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Clinical manifestations and diagnosis of Graves disease in children and adolescents

Clinical manifestations and diagnosis of Graves disease in children and adolescents
Literature review current through: Jan 2024.
This topic last updated: Mar 03, 2022.

INTRODUCTION — Graves disease is caused by autoantibodies that bind to the thyrotropin receptor (TSHR-Ab), stimulating growth of the thyroid and overproduction of thyroid hormone. It is by far 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 ophthalmopathy, which is not found in other etiologies of hyperthyroidism. In 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 during 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. However, strictly speaking, 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.

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 in which the primary mechanism is stimulating antibodies to the thyrotropin receptor (TSHR-Ab). Other types of 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.

Stimulating or blocking TSHR-Ab also may be present in some types of destructive thyroiditis, but these disorders are distinct from Graves disease because the antibodies are not the primary cause of the thyroid dysfunction. (See 'Destructive thyroiditis with thyrotoxic phase' below.)

Genetic factors strongly influence the predisposition to Graves disease, as shown in a population-based study of Danish twins that estimated 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 "Immune reconstitution inflammatory syndrome".)

Graves ophthalmopathy is not a secondary consequence of thyrotoxicosis. Instead, it may result from antibodies against a TSHR-like protein 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 ophthalmopathy, 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 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]. The patients themselves 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) also have an increased risk for Graves disease [15]. In a review from Spain, 12 of 1832 patients with Down syndrome were diagnosed with hyperthyroidism (6.5 cases/1000) [16]. In a separate series, Down syndrome patients tended to be diagnosed with hyperthyroidism at an earlier age as compared with children without Down syndrome and they did not show the usual female preponderance [17]. Patients with Turner syndrome may also be at increased risk for hyperthyroidism; in one series, 2 out of 119 patients developed Graves disease [18]. (See "Down syndrome: Clinical features and diagnosis" and "Clinical manifestations and diagnosis of Turner syndrome".)

CLINICAL MANIFESTATIONS — Many of the clinical features of hyperthyroidism in children and adolescents are similar to those in adults [10,19]. The onset of these manifestations is often insidious, and the changes may be present for months or years before the diagnosis is made. Hyperthyroidism has unique effects in children on growth and pubertal development.

General symptoms and signs of thyrotoxicosis — Graves disease is 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 [20]. 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 [21].

Patients with hyperthyroidism tend to have low serum total and high-density lipoprotein (HDL) cholesterol concentrations and a low total cholesterol:HDL cholesterol ratio. These values increase after treatment [22].

Gastrointestinal – Failure to gain weight or weight loss, despite an increase in appetite, is common. Weight loss is caused primarily by increased calorigenesis and secondarily by increased gut motility and associated hyperdefecation and malabsorption. With treatment, children regain lost weight [23]. 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 [24].

The prevalence of celiac disease and inflammatory bowel disease is probably modestly increased among individuals with autoimmune thyroid disease [25,26]. 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 [27].

It is important to distinguish lid lag and stare from features of ophthalmopathy (proptosis and periorbital edema), which are found in Graves disease but almost never in other forms of hyperthyroidism. (See 'Graves ophthalmopathy' below.)

Neurologic – Graves disease can be associated with a variety of neurologic manifestations (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 [28].

Cognitive dysfunction – Among very young children (<4 years), hyperthyroidism may cause neurodevelopmental delay [29]. In particular, speech and language delay has been reported as an unusual presentation of hyperthyroidism and improves with treatment for the hyperthyroidism [30].

Peripheral nervous system – Proximal muscle weakness may be present, with decreased muscle mass and decreased efficiency of muscle contraction [31]. Rarely, patients may 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".).

Rare neurologic manifestations that have been reported in Graves disease include benign intracranial hypertension, which was reported in a child presenting with headache and papilledema; these findings reversed with treatment [32]. Graves disease also has been reported in association 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 [33]. Although it is rare, moyamoya disease should be considered in patients with Graves disease and focal neurologic symptoms. A case report describes the initial co-presentation 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 [34]. (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 [35]. Their attention span decreases, they are usually hyperactive, they sleep poorly, and their school performance deteriorates. Occasionally, children or adults with hyperthyroidism may experience marked personality changes, agitation, anxiety, depression, mania, or psychosis [36,37]. (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 [37].

