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Clinical manifestations and diagnosis of Graves

disease in children and adolescents
Author: Stephen LaFranchi, MD
Section Editor: Mitchell E Geffner, MD
Deputy Editor: Alison G Hoppin, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2019. | This topic last updated: Jul 19, 2018.

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 and is not caused by the high serum thyroid hormone
concentrations. 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 about 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 about 80 percent of
pediatric cases occur after 11 years of age [1-4]. During adolescence, a strong female
predominance develops, at a ratio of about 5:1 [2-4]. The ratio is considerably lower among
younger children, suggesting that estrogen secretion in some way affects the occurrence of
Graves disease. A report using data from the US National Health and Nutritional
Examination Surveys analyzing adolescents and young adults found that thyrotoxicosis was
more common in non-Hispanic blacks than Mexican Americans, in whom it was more
common than non-Hispanic whites [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 thyrotropin receptor
(TSHR). These blocking antibodies may be produced intermittently in patients with Graves
disease, and so 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, which 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, 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 retroorbital 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 Graves' orbitopathy (ophthalmopathy)"). The same
mechanism may be responsible for Graves dermopathy, as 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 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" and "Epidemiology and environmental factors in inflammatory bowel disease
in children and adolescents".)

● Eyes – Stare and lid lag occur in many children with hyperthyroidism. "Stare" refers to
the patient's widely opened eyes, which give the appearance of staring. Lid lag is
evaluated by having the patient follow the examiner's finger as it is moved up and
down. The patient has lid lag if the sclera can be seen above the iris as the patient
looks downward. These symptoms are caused by sympathetic overactivity, possibly
mediated by increased alpha-adrenergic receptors in some tissues, and so may be
seen in any form of hyperthyroidism [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 Asian
adolescent boys.

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:
Etiology, clinical features, and diagnosis".)

● Behavioral and psychiatric – Children with hyperthyroidism tend to have greater

mood swings and disturbances of behavior, as 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, depression, mania, or
psychosis [36]. (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.

● Bone – Thyroid hormone stimulates bone resorption, resulting in increased porosity of

cortical bone and reduced volume of trabecular bone [37]. 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 [38]. Sweating is increased because
of increased calorigenesis. Onycholysis (loosening of the nails from the nail bed,
Plummer's 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 [39]. 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 [40]. 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 does not
appear to be altered by hyperthyroidism [40]. Girls who have undergone menarche may
develop oligomenorrhea or secondary amenorrhea; anovulatory cycles are common
[41]. 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 Graves' orbitopathy (ophthalmopathy)".)

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 these findings almost always have Graves
disease. 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 [42]. 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 [42,43]. In a series of 152 children with Graves disease,
only 17 percent required referral to an ophthalmologist for management of Graves eye
disease [44]. Another study showed a trend toward less severe eye findings in prepubertal
as compared with postpubertal children [45]. Ophthalmopathy is more common in patients
who smoke cigarettes.

Goiter — Most children with Graves hyperthyroidism have a diffuse goiter [43]. The
surface tends to be smooth, fleshy in consistency, 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.
Besides thyroid function tests, children presenting with these findings should be evaluated
further with ultrasound and radionuclide uptake and scan. (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. The presence in children of 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 should raise a clinical
suspicion of Graves disease, and be followed by an appropriate diagnostic evaluation.

Serum thyroid function tests — If hyperthyroidism is suspected clinically, the first step is
to measure serum levels of thyrotropin (TSH), free thyroxine (fT4), and triiodothyronine (T3)
[46]. 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, four developed hypothyroidism,
four maintained a suppressed TSH but normal fT4, while two progressed to overt
hyperthyroidism [47]. 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.

● Normal results – Normal results of thyroid function tests essentially excludes

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 thyroxine (T4) concentration that is proportionally more elevated and T3 less
elevated than typically seen with Graves disease, with suppressed TSH [48]. By contrast,
predominant T3 elevation suggests an autonomously functioning nodule [48] 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 [49,50]. (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 uptake (table 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
[51-53]. One study, describing a new technique, which employs a novel chimeric thyrotropin
receptor (TSHR) bioassay and a cAMP response element-dependent luciferase, reported
that a TSHR-stimulating Ab was present in 94 percent of children with Graves disease,
including 100 percent of untreated children at diagnosis [52].

