Version July 2025
INTRODUCTION —
Graves disease is caused by autoantibodies that bind to and activate the thyroid-stimulating hormone (TSH) receptor (TSHR-Ab) or thyrotropin receptor antibodies (TRAb), stimulating growth of the thyroid and overproduction of thyroid hormone. It is the most common cause of hyperthyroidism in children.
Clinical manifestations of Graves disease include diffuse goiter and symptoms and signs resulting from hyperthyroidism. Graves disease is often associated with thyroid eye disease (TED; previously called "Graves ophthalmopathy"), which is only rarely associated with other causes of thyrotoxicosis. By contrast, "stare" and lid lag (eye findings resulting from sympathetic overactivity) may be present in any form of hyperthyroidism. In children, hyperthyroidism also tends to have effects on growth and development.
The clinical presentation and laboratory evaluation of children with hyperthyroidism are discussed here. Treatment of hyperthyroidism is discussed separately. Hyperthyroidism presenting in the neonatal period also is discussed separately. (See "Treatment and prognosis of Graves disease in children and adolescents" and "Evaluation and management of neonatal Graves disease".)
TERMINOLOGY
Hyperthyroidism versus thyrotoxicosis — The terms "hyperthyroidism" and "thyrotoxicosis" are often used interchangeably, but they are technically distinct. Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland, while thyrotoxicosis refers to the clinical and biochemical manifestations of excess thyroid hormones.
Most cases of thyrotoxicosis are caused by hyperthyroidism, particularly in children. However, thyrotoxicosis occasionally is caused by release of preformed stored thyroid hormone, as in some cases of destructive thyroiditis. The distinction is important because interventions that decrease thyroid hormone production (eg, antithyroid drugs) are effective only for treating hyperthyroidism, not destructive thyroiditis. (See "Disorders that cause hyperthyroidism", section on 'Increased thyroid hormone synthesis' and "Disorders that cause hyperthyroidism", section on 'Release of preformed thyroid hormone'.)
EPIDEMIOLOGY —
Hyperthyroidism occurs in approximately 1 per 5000 children and adolescents, and Graves disease accounts for the vast majority of these cases. Other causes are outlined in the table (table 1) [1]. In a national population-based study of thyrotoxicosis from the United Kingdom and Ireland in 2004, the annual incidence was 0.9 per 100,000 children <15 years of age, with Graves disease accounting for 96 percent of cases [2]. A nationwide study from Denmark reported an incidence of 0.79 per 100,000 in children <15 years of age in the time period of 1982 to 1988, with a doubling to 1.58 per 100,000 in the years 1998 to 2012 [3].
The incidence of Graves disease rises sharply during puberty, so that approximately 80 percent of pediatric cases occur after 11 years of age [1-4]. During adolescence, a strong female predominance develops, at a ratio of approximately 5:1 [2-4]. The ratio is considerably lower among younger children, suggesting that estrogen secretion in some way affects the autoimmune predisposition to Graves disease. A report using data from the United States National Health and Nutritional Examination Surveys analyzing adolescents and young adults found that thyrotoxicosis was more common in non-Hispanic Black Americans than Mexican Americans, in whom it was more common than non-Hispanic White Americans [5].
PATHOGENESIS
Autoimmune mechanisms — Graves disease refers to the clinical syndrome of hyperthyroidism caused by stimulating antibodies to the thyroid-stimulating hormone receptor (TSHR). Other antibodies block the TSHR. These blocking antibodies may be produced intermittently in patients with Graves disease and therefore may affect the clinical expression of the disease. (See "Pathogenesis of Graves' disease", section on 'Thyroid autoantibodies'.)
Stimulating or blocking TSHR antibodies (TSHR-Ab) also may be present in some kinds of destructive thyroiditis, but these disorders are distinct from Graves disease because the antibodies are not the primary cause of thyroid dysfunction. (See 'Destructive thyroiditis with thyrotoxic phase' below.)
Genetic factors strongly influence the predisposition to Graves disease, and twin studies indicated that approximately 80 percent of the risk of Graves disease is attributable to genetic factors [6] (see "Pathogenesis of Graves' disease"). The development of Graves disease has also been reported in children after hematopoietic stem cell transplantation—the so-called Graves immune reconstitution inflammatory syndrome [7]. The mechanism is believed to be immunologic dysregulation during T cell engraftment, with subsequent production of TSHR-Ab by B cells. (See "Overview of immune reconstitution inflammatory syndromes".)
Thyroid eye disease (TED) is a common clinical manifestation of Graves disease resulting from autoantibodies directed against the TSHR expressed in retro-orbital connective tissue [8]. A study in children with Graves disease reported a positive association between elevated levels of thyroid-stimulating immunoglobulin (TSI) and the development of TED, further suggesting that the eye complications are a part of the autoimmune process [9]. (See "Clinical features and diagnosis of thyroid eye disease".)
The same mechanism may be responsible for Graves-related dermopathy because normal dermal fibroblasts have been demonstrated to express TSHR protein. (See "Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease".)