Bone – Thyroid hormone stimulates bone resorption, resulting in increased porosity of cortical bone and reduced volume of trabecular bone [38]. 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 [39]. Sweating is increased because of increased calorigenesis. Onycholysis (loosening of the nails from the nail bed [Plummer nails]) and softening of the nails and thinning of the hair may occur. Vitiligo and alopecia areata can occur in association with 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 [40]. 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 [41]. Nonetheless, adult height was normal after treatment with antithyroid drugs and was even slightly increased in the boys 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 [41]. Girls who have undergone menarche may develop oligomenorrhea or secondary amenorrhea; anovulatory cycles are common [42]. Hyperthyroidism is associated with high levels of sex hormone-binding globulin, which may result in high serum estradiol levels in girls and testosterone levels in boys. 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 men; there have been no reports of gynecomastia in boys with Graves hyperthyroidism.

Other characteristic features of Graves disease — Ophthalmopathy and goiter are seen in most cases of Graves disease and help to distinguish this disorder from other causes of hyperthyroidism.

Graves ophthalmopathy — In a child with thyrotoxicosis, the presence of eye findings such as exophthalmos or ocular muscle dysfunction essentially always points to Graves disease as the underlying etiology of these features. Even in children with hyperthyroidism who have a goiter but who lack ophthalmopathy, Graves disease is still the most likely cause. (See "Clinical features and diagnosis of thyroid eye disease".)

Ophthalmopathy is characterized by inflammation of the extraocular muscles and orbital fat and connective tissue, which results in proptosis (exophthalmos), impairment of eye muscle function, and periorbital edema. Patients with ophthalmopathy 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 [43]. Although 50 to 75 percent of children with Graves disease have some features of Graves ophthalmopathy, the symptoms tend to be milder than those seen in adults [43,44]. In a series of 152 children with Graves disease, only 17 percent required referral to an ophthalmologist for management of Graves eye disease [45]. Another study showed a trend toward less severe eye findings in prepubertal as compared with postpubertal children [46]. Ophthalmopathy is more common in patients who smoke cigarettes.

Goiter — Most children with Graves hyperthyroidism have a diffuse goiter [44]. 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 less common 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 a suspicion of an autonomously functioning adenoma ("toxic adenoma"), while multiple palpable nodules are present in toxic multinodular goiter. Children presenting 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.)

DIAGNOSTIC EVALUATION — In many children and adolescents, the presence of hyperthyroidism is obvious from the history and physical examination, once it is considered. However, because the symptoms and signs 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; 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 clinicians should perform an appropriate diagnostic evaluation.

Serum thyroid function tests — If hyperthyroidism is suspected clinically, the first step is to measure serum levels of thyrotropin (thyroid-stimulating hormone [TSH]), free thyroxine (fT4), and triiodothyronine (T3) [47]. Results are interpreted as follows:

FT4 and T3 elevated for age, with suppressed TSH – These findings confirm thyrotoxicosis.

Normal fT4 with suppressed TSH – Some children who undergo thyroid function tests for a suspected thyroid disorder manifest suppressed serum TSH levels but normal fT4 levels (and normal T3 levels, if measured). Such results are compatible with "subclinical hyperthyroidism." In one study, follow-up testing of 23 such children over a several-month period showed that 14 returned to euthyroidism, 4 developed hypothyroidism, and 3 maintained a suppressed TSH but normal fT4, while 2 progressed to overt hyperthyroidism [48]. Thus, it is prudent to follow such children with serial testing to determine whether a thyroid disorder requiring treatment develops or whether thyroid function returns to normal. In patients taking biotin, suppressed TSH may be caused by a laboratory artifact, as described immediately below.

Normal results – Normal results of thyroid function tests essentially exclude thyrotoxicosis. Rarely, some children will have normal thyroid function tests despite typical physical features of Graves disease, including a goiter and Graves eye findings and positive thyrotropin receptor antibodies (TSHR-Ab); this presentation is termed "euthyroid Graves disease." Such patients generally are followed without treatment, with periodic monitoring of thyroid function tests.

These tests also may help to identify causes of thyrotoxicosis other than Graves disease. As an example, the possibility of some form of destructive thyroiditis is suggested by the presence of a T4 concentration that is proportionally more elevated and T3 less elevated than typically seen with Graves disease, with suppressed TSH [49]. By contrast, predominant T3 elevation suggests an autonomously functioning nodule [49] or toxic multinodular goiter. (See 'Differential diagnosis: Other causes of thyrotoxicosis' below and "Laboratory assessment of thyroid function".)

