 90 days after starting an antithyroid drug (85 percent of patients) [19].

●Antineutrophil cytoplasmic antibodies (ANCA), markers of vasculitis, are more common with PTU treatment [20,21]. A review reported that ANCA are present in 4 to 64 percent of patients on PTU and 0 to 16 percent of patients on MMI; however, only approximately 15 percent (1 in 6) of ANCA-positive patients develop clinical evidence of vasculitis [22].

●Severe hepatitis develops in up to 0.1 percent of children treated with PTU, with liver failure occurring in 1:2000 to 1:4000 [7,17]. Almost all cases of severe hepatitis have been associated with PTU treatment. Routine biochemical surveillance of liver function probably is not effective in avoiding the risk of liver failure.

In any patient who has a major side effect, the drug should immediately be discontinued; the patient should be treated with RAI or surgery instead of antithyroid medication. (See "Thionamides: Side effects and toxicities".)

Adolescent females of reproductive age should be warned about the risks of birth defects reported with antithyroid drug use during pregnancy and provided with counseling about contraceptives as needed [23]. Birth defects in babies born to mothers who take MMI and PTU in the first trimester occur at approximately twice the rate of a control population [24]. MMI is associated with an embryopathy characterized by cutis aplasia, congenital heart defects (septal defects) [25], urinary tract malformations, and omphalocele; PTU is associated with malformations of the face and neck and urinary tract malformations [26].

Adjunctive therapies

Adding beta blockers — Patients who develop prominent symptoms of adrenergic overactivity, such as palpitations and tremor, can be treated with beta blockers until thyroid hormone levels decline in response to the antithyroid drug therapy [16]. We suggest atenolol because it is cardioselective and therefore has reduced risk of bronchospasm as compared with other beta blockers. In addition, it is administered once daily, resulting in better compliance. The typical dose of atenolol for children and adolescents is 1 to 2 mg/kg daily. Propranolol, which has the potential benefit of decreasing T4 to T3 conversion, is preferred by some clinicians. Propranolol, at a dose of 0.5 to 2.0 mg/kg daily, is divided into three or four doses daily.

Adjunctive thyroxine: Not recommended — We do not recommend adjunctive treatment with thyroxine during MMI therapy (the so-called "block and replace" method), consistent with more current guidelines [27]. Adding thyroxine to the treatment regimen does not affect the likelihood of sustained remission [28-30] but does make it more difficult to judge when a remission is likely to have occurred and, therefore, when the antithyroid drug can be discontinued. In addition, patients managed with "combination" therapy are more likely to be treated with a higher dose of MMI, exposing them to the dose-related side effects of MMI.

Stopping therapy — There are two general approaches to predict whether a child or adolescent will enter a remission after discontinuing MMI treatment (defined as staying euthyroid for one year after discontinuation of the antithyroid drug):

●Dose titration method – My practice is to use dose titration to determine when to stop MMI therapy, rather than giving the drug for an arbitrary time period (as is often done in adults). As the hyperthyroidism improves with therapy, I gradually reduce the dose to maintain normal levels of free T4, total T3, and TSH (algorithm 1). When only a low dose is needed to maintain a euthyroid state (eg, 2.5 to 5 mg of MMI), which typically occurs with a decrease in size of the thyroid gland, I stop the drug and follow the patient closely, as described below (see 'Lifelong monitoring' below). Using this approach, a typical course of antithyroid drug treatment is approximately four to five years [6]. The course is shorter in some patients, while others continue treatment for as long as 8 to 10 years. This practice is supported by several reports demonstrating that remission rates improve with long-term treatment. (See 'Remission rate' below.)

●Antibodies to the TSH receptor (TSHR-Ab) titers – Alternatively or in addition, TSHR-Ab can be used to help determine whether to stop MMI. If a patient has a positive TSHR-Ab titer, remission is very unlikely; in one study, 100 percent of children who relapsed after stopping antithyroid drug treatment had detectable TSHR-Ab [31]. Thus, in children with a positive TSHR-Ab, we recommend continuing treatment. Children with a negative TSHR-Ab have a good chance to enter remission, but this test is not a perfect predictor. In the same study, 75 percent of patients with undetectable TSHR-Ab went into a remission, but 25 percent relapsed. Thus, if a decision is made to stop MMI treatment, thyroid function tests should be rechecked four to six weeks later, then every three to four months for the next year.