Associated conditions — Many children and adolescents with Graves hyperthyroidism have a family history of autoimmune thyroid disease [10]. Patients may have an increased frequency of other autoimmune endocrine diseases (eg, diabetes mellitus, celiac disease [11], and primary adrenal insufficiency) and nonendocrine autoimmune disorders (eg, vitiligo, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis [12], thrombocytopenic purpura, and pernicious anemia). Conversely, patients with type 1 diabetes have a somewhat increased incidence of hyperthyroidism [13]. Some patients with Graves disease have antineutrophil antibodies [14].
Children with trisomy 21 (Down syndrome) have an increased risk for hyperthyroidism [15,16]. In a review from Spain, 12 of 1832 patients with trisomy 21 were diagnosed with hyperthyroidism (6.5 cases per 1000) [17]. Patients with trisomy 21 tend to be diagnosed with hyperthyroidism at an earlier age compared with children without T21 and do not show the usual female preponderance [18,19]. Patients with Turner syndrome may also be at increased risk for hyperthyroidism; in one series, 2 out of 119 patients developed Graves disease [20]. (See "Down syndrome: Clinical features and diagnosis" and "Turner syndrome: Clinical manifestations and diagnosis".)
Other risk factors for development of Graves disease are discussed elsewhere. (See "Pathogenesis of Graves' disease", section on 'Precipitating and predisposing factors'.)
CLINICAL MANIFESTATIONS —
Many features of thyrotoxicosis in children and adolescents are similar to those in adults [10,21]. Children with mild hyperthyroidism may have few clinical manifestations or may be asymptomatic. The onset of symptoms is often insidious, and the changes may be present for months or years before the diagnosis is made. In children, prolonged hyperthyroidism may have effects on growth and pubertal development.
General symptoms and signs of thyrotoxicosis — Graves disease may be associated with the following symptoms and signs, which are also seen in other causes of thyrotoxicosis:
●Cardiovascular – Patients with hyperthyroidism have an increase in cardiac output caused by both increased peripheral oxygen needs and increased cardiac contractility. Heart rate is increased, pulse pressure is widened, and peripheral vascular resistance is decreased [22]. Beta blockers may be used to manage cardiac manifestations. (See "Treatment and prognosis of Graves disease in children and adolescents", section on 'Adjunctive therapies'.)
Atrial fibrillation, which occurs in 10 to 20 percent of adults with hyperthyroidism, is rare in children. Mitral valve prolapse, which is common in adults with thyrotoxicosis, has also been reported in children [23].
Patients with hyperthyroidism tend to have low serum total and high-density lipoprotein (HDL) cholesterol concentrations as well as low total cholesterol to HDL cholesterol ratios. These values increase after treatment [24].
●Gastrointestinal – Weight loss or failure to gain weight, despite an increase in appetite, is common. Weight loss is caused primarily by increased calorigenesis and secondarily by increased gut motility and associated increased stooling and malabsorption. With treatment, children regain lost weight [25]. However, with the increased prevalence of childhood obesity, some children may have normal weight at the time of diagnosis; persistence of hyperphagia after treatment that restores euthyroidism may result in excessive weight gain [26].
The prevalence of celiac disease and inflammatory bowel disease is probably modestly increased among individuals with autoimmune thyroid disease [27,28]. Patients with persistent gastrointestinal symptoms should undergo screening for these diseases. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)
●Eyes – "Stare" and lid lag are common in children with any form of hyperthyroidism. These findings appear to be mediated by sympathetic overactivity, causing increased tightness of the levator palpebrae [29].
It is important to distinguish lid lag and stare from features of thyroid eye disease (TED) such as proptosis, periorbital edema, and extraocular muscle dysfunction (disconjugate gaze), which are found in Graves disease but only rarely in other forms of hyperthyroidism. (See 'Thyroid eye disease' below.)
●Neurologic – Graves disease can be associated with a variety of neurologic manifestations in children, which overlap with some findings in adults (see "Neurologic manifestations of hyperthyroidism and Graves' disease"):
•Movement disorders – Tremulousness and tremor are common in hyperthyroidism. The tremor is best demonstrated from the outstretched hands or the tongue (fasciculations). Deep tendon reflexes are hyperactive. Ataxia and chorea, which resolve with treatment of hyperthyroidism, have been reported [30].
•Cognitive dysfunction – Among very young children (<4 years), hyperthyroidism may cause neurodevelopmental delay [31]. In particular, speech and language delay has been reported as an unusual presentation of hyperthyroidism and improves with treatment for the hyperthyroidism [32].
•Peripheral nervous system – Proximal muscle weakness may be present with decreased muscle mass and decreased efficiency of muscle contraction [33]. Rarely, patients may also develop myasthenia gravis and thymic enlargement.
•Periodic paralysis – Hypokalemic periodic paralysis (thyrotoxic periodic paralysis) is a rare disorder that may be associated with hyperthyroidism, especially in adolescent boys of East Asian descent (Chinese, Japanese, Vietnamese, Korean, and Filipino). (See "Thyrotoxic periodic paralysis".)