An alternative TSHR-Ab test is thyrotropin-binding inhibitor immunoglobulin (TBII). This test,

employing competitive protein-binding methodology, shows that there is an antibody that
competes with TSH binding to its receptor, but it 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 [53]. 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 [54].

Other antithyroid antibodies, such as antithyroid peroxidase (anti-TPO) and

antithyroglobulin (anti-Tg) antibodies generally are not obtained on initial laboratory testing.
However, in children with confirmed hyperthyroidism in whom TSHR-Ab tests are negative,
measurement of anti-TPO and anti-Tg antibodies can help evaluate for a possible thyrotoxic
phase of autoimmune thyroiditis ("Hashitoxicosis"). Anti-TPO and anti-Tg antibodies 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.)

Radionucleotide uptake and scan — If the TSI level is not elevated, the next step is to
perform radioactive iodine (RAI) uptake. 123-I is the radionucleotide of choice for thyroid
uptake and scans, as it has a shorter half-life (13.2 hours) and delivers a much smaller
radiation dose to the thyroid gland as compared with 131-I. The RAI uptake (typically
assessed at 6 and 24 hours after isotope administration) is elevated in Graves disease, and
the accompanying scan typically will show diffuse uptake throughout the gland, confirming
the diagnosis of Graves hyperthyroidism [55]. The RAI uptake and scan also will help 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 123-I, 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.)

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
(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 thyrotropin receptor (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 [54]. 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). (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 [56]; many of these have been shown to be the
result of thyrotropin receptor (TSHR) gene-activating mutations [57,58]. Thyroid
adenomas typically produce triiodothyronine (T3), so serum testing may show an
elevated T3 and suppressed thyrotropin (TSH), with a normal or elevated free thyroxine
(fT4) [48]. 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 [55]. The hyperthyroidism can
be treated with antithyroid drugs, but ultimately most are managed by surgical resection
of the adenoma. Small nodules, eg, <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, as it is more sensitive than physical examination
in detecting multiple nodules [55]. 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 [58].
 In addition, approximately one-third of children with McCune-Albright syndrome develop
hyperthyroidism and a multinodular goiter [59]. 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. Again, 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 [60,61]. Cases of TSH-secreting pituitary
adenomas have been described in children in association with type 1 autoimmune
polyglandular syndrome [62], and with resistance to thyroid hormone [63]. 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
[64,65]. 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, as 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
"Impaired sensitivity to thyroid hormone".)

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 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.

Antithyroglobulin (anti-Tg) antibodies and antithyroid peroxidase (anti-TPO) are

commonly positive (similar to Graves disease). In contrast with what is found in Graves
disease, thyrotropin receptor 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 [66]. As 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 their hyperthyroidism during treatment with
antithyroid drugs, typically within six months of diagnosis. Indeed, whether
Hashitoxicosis is a distinct entity remains controversial because its clinical features and
 mechanisms overlap with both Graves disease and with 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 [67]. (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 [66]. As is typical in Hashitoxicosis, the duration of hyperthyroidism was
shorter than in Graves disease, ranging from 31 to 168 days. However, a minority of
these patients had elevated RAI uptake or mildly increased TSI levels, consistent with a
form of hyperthyroidism that is mediated by thyroid-stimulating antibodies.

● 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. 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 [55]. 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 [68].
(See "Suppurative thyroiditis in children and adolescents".)

Thyroid injury — Rarely, transient thyrotoxicosis may be caused by release of preformed

thyroid hormone in these disorders:

● Neck trauma-induced thyrotoxicosis – Significant neck trauma can result in

thyrotoxicosis [69]. 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 [70]. 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 elderly 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) [71], induces thyrotoxicosis. RAI uptake is
decreased. 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 an adolescent
with access to thyroxine (T4) who is trying to lose weight. Measurement of serum
thyroglobulin (T4 and T3) is useful, as it is elevated in all the endogenous forms of
hyperthyroidism, but low in factitious thyrotoxicosis. RAI uptake will also be low or
absent [55]. (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".)