Of note, pharmacologic doses of biotin (such as those used for certain inherited metabolic diseases) may cause artifactual abnormalities in laboratory tests of TSH, T4, and TSHR-Ab. These vary with the assay used, but subnormal serum TSH levels have been reported, thus mimicking hyperthyroidism [50,51]. (See "Overview of water-soluble vitamins", section on 'Multiple carboxylase deficiency'.)

Serum thyroid antibody tests — After thyroid function testing confirms that the patient is hyperthyroid, the next step is to determine the cause of hyperthyroidism. The various etiologies can be distinguished by the clinical examination, serum antithyroid antibody measurement, and radioactive iodine (RAI) uptake (table 1 and algorithm 1). (See 'Differential diagnosis: Other causes of thyrotoxicosis' below.)

Since Graves disease is by far the most common cause of thyrotoxicosis, the evaluation typically begins by measurement of TSHR-Ab to confirm this diagnosis. We recommend starting with a measurement of thyroid-stimulating immunoglobulin (TSI). TSI 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 [52-54]. 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 [53].

An alternative TSHR-Ab test is thyrotropin-binding inhibitory immunoglobulin (TBII). This test, employing competitive protein-binding methodology, shows that there is an antibody that competes with TSH binding to its receptor, but the test does not provide information about whether it is a stimulating or blocking antibody. One study of 57 children with Graves disease actually reported that TBII was positive in all patients measured (n = 18), while TSI was positive in only 57 percent of patients [54]. Thus, TBII may be helpful in establishing a diagnosis of Graves disease in patients with typical symptoms and signs but in whom TSI is negative. Newer third-generation TSHR-Ab immunoassays, also using competitive protein-binding methodology, have been reported to be positive in close to 97 percent of adults with Graves disease [55].

Other antithyroid antibodies, such as thyroid peroxidase antibodies (TPO-Ab) and thyroglobulin antibodies (Tg-Ab) generally are not obtained on initial laboratory testing. However, in children with confirmed hyperthyroidism in whom TSHR-Ab tests are negative, measurement of TPO-Ab and Tg-Ab can help evaluate for a possible thyrotoxic phase of autoimmune thyroiditis ("Hashitoxicosis"). TPO-Ab and Tg-Ab are also present in Graves disease, but the levels tend to be even more elevated in autoimmune thyroiditis. (See 'Destructive thyroiditis with thyrotoxic phase' below.)

Radionuclide uptake and scan — If the TSI level is not elevated, the next step is to perform RAI uptake. Iodine-123 (I-123) is the radionuclide of choice for thyroid uptake and scans because it has a shorter half-life (13.2 hours) and delivers a much smaller radiation dose to the thyroid gland as compared with I-131. The RAI uptake (typically assessed at 6 and 24 hours after isotope administration) is elevated in Graves disease, and the accompanying scan typically shows diffuse uptake throughout the gland, confirming the diagnosis of Graves hyperthyroidism [56]. The RAI uptake and scan also helps to delineate etiologies other than Graves disease. 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.

Increased RAI uptake in the location of a palpable nodule, with reduced or absent uptake in the rest of the gland, is typical of a toxic adenoma. Spotty uptake in multiple areas of the gland is typical of toxic multinodular goiter. RAI uptake will be reduced or absent in the various forms of destructive thyroiditis. (See 'Differential diagnosis: Other causes of thyrotoxicosis' below.)

Ultrasound — Thyroid ultrasonography is not part of the routine diagnostic evaluation in children with hyperthyroidism. It may be performed in cases where a single or multiple nodules are identified on physical examination, so as to provide more objective characteristics of these nodules, or when significant neck trauma precedes discovery of thyrotoxicosis.

DIAGNOSIS OF GRAVES DISEASE — Graves disease should be suspected in patients presenting with signs and symptoms of thyrotoxicosis (tachycardia, weight loss or poor weight gain, and lid lag, often with tremor and neuropsychiatric symptoms). Most patients have goiter and ophthalmopathy. Not all eye findings indicate Graves disease; stare and lid lag may be present with other causes of hyperthyroidism, and true findings of Graves eye disease may be subtle and apparent only when examined by an ophthalmologist. (See 'Clinical manifestations' above.)

Thyrotoxicosis – The diagnosis of thyrotoxicosis is confirmed by the findings of elevated free thyroxine (fT4) and triiodothyronine (T3), with suppressed thyrotropin (thyroid-stimulating hormone [TSH]).