•Other rare neurologic manifestations – Benign intracranial hypertension was reported in a child with Graves disease presenting with headache and papilledema. These findings reversed with treatment of Graves disease [34]. Graves disease also has been associated with moyamoya disease, a cerebrovascular disorder characterized by severe bilateral stenosis of the terminal portions of the carotid arteries with prominent collateral circulation and cerebral ischemic events or epilepsy [35]. Although it is rare, moyamoya disease should be considered in patients with Graves disease and focal neurologic symptoms. A case report describes the initial copresentation of new-onset Graves disease (with thyroid storm) and type 1 diabetes mellitus, leading to cerebral infarctions and the additional diagnosis of moyamoya disease in a 16-year-old girl [36]. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".)
●Behavioral and psychiatric – Children with hyperthyroidism tend to have greater mood swings and disturbances of behavior compared with adults [37]. Their attention span decreases; they may be hyperactive and sleep poorly. School performance may deteriorate. Occasionally, children or adults with hyperthyroidism experience marked personality changes, agitation, anxiety, depression, mania, or psychosis [38,39]. (See "Neurologic manifestations of hyperthyroidism and Graves' disease".)
Many hyperthyroid children are referred to a developmental specialist or child psychiatrist to evaluate emotional and behavioral symptoms before the presence of hyperthyroidism is suspected. Short attention span and poor school performance are often incorrectly ascribed to attention-deficit hyperactivity disorder [39].
●Bone – Thyroid hormone stimulates bone resorption, resulting in increased porosity of cortical bone and reduced volume of trabecular bone [40]. Serum alkaline phosphatase and osteocalcin concentrations are high, indicative of increased bone turnover. The increase in bone resorption may lead to an increase in serum calcium concentrations, thereby inhibiting parathyroid hormone secretion and the conversion of calcidiol (25-hydroxyvitamin D) to calcitriol (1,25-dihydroxyvitamin D). The net effect is osteoporosis and an increased fracture risk in patients with chronic hyperthyroidism. (See "Bone disease with hyperthyroidism and thyroid hormone therapy".)
●Skin – The skin is warm in hyperthyroidism because of increased blood flow; it is also smooth because of a decrease in the keratin layer [41]. Sweating is increased because of increased calorigenesis. Onycholysis (loosening of the nails from the nail bed [Plummer nails]), softening of the nails, and thinning of the hair may occur. Vitiligo and alopecia areata can occur as associated autoimmune disorders.
Dermopathy (pretibial myxedema), a component of the classic triad of Graves disease in adults, is rarely (if ever) reported in children. (See "Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease".)
Effects on growth and development
●Growth – Acceleration of growth is accompanied by advancement of epiphyseal maturation. The acceleration in growth is usually subtle and depends upon the duration of hyperthyroidism before diagnosis. As an example, in children who have had hyperthyroidism for one to two years, height may increase from the 50th to the 75th percentile. The effect on growth may be more pronounced if hyperthyroidism presents in early childhood. In a report of children aged 3.4 to 7.5 years, median height was +1.25 standard deviations (SD), while body mass index was -0.48 SD [42]. With antithyroid drug treatment, height velocity and bone age approach a more normal pattern. In a report of 101 children with Graves disease from Italy, bone age was advanced at presentation [43]. Nonetheless, adult height was normal after treatment with antithyroid drugs and was even slightly increased in males who were diagnosed during puberty.
●Puberty – The age of onset of puberty and attainment of pubertal stages do not appear to be altered by hyperthyroidism [43]. Pre-adolescent or adolescent patients who have undergone menarche may develop oligomenorrhea or secondary amenorrhea, and anovulatory cycles are common [44]. Hyperthyroidism is associated with high levels of sex hormone-binding globulin, which may result in high serum estradiol in females and testosterone in males. However, unbound or free levels of these hormones are decreased, perhaps explaining why luteinizing hormone levels are slightly elevated. Hyperthyroidism also is associated with increased aromatization of androgens to estrogens. These hormonal changes have been associated with gynecomastia in males; there have been no reports of gynecomastia in boys with Graves hyperthyroidism.
Other characteristic features of Graves disease — Goiter is seen in most cases of Graves disease, and TED helps to distinguish this disorder from other causes of hyperthyroidism.
Thyroid eye disease — In a child with thyrotoxicosis, eye findings such as exophthalmos (proptosis) or ocular muscle dysfunction implicate Graves disease as the most likely etiology. However, the absence of TED does not preclude a diagnosis of Graves disease. TED is caused by inflammation of the extraocular muscles, orbital fat, and connective tissue, which results in impaired eye muscle function and periorbital edema. (See "Clinical features and diagnosis of thyroid eye disease", section on 'Pathogenesis'.)
Patients with TED may have a gritty feeling or pain in their eyes, and they may have diplopia caused by extraocular muscle dysfunction. Corneal ulceration can occur as a result of proptosis and lid retraction [45]. The reported prevalence of TED in children with Graves disease is 33 to 67 percent [46,47]. However, the prevalence of TED may be overestimated because some studies do not distinguish findings of orbital inflammation specific to Graves disease from nonspecific findings of thyrotoxicosis (eg, lid lag, stare).
In general, symptoms of TED in children tend to be milder than those seen in adults [45,48]. In a series of 152 children with Graves disease, only 17 percent required referral to an ophthalmologist for management of TED [49]. Another study showed a trend toward less severe eye findings in prepubertal compared with postpubertal children [50]. TED is more common in patients who smoke cigarettes. (See "Clinical features and diagnosis of thyroid eye disease", section on 'Symptoms and signs'.)