Remission rate — The rate of remission of Graves hyperthyroidism in children and adolescents (defined as the proportion of patients who remain euthyroid for at least 12 months after discontinuation of antithyroid drug therapy) varies from 25 to 65 percent in different series [2-6,32,33].

In children, prolonged courses of antithyroid drugs are often necessary and efficacious. Many pediatric endocrinologists prescribe antithyroid drugs for many years until a remission occurs, providing this continues to be the preferred treatment choice of the patient and parents and no major side effects occur. In pediatric patients, long-term treatment for up to 10 years appears to improve remission rates. This was shown in a randomized trial that compared long-term therapy with MMI (mean 109 months) to short-term therapy (18 to 24 months) [34]. Among children treated with long-term therapy, the Graves disease remained in remission in 92 percent of subjects one year after stopping therapy and 88 percent of subjects four years after stopping therapy, compared with 46 and 33 percent, respectively, for those treated with short-term therapy. By contrast, studies in adults indicate that the probability of remission is not improved if therapy is continued beyond 18 months [35].

Several previous studies also have demonstrated efficacy and relative safety of long-term antithyroid drug treatment in children and adolescents with Graves disease, although none achieved efficacy as high as that demonstrated in the randomized trial above. In a report of treatment of a large group of children from France (n = 154), estimated remission rates were 20, 37, 45, and 49 percent after 4, 6, 8, and 10 years of follow-up, respectively [36]. In a long-term study from Japan (n = 1138), 46.2 percent achieved a remission after a median treatment period of 3.8 years (range 0.3 to 24.8 years) [37].

Predictors of remission in one multicenter trial were lower thyroid hormone concentrations at presentation, older age, and euthyroid status after three months of antithyroid drug therapy [38]. Similarly, another series found that prepubertal children may take longer to enter remission than pubertal children (median time to remission eight versus four years) and are also less likely to enter remission even after prolonged treatment [39]. In two retrospective studies, smaller goiter size and higher body mass index were predictors of an early remission [40,41].

Patients who enter remission need lifelong monitoring after antithyroid drugs are stopped. (See 'Lifelong monitoring' below.)

Management of patients who do not enter remission — Approximately one-half of children will achieve a remission if treated long term with MMI, as noted in the section above. For this reason, we do not recommend a trial off of MMI after an arbitrary period of treatment, as is common in adults, and we prescribe MMI indefinitely (see 'Stopping therapy' above). However, some patients who do not achieve a remission while on antithyroid drug therapy may eventually choose to proceed to a definitive treatment (eg, when leaving home for college). At this point, most select RAI treatment, while some choose surgery.

Management of patients who relapse — Once remission occurs, the relapse rate in children varies from 3 to 47 percent in different series [2-6]. Most relapses occur within one year, but later relapses do occur. The risk of relapse is higher in patients with higher initial free T4 and in those with African or Asian heritage compared with White patients; the risk decreases with increasing age and with longer duration of antithyroid drug therapy [42]. Children who relapse can be treated with any of the same three treatment modalities offered to newly diagnosed patients (ie, resuming MMI, or moving on to RAI or surgery). The choice of treatment is usually driven by patient and parent preference. Younger patients and those previously treated with antithyroid drugs for shorter periods are usually restarted on MMI.

RADIOACTIVE IODINE

Patient selection and dose — RAI (iodine-131) therapy is an effective alternative treatment for children and adolescents with Graves hyperthyroidism (algorithm 1). We recommend it as secondary therapy for patients who have recurrent hyperthyroidism after long-term treatment with an antithyroid drug who request definitive treatment and for those who have a major side effect while receiving an antithyroid drug. However, some pediatric endocrinologists consider it the initial treatment of choice in older children and adolescents [2,43,44]. (See "Radioiodine in the treatment of hyperthyroidism".)