Graves disease – The diagnosis of Graves disease as the cause of the thyrotoxicosis is confirmed by the presence of thyrotropin receptor antibodies (TSHR-Ab), which are detectable in the majority of children with Graves disease. A positive thyroid-stimulating immunoglobulin (TSI) confirms the presence of a TSHR-stimulating antibody. If the TSI is not elevated, an alternative TSHR-Ab test by competitive protein-binding methodology, such as one of the newer third-generation immunoassays, may confirm the diagnosis of Graves disease [55]. When antibodies are not detected, the diagnosis can be supported by a 24-hour radioactive iodine (RAI) uptake and scan that shows diffuse increased uptake. (See 'Diagnostic evaluation' above.)

If this testing fails to confirm the diagnosis of Graves disease, other less common causes of thyrotoxicosis should be considered (table 1 and algorithm 1). (See 'Differential diagnosis: Other causes of thyrotoxicosis' below.)

Mild hyperthyroidism – Some children with mild hyperthyroidism are detected when thyroid function tests are obtained for other reasons. Such patients may have few clinical manifestations to suggest hyperthyroidism or may be asymptomatic. Often, these patients have a suppressed TSH with normal fT4 and T3 (subclinical hyperthyroidism) or mild elevations of fT4 and/or T3. Measurement of TSHR-Ab (either TSI or thyrotropin-binding inhibitor immunoglobulin [TBII]) may be borderline or normal.

In such patients, we recommend observation without treatment, with monitoring of thyroid function tests every six weeks to three months. For children who have mild symptoms that might be related to hyperthyroidism, such as palpitations, tremor, or anxiety, a trial of a beta blocker is a treatment option while monitoring thyroid function. Patients with Graves disease will usually progress to true hyperthyroidism, whereas patients with some form of destructive thyroiditis will experience a gradual return to normal thyroid function. High doses of biotin may cause artifactual abnormalities in thyroid tests.

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:

Toxic adenoma – Solitary nodules, or "toxic adenomas," are an uncommon cause of hyperthyroidism in childhood. They are suspected in the setting of hyperthyroidism and palpation of a nodule on neck examination. In general, to produce hyperthyroidism, most nodules must be large (>3 cm) [57]; many of these have been shown to be the result of thyrotropin receptor (TSHR) gene-activating mutations [58,59]. Thyroid adenomas typically produce triiodothyronine (T3), so serum testing may show an elevated T3 and suppressed thyrotropin (thyroid-stimulating hormone [TSH]), with a normal or mildly elevated free thyroxine (fT4) [49]. Thyroid antibodies, including thyroid-stimulating immunoglobulin (TSI), are negative. Radioactive iodine (RAI) uptake and scan will show uptake only in the functioning nodule, with the rest of the gland suppressed [56]. The hyperthyroidism can be treated with antithyroid drugs, but ultimately, most are managed by surgical resection of the adenoma. Small nodules (<1 cm), often discovered incidentally during imaging, are less likely to cause hyperthyroidism, and another cause should be sought.

Toxic multinodular goiter – Toxic multinodular goiters are another relatively uncommon cause of hyperthyroidism in children. They are suspected in the setting of hyperthyroidism and palpation of a goiter with multiple nodules. An ultrasound examination is generally undertaken because it is more sensitive than physical examination in detecting multiple nodules [56]. Antithyroid antibodies, including TSI, are negative. Generally, an RAI uptake and scan is indicated to separate this condition from the thyrotoxic phase of autoimmune thyroiditis ("Hashitoxicosis"), or subacute granulomatous thyroiditis. The uptake will be elevated and seen in the multiple nodules. Some cases of toxic multinodular goiter have been shown to be the result of TSHR gene-activating mutations, as described for solitary nodules [59].

In addition, approximately one-third of children with McCune-Albright syndrome develop hyperthyroidism and a multinodular goiter [60]. McCune-Albright syndrome, caused by an activating mutation of the gene-encoding alpha subunit of the stimulatory G protein, is characterized (in its classic form) by café-au-lait pigmentary skin lesions, fibrous dysplasia of the bones, and precocious puberty. While the hyperthyroidism can be treated with antithyroid drugs, eventually, a more permanent form of treatment, such as surgical thyroidectomy or RAI ablation, must be considered. (See "Definition, etiology, and evaluation of precocious puberty", section on 'McCune-Albright syndrome'.)