Goiter — Most children with Graves hyperthyroidism have a diffuse goiter [48]. The surface tends to be smooth, fleshy in consistency, and without palpable nodules. A large goiter may cause dysphagia and tracheal compression with complaints of dyspnea. A bruit can often be auscultated over the gland in hyperthyroid patients.
Goiter is also present in several other causes of hyperthyroidism, such as "Hashitoxicosis" (autoimmune thyroiditis), subacute thyroiditis, or forms of nonautoimmune hyperthyroidism. (See 'Destructive thyroiditis with thyrotoxic phase' below.)
Large solitary nodules should raise suspicion of an autonomously functioning adenoma ("toxic adenoma"), while multiple palpable nodules are present in toxic multinodular goiter. Children with these findings should be evaluated further with ultrasound and radionuclide uptake and scan in addition to thyroid function tests. (See 'Thyroid gland hyperfunction' below and "Thyroid nodules and cancer in children", section on 'Evaluation of thyroid nodules'.)
DIAGNOSTIC EVALUATION —
Because the symptoms and signs of Graves disease often arise gradually, they may not be recognized as abnormal by the family or clinician. Unexplained weight loss and/or an increased rate of linear growth (in the absence of puberty); onset of emotional lability, poor attention span, and hyperactivity; diffuse goiter; suspicious eye findings; tachycardia; and/or brisk reflexes in children should raise a clinical suspicion of Graves disease and prompt an appropriate diagnostic evaluation. The evaluation should begin with a thorough history to identify other causes of hyperthyroidism (eg, medication-induced hyperthyroidism or thyroid injury) and a physical examination.
Serum thyroid function tests — After conducting a history and physical examination, the next step in patients with concern for Graves disease is to measure serum levels of thyroid-stimulating hormone (TSH; also known as thyrotropin), free thyroxine (fT4), and triiodothyronine (T3) [51]. (See "Laboratory assessment of thyroid function", section on 'Laboratory tests used to assess thyroid function'.)
●Potential medication interference – Several medications can cause suppressed TSH and/or elevated fT4 and T3 in the absence of true hyperthyroidism, resulting from interference with assays (table 2).
As an example, pharmacologic doses of biotin (used as a supplement for hair and nails, also used for certain inherited metabolic diseases) may cause artifactual abnormalities in laboratory tests of TSH, T4, and TSH receptor antibodies (TSHR-Ab). These vary with the assay used, but subnormal serum TSH levels have been reported, mimicking hyperthyroidism. Patients taking biotin should hold the supplement for at least two days prior to assessing thyroid function and longer if they are taking more than 10 mg per day. (See "Laboratory assessment of thyroid function", section on 'Assay interference with biotin ingestion'.)
●Interpretation − Thyroid function tests are interpreted as follows:
•Suppressed TSH with fT4 and/or elevated T3 – These results confirm thyrotoxicosis. Due to increased T3 production and T4-to-T3 conversion, patients with Graves disease typically have disproportionate elevation of T3 relative to fT4. In some cases, this may result in the pattern of suppressed TSH with elevated T3 levels but normal fT4 levels. (See "Diagnosis of hyperthyroidism", section on 'Thyroid tests'.)
•Suppressed TSH with normal fT4 and T3 – These results are compatible with "subclinical hyperthyroidism." In one study, follow-up testing of 23 children with these lab findings over a several-month period showed that 14 returned to euthyroidism, four developed hypothyroidism, and three maintained suppressed TSH but normal fT4 levels, while two progressed to overt hyperthyroidism [52]. Therefore, it is prudent to follow such children with serial testing of thyroid function testing (every six weeks to three months). Patients with Graves disease will usually progress to overt hyperthyroidism, whereas patients with destructive thyroiditis will experience a gradual return to normal thyroid function. (See "Diagnosis of hyperthyroidism", section on 'Subclinical hyperthyroidism'.)
•Normal results – Normal results of thyroid function tests exclude thyrotoxicosis. Rarely, some children will have normal thyroid function tests despite physical features of Graves disease, including a goiter, findings of thyroid eye disease (TED), and positive TSHR-Ab. This presentation has been termed "euthyroid Graves disease." Such patients generally are followed without treatment, with periodic monitoring of thyroid function tests.
•Patterns associated with specific causes of thyrotoxicosis – Thyroid function tests also may help to identify causes of thyrotoxicosis other than Graves disease (table 1). As an example, the possibility of destructive thyroiditis is suggested by suppressed TSH in the presence of a T4 concentration that is proportionally more elevated and T3 less elevated than typically seen with Graves disease [53]. By contrast, predominant T3 elevation suggests Graves disease, an autonomously functioning nodule [53], or toxic multinodular goiter. (See 'Differential diagnosis: Other causes of thyrotoxicosis' below and "Laboratory assessment of thyroid function".)