●Patient selection – RAI usually should be restricted to children older than 10 years of age, consistent with guidelines from the American Thyroid Association (ATA), American Association of Clinical Endocrinologists (AACE) and European Thyroid Association (ETA) [11,27]. The guidelines further recommend that RAI should not be used in children younger than five years of age, and that if it is used in children between 5 and 10 years of age, the total dose should be limited, as discussed below. This recommendation is based on observations suggesting that the young thyroid gland may be particularly sensitive to radiation, raising the theoretical concern that young children might therefore have an increased risk for thyroid cancer after radiation exposure (see 'Other side effects' below). For children with a very large goiter, surgery may be more effective than RAI, as discussed below. (See 'Surgery' below.)

RAI should not be selected for children who have evidence for a "destructive" form of hyperthyroidism, as is usually the case with thyrotoxicosis resulting from Hashitoxicosis. Most children with Hashitoxicosis will have a negative thyroid-stimulating immunoglobulin (TSI) test and RAI uptake will be low or nil, separating them from children with Graves disease. However, in some cases, it may be impossible to distinguish all those with Hashitoxicosis from Graves disease initially because some children with Hashitoxicosis may have positive TSI and elevated 24-hour iodine-123 uptake at presentation [45]. During the hyperthyroid phase, clinical clues that suggest Hashitoxicosis rather than Graves disease include relatively rapid resolution of their hyperthyroidism during treatment with antithyroid drugs. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents", section on 'Destructive thyroiditis with thyrotoxic phase'.)

●Dose – We and many other endocrinologists, including published guidelines, now recommend relatively high doses of RAI (eg, 200 to 300 microCi/gram of thyroid tissue [11,27,46], except for children between 5 and 10 years, the total dose should be limited to <10 milliCi). This dose leads to permanent resolution of the hyperthyroidism in a high percentage of patients; in addition, ablation of the gland likely will reduce the risk of future thyroid tumor development. This dose will lead to hypothyroidism in most patients, necessitating lifelong thyroid hormone replacement. In order to get a quantitative assessment of thyroid gland weight, guidelines recommend obtaining an ultrasound examination prior to RAI administration, rather than an estimate based on neck palpation (assume 1 cc = 1 gram) [27]. In addition, we undertake a diagnostic iodine-123 uptake. The fractional uptake is used in the formula to calculate the treatment dose:  

Treatment dose = 0.2 to 0.3 milliCi × weight in grams ÷ fractional uptake

Some clinicians prefer to use a "fixed dose" of iodine-131 rather than using the above formula. In one study, a fixed dose of 14.7 milliCi (range 13.8 to 15.6 milliCi) produced permanent hypothyroidism in all patients at an average of 77 days (range 28 to 194 days) after receiving the RAI [47]. Antithyroid drugs should be stopped seven days before RAI administration to permit adequate uptake of RAI by the thyroid [48].

Hypothyroidism — As in adults, the major consequence of RAI treatment is hypothyroidism. With the conventional doses used in the past, between 20 to 40 percent of patients become hypothyroid in the first year and 2 to 3 percent per year thereafter. With the higher doses described above, virtually all will become hypothyroid. (See "Radioiodine in the treatment of hyperthyroidism".)

We measure serum free T4 and TSH six weeks after RAI treatment and then at three-month intervals. When hypothyroidism develops, it is treated with thyroid hormone replacement, similar to other causes of hypothyroidism. Laboratory monitoring can be performed less frequently thereafter, usually every six months. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

Other side effects — There is no evidence that RAI causes or worsens Graves ophthalmopathy in children or adolescents, as has been described in adults [49-51]. Immediate side effects of RAI include local pain associated with radiation thyroiditis and the rare risk of "thyroid storm" [52,53]. Because the antithyroid action of RAI is relatively slow, patients with many or bothersome symptoms may benefit from treatment with a beta blocker (atenolol preferred) or an antithyroid drug for four to eight weeks after being given a therapeutic dose of RAI.