Pituitary TSH-secreting adenoma – TSH-secreting adenomas are rare at any age, and only a few have been reported in children [61,62]. Cases of TSH-secreting pituitary adenomas have been described in children in association with type 1 autoimmune polyglandular syndrome [63] and with resistance to thyroid hormone [64]. Laboratory testing typically shows an elevated fT4 with a normal (not suppressed) TSH level. The diagnosis is made by finding a high serum alpha subunit concentration, high alpha subunit-to-TSH ratio, and little or no TSH response to TSH-releasing hormone. A pituitary adenoma is confirmed on magnetic resonance imaging. Treatment is surgical resection. (See "TSH-secreting pituitary adenomas".)

Resistance to thyroid hormone – Resistance to thyroid hormone is an autosomal dominant disorder usually due to a mutation in the thyroid hormone receptor beta gene [65,66]. Affected children commonly present with a goiter and elevated serum fT4 and, to a lesser extent, elevated T3 levels, while TSH is normal or slightly elevated. They are usually euthyroid because the elevated thyroid hormone concentrations are able to overcome the nuclear receptor defect. However, they may have some tissue-specific clinical manifestations of hypothyroidism and/or hyperthyroidism because the most common defect involves the receptor beta gene and tissues with predominantly alpha receptors will respond to the excess thyroid hormone concentrations. In addition, those with apparent preferential pituitary resistance may manifest thyrotoxic clinical features. (See "Resistance to thyroid hormone and other defects in thyroid hormone action".)

Attempts have been made to try to distinguish pituitary from generalized resistance to thyroid hormone by measuring other biochemical markers of hyperthyroidism (eg, serum cholesterol, ferritin, and sex hormone-binding globulin) or by measuring the basal metabolic rate. Children with generalized resistance to thyroid hormone probably are not helped by any treatment. Children with more pituitary resistance may need some form of treatment of their hyperthyroidism, such as partial thyroidectomy or RAI ablation. However, such patients will be at risk for pituitary thyrotroph hypertrophy, which in the long term, may produce complications similar to a pituitary adenoma.

Destructive thyroiditis with thyrotoxic phase — Destructive thyroiditis may be associated with transient thyrotoxicosis due to release of preformed stored thyroid hormones.

Autoimmune thyroiditis with thyrotoxic phase – Autoimmune thyroiditis (also known as chronic lymphocytic thyroiditis or "Hashimoto thyroiditis") generally is associated with euthyroidism, while, in some cases, it causes hypothyroidism due to destruction of thyroid tissue. However, approximately 5 to 10 percent of children present with a hyperthyroid (thyrotoxic) phase, sometimes termed "Hashitoxicosis." Hyperthyroidism in this entity is usually caused by inflammation and autonomous release of preformed stored thyroid hormone. The thyrotoxicosis tends to have a brief course, lasting a few weeks to months, and Graves ophthalmopathy is absent. These features help to distinguish this disorder from Graves disease.

Thyroglobulin antibodies (Tg-Ab) and thyroid peroxidase antibodies (TPO-Ab) are commonly positive (similar to Graves disease). In contrast with what is found in Graves disease, TSHR antibodies (TSHR-Ab), when measured as TSI, are typically negative in patients with Hashitoxicosis, although thyrotropin-binding inhibitor immunoglobulin (TBII) may be positive (table 1). RAI uptake also helps to distinguish between Graves disease and Hashitoxicosis: RAI uptake is high (and diffuse) in Graves disease and low or absent in most cases of Hashitoxicosis, and a scan will show an inhomogeneous picture [67]. Thyroid ultrasound typically shows a "moth-eaten" pattern of scattered hypo- or hyperechogenicity (image 1). Because there is no overproduction of thyroid hormone, antithyroid drug treatment is not effective; patients can be treated with beta-adrenergic antagonists until the thyrotoxicosis resolves.

Despite these typical differences, it is sometimes impossible to distinguish between Graves disease and Hashitoxicosis initially since some children with Hashitoxicosis have positive TSI or elevated 24-hour RAI uptake at presentation. During the hyperthyroid phase, clinical clues that suggest Hashitoxicosis rather than Graves disease include relatively rapid resolution of hyperthyroidism during treatment with antithyroid drugs, typically within six months of diagnosis. 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 [68]. (See 'Diagnostic evaluation' above.)