Serum thyroid antibody tests — After thyroid function testing confirms thyrotoxicosis, the next step is to determine the cause. The various etiologies of thyrotoxicosis can be distinguished by the clinical examination, serum antithyroid antibody measurement, and radioactive iodine (RAI) uptake (table 1). (See 'Differential diagnosis: Other causes of thyrotoxicosis' below.)
●TSH receptor antibodies – Because Graves disease is by far the most common cause of thyrotoxicosis, our evaluation typically begins with measurement of TSHR-Ab (also known as thyrotropin receptor antibodies [TRAb]) to confirm this diagnosis.
Two testing modalities are available for TSHR-Ab:
•Thyroid-stimulating immunoglobulin (TSI) – This is a functional assay measuring production of cyclic adenosine monophosphate (cAMP) in cultured thyroid follicular cells, confirming the presence of a stimulating antibody. Studies report that TSI is detectable in 60 to 94 percent of children with clinically diagnosed Graves hyperthyroidism [54-56]. One study, describing a new technique that employs a novel chimeric TSHR bioassay and a cAMP response element-dependent luciferase, reported that a TSHR-stimulating antibody was present in 94 percent of children with Graves disease, including 100 percent of untreated children at diagnosis [55].
•Thyrotropin-binding inhibitory immunoglobulin (TBII; sometimes known as TSHR-Ab or TRAb) – This is a competitive protein-binding assay that demonstrates the presence of an antibody that competes with TSH for binding to its receptor. This test does not provide direct information about whether the TSHR-Ab is stimulating or blocking, but in a patient with thyrotoxicosis, any TSHR-Ab present can be inferred to have overall TSHR-stimulating activity. In general, third-generation TBII assays have high sensitivity and specificity for Graves disease similar to those of TSI [57].
●Other antithyroid antibodies – Thyroid peroxidase antibodies (TPO-Ab) and thyroglobulin antibodies (Tg-Ab) are present in both Graves disease and autoimmune thyroiditis (Hashimoto disease). While we often measure these antibodies as part of the initial evaluation, they do not distinguish between these etiologies.
In children with confirmed hyperthyroidism in whom TSHR-Ab tests are negative, we measure TPO-Ab and Tg-Ab (if not already measured), as these tests can help identify a thyrotoxic phase of autoimmune thyroiditis ("Hashitoxicosis").
•TPO-Ab and/or Tg-Ab positive – If these are positive, we then continue to monitor thyroid function tests (TSH, fT4) every month. (See 'Destructive thyroiditis with thyrotoxic phase' below.)
We perform uptake and scan if thyrotoxicosis persists after 12 weeks. (See 'Radionuclide uptake and scan for selected patients' below.)
•TPO-Ab and Tg-Ab negative – If antibodies are negative, and the medical history does not indicate an etiology for hyperthyroidism (eg, post-viral thyroiditis), we perform a RAI uptake test. Some experts prefer to perform a RAI uptake immediately if TSHR-Ab are negative in order to prevent a potential delay in treatment of Graves disease. (See 'Radionuclide uptake and scan for selected patients' below.)
Radionuclide uptake and scan for selected patients — If the diagnostic evaluation does not indicate an etiology for thyrotoxicosis, or if thyrotoxicosis persists at or beyond 12 weeks, we perform a RAI uptake and scan in patients who are not pregnant or breastfeeding. Some experts prefer to perform a RAI uptake immediately if TSHR-Ab is negative in order to prevent a potential delay in the treatment of Graves disease.
Iodine-123 (I-123) is the radionuclide of choice for thyroid uptake tests because it has a shorter half-life (13.2 hours) and delivers a smaller radiation dose to the thyroid gland than iodine-131. Technetium is occasionally used for this purpose because the radiation dose is lower and the scan can be performed more rapidly. However, we and many others prefer I-123 because it provides a quantifiable measure of uptake.
The RAI uptake is typically assessed 6 and 24 hours after isotope administration. The uptake will be elevated (or inappropriately normal in the setting of suppressed TSH) in Graves disease, and the accompanying scan typically shows diffuse uptake throughout the gland [58]. (See "Diagnosis of hyperthyroidism", section on 'Radioiodine uptake' and 'Differential diagnosis: Other causes of thyrotoxicosis' below.)
Ultrasound (not routinely used) — Thyroid ultrasonography is not part of the routine diagnostic evaluation in children with hyperthyroidism. Ultrasound is used to evaluate suspected thyroid nodules (single or multiple) identified on physical examination or when significant neck trauma precedes the discovery of thyrotoxicosis.
DIAGNOSIS OF GRAVES DISEASE —
Graves disease should be suspected in patients presenting with signs and symptoms of thyrotoxicosis and characteristic physical examination findings such as goiter and thyroid eye disease (TED). (See 'Clinical manifestations' above.)
The diagnosis of Graves disease is confirmed by the presence of thyroid-stimulating hormone (TSH) receptor antibodies (TSHR-Ab), which are detectable in most children with Graves disease. A positive thyroid-stimulating immunoglobulin (TSI) or thyrotropin-binding inhibitory immunoglobulin (TBII) level confirms the presence of TSHR-Ab. When TSHR-Ab are not detected, the diagnosis can be supported by an elevated 24-hour radioactive iodine (RAI) uptake and scan that shows diffuse uptake in the presence of suppressed TSH. (See 'Diagnostic evaluation' above.)