Long term, the reservations about the use of RAI in children and adolescents have centered on the possibility that the treatment could result in thyroid cancer or other neoplasms, affect fertility, or damage sperm or ova, thereby affecting the patient's offspring. The concern about thyroid cancer arose from observations of the increased incidence of thyroid cancer in infants and children who were exposed to external radiation during the 1940s and 1950s for a variety of "indications" including enlarged tonsils, croup (large thymus), or acne [54]. In addition, there was a dramatic rise in thyroid cancer in children exposed to radiation from the Chernobyl nuclear accident [55] (see "Radiation-induced thyroid disease"). However, it should be noted that there is increasing evidence to suggest that exposure to therapeutic or diagnostic doses of RAI does not increase the risk of thyroid cancer [56]. The exposures at Hiroshima and Chernobyl and to external beam radiation all included ionizing radiation. By contrast, among children whose environmental exposure was limited to RAI, there is no increase in thyroid cancer or autoimmune thyroid disease with up to 50 years' follow-up [57]. Similarly, in one older study in children treated with lower doses of RAI, there was a small increase in the incidence of benign thyroid adenomas but no increase in thyroid carcinoma [58]. Subsequent studies have not revealed an increased risk of thyroid cancer, leukemia, or other cancers [59].

A cohort study of 18,805 adults with hyperthyroidism treated with RAI reported a statistically significant, though modest, positive dose-response relationship for risk of death for all solid cancers (6 percent increase in risk per 100-mGy dose to the stomach) and breast cancer (12 percent increase in risk per 100-mGy dose to the breast) [60]. This study did not include children. While findings from studies that did include children are reassuring, a small risk of other cancers cannot be excluded, due to the relatively small number of children treated with RAI.

Among children of women treated with RAI during childhood or adolescence, 3 percent have congenital anomalies, a value that is not different from the general population [61], and the incidence of infertility, miscarriage, and prematurity is not increased [62].

SURGERY — Surgery, usually subtotal thyroidectomy, is an effective therapy for Graves hyperthyroidism. Surgery is most commonly used as a secondary treatment option in children. When antithyroid drug therapy fails or causes side effects, many clinicians, children and adolescents, and their parents prefer surgery to RAI (algorithm 1). In particular, thyroidectomy is the preferred treatment for Graves disease in children younger than five years of age when definitive therapy is required because RAI is not recommended for this young age group [27]. Surgery also may be particularly appropriate for those with very large goiter as studies in adults suggest that individuals with large thyroid glands (greater than 80 grams) are less likely to have their hyperthyroidism cured by RAI treatment [63]. Selection of surgery for treatment also depends on availability of an experienced thyroid surgeon [27]. Surgery also may be offered as a primary treatment option, particularly in younger children or those with large thyroid glands, for the reasons noted above.

If surgery is planned, the patient should be treated with an antithyroid drug, if possible, or at least a beta blocker and inorganic iodine before surgery is undertaken. Treatment with iodine preoperatively has been shown to reduce thyroid blood flow and blood loss during surgery. We use either of the following for 7 to 10 days prior to surgery:

●Potassium iodide and iodine (Lugol's solution: 8 mg/drop, 20 drops per mL), 1 drop by mouth three times daily, or

●Potassium iodide (SSKI; Thyroshield: 35 to 50 mg/drop), 1 drop by mouth daily

A beta blocker such as atenolol (1 to 2 mg/kg once daily) over this same 7- to 10-day period will help to reduce adrenergic symptoms.

The operation of choice is near-total thyroidectomy to reduce the risk of persistent or recurrent hyperthyroidism as much as possible.

The complications of surgery in children are similar to those in adults, and mortality is very rare. Transient hypocalcemia occurs in 10 to 30 percent of children and permanent hypoparathyroidism in 1 to 2 percent. Injury to the recurrent laryngeal nerve occurs in approximately 1 percent and postoperative hemorrhage in up to 4 percent [64]. Hypothyroidism occurs in approximately one-half of patients within the first year after surgery and in approximately 1 to 2 percent per year thereafter. (See "Surgical management of hyperthyroidism".)

LIFELONG MONITORING — Regardless of which of the above treatments is used for children and adolescents with Graves hyperthyroidism, lifelong monitoring of thyroid function is necessary. For those who become hypothyroid after any of these treatments, lifelong monitoring will be needed to manage thyroid hormone replacement. For those who enter remission and remain euthyroid after antithyroid drug therapy is discontinued (and also for the small percentage of patients who are euthyroid after radioactive iodine [RAI] or surgery), lifelong monitoring will be needed to detect hyperthyroidism or hypothyroidism, which may develop at any time.