Some patients with autoimmune thyroid disease appear to produce both TSHR-Ab (as do patients with Graves disease) and thyroid-blocking antibodies. In this case, the clinical course depends on which antibody predominates and the patients tend to 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 [67]. 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.

Subacute granulomatous thyroiditis – Subacute thyroiditis, also known as de Quervain disease or painful thyroiditis, is rare in childhood. It is characterized by painful swelling of the thyroid gland and most likely is caused by a viral infection, and has now been reported with coronavirus disease 2019 (COVID)-19 infections [69]. The inflammation results in autonomous release of preformed stored thyroid hormone, resulting initially in a thyrotoxic phase, followed by euthyroidism, then hypothyroidism, and usually returning to euthyroidism. Thyroid antibodies are negative; RAI uptake is low or absent during the thyrotoxic phase [56]. During the thyrotoxic phase, patients can be treated with beta-adrenergic antagonists. (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 [70]. (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 [71]. 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 [72]. 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 autonomously functioning nodules as part of a multinodular goiter. It occurs primarily in older adult men 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) [73], induces thyrotoxicosis. RAI uptake is usually decreased, though it may be normal or increased. Symptoms can be managed with beta-adrenergic antagonists until the thyrotoxicosis resolves spontaneously. (See "Disorders that cause hyperthyroidism", section on 'Iodine-induced hyperthyroidism'.)

Other drugs – Drugs such as lithium and the expanding category of drugs that cause dysregulation of the immune system (interferon-alfa, interleukin-2, checkpoint 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 hyperthyroidism but absent goiter. It is most commonly seen in adolescents with access to T4 who are trying to lose weight. Measurement of serum Tg is useful because it is elevated in all of the endogenous forms of hyperthyroidism but is low in factitious thyrotoxicosis. RAI uptake will also be low or absent [56]. (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 by far the most common cause of hyperthyroidism in children and adolescents, is more common in females, and usually presents during early adolescence. It is characterized by excessive thyroid hormone production, caused by stimulating thyrotropin receptor antibodies (TSHR-Ab). (See 'Epidemiology' above and 'Autoimmune mechanisms' above.)

Clinical manifestations

Symptoms and signs – Clinical manifestations of hyperthyroidism include modest acceleration of linear growth and epiphyseal maturation, weight loss or failure to gain weight, excessive retraction of the eyelids causing lid lag and stare, tachycardia and increased cardiac output, increased gastrointestinal motility, proximal muscle weakness, tremor, hyperreflexia, sleep disturbance, distractibility with unexplained poor school performance, and emotional lability. Children with Graves disease frequently have mild ophthalmopathy, with proptosis and a gritty sensation; ophthalmopathy is not seen in other forms of hyperthyroidism. A diffuse goiter is also common in Graves disease but may be seen in other forms of thyrotoxicosis as well. (See 'Clinical manifestations' above.)

Thyroid function tests – Hyperthyroidism is suspected on the basis of the above clinical findings and confirmed by measurement of serum thyroid function tests (algorithm 1). Serum thyrotropin (thyroid-stimulating hormone [TSH]) is suppressed, and free thyroxine (fT4) and triiodothyronine (T3) are elevated for age. (See 'Serum thyroid function tests' above.)

Diagnosis – In children with suspected or confirmed hyperthyroidism, TSHR-Ab should be measured (algorithm 1). In our practice, we start with measurement of thyroid-stimulating immunoglobulin (TSI); TSI will be positive in 60 to 94 percent of children with Graves disease. If the TSI is not elevated, a TSHR-Ab test, or thyrotropin-binding inhibitory immunoglobulin (TBII), may confirm the diagnosis of Graves disease. If neither of these antibody tests confirm Graves disease, then a radioactive iodine (RAI) uptake should be performed; elevated RAI with a diffuse pattern is typical of Graves disease. (See 'Serum thyroid antibody tests' above.)

Differential diagnosis – Other causes of hyperthyroidism in children include autoimmune thyroiditis with a thyrotoxic phase ("Hashitoxicosis"), subacute thyroiditis ("de Quervain disease"), toxic adenoma, toxic multinodular goiter, TSH-secreting pituitary adenoma, pituitary resistance to thyroid hormone, factitious thyrotoxicosis, and certain drugs (table 1). (See 'Destructive thyroiditis with thyrotoxic phase' above.)

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Topic 5841 Version 29.0

References

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