If this testing fails to confirm the diagnosis of Graves disease, less common causes of thyrotoxicosis should be considered (table 1). (See 'Differential diagnosis: Other causes of thyrotoxicosis' below.)
DIFFERENTIAL DIAGNOSIS: OTHER CAUSES OF THYROTOXICOSIS
Thyroid gland hyperfunction — Graves disease is by far the most common cause of thyroid hyperfunction (hyperthyroidism), as detailed above. Other causes are:
●Autonomous thyroid nodules – Solitary autonomous nodules (or "toxic adenomas") are an uncommon cause of hyperthyroidism in childhood. They are suspected in the setting of thyrotoxicosis and palpation of a nodule on neck examination. In general, to produce systemic hyperthyroidism, most nodules must be large (>2 cm) [59]. Small nodules (<1 cm), which are often discovered incidentally during imaging, are less likely to cause hyperthyroidism. If small nodules are identified in a patient with thyrotoxicosis, we evaluate for another potential cause. Many autonomous nodules have been shown to be the result of thyroid-stimulating hormone (TSH) receptor (TSHR) gene-activating mutations [60,61].
Autonomous nodules typically produce triiodothyronine (T3), so serum testing may show an elevated T3 and suppressed TSH with a normal or mildly elevated free thyroxine (fT4) [53,59]. Thyroid antibodies, including TSHR antibodies (TSHR-Ab), are negative. Radioactive iodine (RAI) uptake and scan will show uptake only in the functioning nodule, with the rest of the gland suppressed [58,59]. The definitive treatment of most autonomous nodules is surgical resection. Ablation with radioactive iodine (I-131) may be considered in select older adolescents. Hyperthyroidism can be treated with antithyroid drugs, but this is usually used temporarily as a bridge to definitive treatment with surgery or radioablation. An approach to evaluating thyroid nodules is discussed elsewhere. (See "Thyroid nodules and cancer in children", section on 'Evaluation of thyroid nodules'.)
●Toxic multinodular goiter – Toxic multinodular goiters are another uncommon cause of hyperthyroidism in children. They are suspected in the setting of thyrotoxicosis and palpation of a goiter with multiple nodules. An ultrasound examination is generally undertaken because it is more sensitive than physical examination for detecting multiple nodules [58]. Antithyroid antibodies are negative.
Generally, a RAI uptake and scan is indicated to distinguish this condition from the thyrotoxic phase of autoimmune thyroiditis ("Hashitoxicosis") or subacute granulomatous thyroiditis. The uptake will be elevated and present in the multiple nodules. Some cases of toxic multinodular goiter have been shown to be the result of TSHR gene-activating pathogenic variants, as described for solitary autonomous nodules [61]. (See "Approach to acquired goiter in children and adolescents", section on 'Toxic adenoma or multinodular goiter'.)
Approximately one-third of children with McCune-Albright syndrome develop hyperthyroidism and a multinodular goiter [62]. McCune-Albright syndrome, caused by an activating pathogenic variant of the gene encoding the alpha subunit of the stimulatory G protein, is classically characterized by café-au-lait pigmentary skin lesions, fibrous dysplasia of the bones, and precocious puberty. While hyperthyroidism can be treated with antithyroid drugs, a more permanent form of treatment (such as surgical thyroidectomy or RAI ablation) may eventually be required in some cases. (See "Definition, etiology, and evaluation of precocious puberty".)
●TSH-secreting pituitary adenoma – TSH-secreting adenomas are rare at any age, and only a few have been reported in children [63,64]. Cases of TSH-secreting pituitary adenomas have been described in children in association with type 1 autoimmune polyglandular syndrome [65] and with resistance to thyroid hormone [66]. Laboratory testing typically shows an elevated fT4 with a normal (not suppressed) TSH level. The diagnosis is supported by a high serum alpha subunit concentration, high alpha subunit-to-TSH ratio, and little or no TSH response to thyrotropin-releasing hormone (TRH). A pituitary adenoma is confirmed by magnetic resonance imaging. Treatment is surgical resection. (See "TSH-secreting pituitary adenomas".)
●Resistance to thyroid hormone beta – Resistance to thyroid hormone beta (RTH-beta) is an autosomal dominant disorder due to a pathogenic variant in the thyroid hormone receptor beta (THRB) gene [67,68]. Affected children commonly present with a goiter, elevated serum fT4, and, to a lesser extent, elevated T3 levels, with a TSH that is normal or slightly elevated. These patients are usually clinically euthyroid because the elevated thyroid hormone concentrations are able to overcome the receptor defect. This is discussed in detail elsewhere. (See "Resistance to thyroid hormone and other defects in thyroid hormone action".)
Destructive thyroiditis with thyrotoxic phase — Destructive thyroiditis may be associated with transient thyrotoxicosis due to release of preformed stored thyroid hormones. Destructive thyroiditis can cause thyrotoxicosis only until the preformed thyroid hormone stored in the gland is exhausted, typically lasting no more than 8 to 12 weeks. Thyrotoxicosis lasting longer than 12 weeks strongly suggests that the cause is a form of hyperthyroidism (such as Graves disease) rather than transient thyroiditis. Laboratory and diagnostic findings are typically distinct from Graves disease.