Monitoring consists of checking serum free T4 (thyroxine) and thyroid-stimulating hormone (TSH) every six months until growth and puberty are complete. After completion of growth, we monitor yearly. Females should be counseled that when they reach reproductive age, there is a risk of neonatal Graves disease in their offspring because of persistent stimulatory antibodies to the TSH receptor (TSHR-Ab) that cross the placenta. (See "Evaluation and management of neonatal Graves disease".)

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: Hyperthyroidism" and "Society guideline links: Pediatric thyroid disorders".)

SUMMARY AND RECOMMENDATIONS

●Initial choice of treatment – Children and adolescents with Graves hyperthyroidism can be effectively treated with antithyroid drug therapy, radioactive iodine (RAI), or surgery (thyroidectomy). The choice of therapy is determined by individual consideration of the risks and benefits of the three treatment modalities and patient/family preference (table 1). An overview of treatment is shown in the algorithm (algorithm 1). (See 'Selection of treatment' above.)

•For most children, we suggest initial treatment with antithyroid medication (thionamides) (Grade 2C). This is generally the treatment choice with the lowest risk, and a significant percentage of children will enter a remission (albeit after several years of treatment) and remain euthyroid off of treatment. (See 'Selection of treatment' above and 'Remission rate' above.)

•RAI or surgery are acceptable primary treatment choices (eg, RAI for adolescents, surgery for children <5 years) and are preferred by some patients and their parents; these may also be more appropriate treatment modalities than antithyroid drugs in settings where close follow-up is unlikely. These modalities cause the patient to become hypothyroid, which requires lifelong thyroid hormone replacement therapy.

●Antithyroid medication

•When antithyroid medication is chosen, we recommend treating with methimazole (MMI) rather than propylthiouracil (PTU) because MMI has fewer side effects (Grade 1A). (See 'Antithyroid drugs' above.)

•We do not recommend a trial off of MMI after an arbitrary period of treatment, as is commonly done in adults. Instead, we prescribe MMI indefinitely, providing that antithyroid drug is the preferred treatment choice of the patient and parents and that no major side effects occur (which would necessitate switching to another treatment modality). For most patients, antithyroid drug therapy can be weaned after 4 to 10 years, guided by thyroid function tests, and sometimes with measures of antibodies to the thyroid-stimulating hormone receptor (TSHR-Ab). (See 'Stopping therapy' above and 'Management of patients who do not enter remission' above.)

●Second-line therapies – RAI or surgery are options for secondary therapy for patients with recurrent hyperthyroidism after long-term treatment with an antithyroid drug and who request definitive treatment and for those who have a major side effect while receiving an antithyroid drug. We choose the treatment modality based upon age and thyroid size (algorithm 1):

•For patients with hyperthyroidism due to a very large thyroid, we suggest surgery rather than RAI (Grade 2C). Thyroid surgery should be performed by an experienced thyroid surgeon. (See 'Surgery' above and "Surgical management of hyperthyroidism".)

•For children older than 10 years who do not have a very large thyroid, we suggest RAI rather than surgery (Grade 2C). (See 'Radioactive iodine' above.)

•Guidelines recommend that RAI not be used in children younger than five years of age. For patients between 5 and 10 years of age, either surgery or RAI (at limited doses) are appropriate choices. (See 'Radioactive iodine' above.)

●RAI dosing – When RAI is selected for therapy, we generally use higher doses (eg, 200 to 300 microCi/gram of thyroid tissue). This dose leads to permanent resolution of the hyperthyroidism in a high percentage of patients; most will also become hypothyroid and will require lifelong thyroid hormone replacement. (See 'Patient selection and dose' above and 'Hypothyroidism' above.)

•For children between 5 and 10 years, guidelines suggest restricting the total RAI dose to <10 milliCi

•Children on antithyroid drugs who are to be treated with RAI should have their antithyroid drug discontinued at least seven days before the RAI administration

●Monitoring – All children with a history of hyperthyroidism should have lifelong monitoring of thyroid function, regardless of treatment choice and outcome. All children have a risk of recurrent hyperthyroidism or developing hypothyroidism, and this may occur at any time. Offspring of women with a history of hyperthyroidism have an increased risk for Graves disease in the neonatal period. (See 'Lifelong monitoring' above.)