●Autoimmune (Hashimoto) thyroiditis with thyrotoxic phase – Autoimmune thyroiditis (also known as chronic lymphocytic thyroiditis or "Hashimoto thyroiditis") generally is associated with euthyroidism or, in some cases, hypothyroidism due to destruction of thyroid tissue. However, approximately 5 to 10 percent of children present with a thyrotoxic phase, sometimes termed "Hashitoxicosis," usually caused by autonomous release of stored thyroid hormone. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Autoimmune thyroiditis' and "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)".)
•Presentation – Unlike in Graves disease, thyroid eye disease (TED; eg, exophthalmos) occurs infrequently in Hashimoto thyroiditis. (See "Clinical features and diagnosis of thyroid eye disease", section on 'Laboratory findings'.)
•Laboratory findings – Thyroglobulin antibodies (Tg-Ab) and thyroid peroxidase antibodies (TPO-Ab) are usually positive in Hashimoto thyroiditis (similar to Graves disease). By contrast, TSHR-Ab are typically negative in patients with Hashitoxicosis, although thyrotropin-binding inhibitor immunoglobulin (TBII) may be positive in rare cases (table 1).
•Imaging – RAI uptake is high (and diffuse) in Graves disease and low or absent in most cases of Hashitoxicosis [69]. A thyroid ultrasound typically shows a "moth-eaten" pattern of scattered hypo- and hyperechogenicity (image 1), but ultrasound is not routinely used to distinguish Graves disease from Hashitoxicosis.
•Clinical course – Hashitoxicosis tends to have a brief course, lasting a few weeks to months. During the hyperthyroid phase, relatively rapid resolution of hyperthyroidism during treatment with antithyroid drugs (typically within six months of diagnosis) suggests Hashitoxicosis rather than Graves disease. Whether Hashitoxicosis is a distinct entity remains controversial because its clinical features and mechanisms overlap with both Graves disease and autoimmune thyroiditis. Furthermore, some children with Graves disease have a preceding history of autoimmune thyroiditis. In one series, 4 of 109 children with Graves hyperthyroidism previously had been diagnosed with autoimmune thyroiditis (with associated hypothyroidism or euthyroidism) from 1.5 to 2.8 years prior to the diagnosis of Graves disease [70]. (See 'Diagnostic evaluation' above.)
Some patients with autoimmune thyroid disease appear to produce both TSHR-Ab with both stimulating (as in Graves disease) and TSHR-blocking activity. In this case, the clinical course depends on which antibody predominates, and the patients may undergo cycles of hyper- and hypothyroidism. As an example, one report described 69 children with autoimmune thyroiditis, eight of whom were considered to have Hashitoxicosis [69]. As is typical in Hashitoxicosis, the duration of hyperthyroidism was shorter than in Graves disease, ranging from 31 to 168 days. The majority of these eight patients appeared to have a destructive form of thyrotoxicosis because only three had increased TSI levels and only two had elevated RAI uptake.
Because there is no overproduction of thyroid hormone in Hashitoxicosis, antithyroid drug treatment is not effective; patients can be treated with beta-adrenergic antagonists until the thyrotoxicosis resolves.
●Subacute thyroiditis – Subacute (granulomatous) thyroiditis, also known as De Quervain disease, is rare in childhood. It is characterized by painful swelling of the thyroid gland and is most likely caused by a viral infection, including some cases associated with coronavirus disease 2019 (COVID-19) infections [71]. Inflammation leads to release of stored thyroid hormone, resulting initially in a thyrotoxic phase followed by euthyroidism, then hypothyroidism, and, usually, a return to euthyroidism. Thyroid antibodies are negative; RAI uptake is low or absent during the thyrotoxic phase [58]. During the thyrotoxic phase, patients can be treated with beta blockers. (See "Overview of thyroiditis".)
●Acute suppurative thyroiditis – Most patients with an acute bacterial infection of the thyroid gland remain euthyroid, but transient thyrotoxicosis has been reported [72]. (See "Suppurative thyroiditis in children and adolescents".)
Thyroid injury — Rarely, transient thyrotoxicosis may be caused by release of preformed thyroid hormone following neck trauma or radiation:
●Neck trauma-induced thyrotoxicosis – Significant neck trauma can result in thyrotoxicosis [73]. This can be considered a form of "destructive" thyrotoxicosis. Ultrasonography will usually show evidence of injury, and RAI uptake is decreased in the area of injury. Thyroid function tests gradually normalize over three to six weeks.
●Radiation-induced thyrotoxicosis – Hyperthyroidism was reported in 23 of 3579 (0.6 percent) childhood survivors of acute lymphoblastic leukemia [74]. This appeared to be a destructive thyrotoxicosis associated with craniospinal radiation; chemotherapy did not appear to be a risk factor.
Drug-induced thyrotoxicosis
●Iodine-induced hyperthyroidism – Iodine-induced hyperthyroidism typically occurs in patients with preexisting autonomous nodules as part of a multinodular goiter. It occurs primarily in adult males and is rare in children. Prior to iodine exposure, patients are euthyroid, though serum TSH may be suppressed. Iodine exposure (eg, with contrast agents or amiodarone) [75] induces thyrotoxicosis. RAI uptake is usually decreased, though it may be normal or increased. Symptoms can be managed with beta blockers until the thyrotoxicosis resolves spontaneously. (See "Disorders that cause hyperthyroidism", section on 'Iodine-induced hyperthyroidism'.)
●Other drugs – Drugs such as lithium, an expanding category of drugs that cause dysregulation of the immune system (interferon-alfa, interleukin-2, checkpoint inhibitors), and systemic kinase inhibitors may also cause hyperthyroidism (and hypothyroidism). (See "Drug interactions with thyroid hormones", section on 'Drugs that cause hyperthyroidism'.)
●Factitious thyrotoxicosis – Factitious thyrotoxicosis should be suspected in the setting of thyrotoxicosis with absent goiter. It is most commonly seen in adolescents with access to T4 who are trying to lose weight. Measurement of serum thyroglobulin (Tg) is useful because it is elevated in all forms of endogenous thyrotoxicosis but is low in factitious thyrotoxicosis. RAI uptake will also be low or absent [58]. (See "Exogenous hyperthyroidism", section on 'Causes'.)
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
●Definition and pathogenesis – Graves disease is the most common cause of hyperthyroidism in children and adolescents, is more common in females, and usually presents during adolescence. It is characterized by excessive thyroid hormone production caused by stimulating thyroid-stimulating hormone (TSH) receptor antibodies (TSHR-Ab). (See 'Epidemiology' above and 'Autoimmune mechanisms' above.)
●Clinical manifestations
•Symptoms and signs – Clinical manifestations of thyrotoxicosis include weight loss or failure to gain weight, modest acceleration of linear growth and epiphyseal maturation, tachycardia and increased cardiac output, lid lag and stare, increased gastrointestinal motility, proximal muscle weakness, tremor, hyperreflexia, sleep disturbance, distractibility, and emotional lability.
Thyroid eye disease (TED) is characterized by proptosis and/or ocular muscle dysfunction and is highly suggestive of Graves disease. However, the absence of TED does not preclude a diagnosis of Graves disease. A diffuse goiter is also common in Graves disease but may be seen in other forms of thyrotoxicosis. (See 'Clinical manifestations' above.)
•Thyroid function tests – Measurement of serum thyroid function tests in patients with Graves disease will usually demonstrate a suppressed serum thyroid stimulating hormone (TSH) and elevated free thyroxine (fT4) and triiodothyronine (T3). This pattern of thyroid function tests will also be seen in other forms of thyrotoxicosis and occasionally in patients taking biotin due to assay interference. Patients should stop taking biotin before thyroid function tests are conducted.
Mild or sub-clinical hyperthyroidism may present with suppressed TSH with normal or slightly elevated fT4 and T3. Patients should be followed with measurement of TSH, fT4 and T3 every six weeks- three months to determine whether a thyroid disorder requiring treatment develops or thyroid function returns to normal. (See 'Serum thyroid function tests' above.)
●Diagnostic evaluation – In children with evidence of thyrotoxicosis, we conduct a thorough history, addressing other causes of hyperthyroidism (eg, medication-induced- hyperthyroidism or thyroid injury). (See 'Differential diagnosis: Other causes of thyrotoxicosis' above.)
We then measure TSHR-Ab either as thyroid-stimulating immunoglobulin (TSI) or thyrotropin-binding inhibitory immunoglobulin (TBII; also known as thyrotropin receptor antibody [TRAb]). If either TSI or TBII is positive, the diagnosis of Graves disease is confirmed. If TSHR-Ab is negative, thyroglobulin antibodies (Tg-Ab) and thyroid peroxidase antibodies (TPO-Ab) are measured, although many experts measure Tg-Ab and TPO-Ab at the same time as TSI or TBII. If Tg-Ab and/or TPO-Ab are positive in a patient with negative TSHR-Ab, a thyrotoxic phase of Hashimoto thyroiditis is likely, and we follow thyroid function tests (TSH, free T4) every month until thyrotoxicosis resolves. (See 'Serum thyroid antibody tests' above.)
If thyrotoxicosis does not resolve by 12 weeks or if Tg-Ab and TPO-Ab are negative, we perform radioactive iodine (RAI) uptake and scan. Some experts perform an RAI uptake and scan immediately if TSHR-Ab is negative in order to prevent a potential delay in treatment of Graves disease. An elevated RAI uptake with a diffuse pattern is typical of Graves disease, but a normal RAI uptake does not exclude Graves disease. (See 'Radionuclide uptake and scan for selected patients' above.)
●Differential diagnosis – The most common non-Graves disease cause of thyrotoxicosis in children is autoimmune thyroiditis with a thyrotoxic phase ("Hashitoxicosis"). Other causes include subacute thyroiditis ("De Quervain disease"), single or multiple autonomous nodules, a TSH-secreting pituitary adenoma, resistance to thyroid hormone beta (RTH-beta), factitious thyrotoxicosis, and certain drugs (table 1). (See 'Destructive thyroiditis with thyrotoxic phase' above.)