SUMMARY AND RECOMMENDATIONS

● Graves disease is by far the most common cause of hyperthyroidism in children and
adolescents, and usually presents during early adolescence. It is characterized by
excessive thyroid hormone production, caused by thyrotropin receptor antibodies
(TSHR-Ab). (See 'Epidemiology' above and 'Autoimmune mechanisms' above.)

● 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 (but not those with other forms of
hyperthyroidism) frequently have mild ophthalmopathy, with proptosis and a gritty
sensation. A diffuse goiter is also common in Graves disease, but also may be seen in
other forms of thyrotoxicosis. (See 'Clinical manifestations' above.)

● Hyperthyroidism is suspected on the basis of the above clinical findings and confirmed
by measurement of serum thyroid function tests. Serum thyrotropin (TSH) is
suppressed and free thyroxine (fT4) and triiodothyronine (T3) are elevated for age.
(See 'Serum thyroid function tests' above.)

● In children with suspected or confirmed hyperthyroidism, TSHR-Ab should be

measured. 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 employing third-generation
competitive protein-binding methodology may confirm the diagnosis of Graves disease.
If neither of these antibody tests confirm Graves disease, then a radioactive iodine
uptake (RAI) should be performed; elevated RAI with a diffuse pattern is typical of
Graves disease. (See 'Serum thyroid antibody tests' above.)

● 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 19.0

GRAPHICS

Causes of thyrotoxicosis in children and adolescents

Antibody
tests
Thyroid
Name Synonyms Mechanism and other RAI
exam
laboratory
tests

Thyroid gland hyperfunction (increased synthesis of thyroid hormones)

Graves disease Hyperthyroid Thyrotropin TSHR-Ab* High, diffuse Symmetric

goiter receptor- positive (TSI nontender
von Basedow stimulating positive and goiter
disease antibodies TBII positive in
(TSHR-Ab) typical cases)
TPO-Ab
positive or
negative

Multinodular Toxic Autonomous All negative Normal or high, Nodular

hyperthyroid multinodular overproduction multifocal
goiter goiter of thyroid
hormone by
nodules

Autonomous Plummer's Same All negative High, single Single nodule

nodule disease focus; rest of
Toxic nodule gland
suppressed

TSH-producing Autonomous All negative High, diffuse Normal or

pituitary overproduction symmetric
adenoma of TSH goiter

Pituitary Overproduction All negative High, diffuse Symmetric

resistance to of TSH goiter
thyroid
hormone

Thyrotoxic phase of thyroiditis (excess release of preformed thyroid hormones)

Thyrotoxic Hashitoxicosis Autoimmune; TPO-Ab Low in Firm goiter,

phase of Lymphadenoid release of positive majority; sometimes
autoimmune goiter preformed Anti- inhomogeneous tender
thyroiditis hormone. thyroglobulin pattern
(Hashimoto antibody
disease) positive
TSHR-Ab*
usually
negative (TSI
is usually
negative; TBII
may be
positive)
 Subacute Painless Autoimmune; TPO-Ab Low (during Firm
autoimmune sporadic release of positive thyrotoxic nontender,
thyroiditis thyroiditis preformed phase) mildly
Silent hormone. May enlarged
thyroiditis also be thyroid
associated with
drugs (IFN-
alpha, IL-2,
lithium).

Subacute Subacute Viral; release TPO-Ab Low (during Painful goiter

granulomatous thyroiditis of preformed negative thyrotoxic
thyroiditis Painful hormone Elevated ESR phase)
subacute
thyroiditis
de Quervain
thyroiditis
Granulomatous
giant cell
thyroiditis

Drug-induced thyrotoxicosis

Factitious Thyrotoxicosis Low serum Low or absent No goiter

thyrotoxicosis factitia thyroglobulin

Iodine-induced Underlying Increased Often

hyperthyroidism multinodular multinodular
goiter; thyroid
hormone
release
triggered by
exposure to
iodine (eg,
contrast
agents,
amiodarone)

RAI: radioactive iodine uptake; TSHR-Ab: thyrotropin receptor-stimulating antibodies; TSI: thyroid-stimulating
immunoglobulin; TBII: thyrotropin-binding inhibitor immunoglobulin; TPO-Ab: thyroid peroxidase antibodies;
TSH: thyrotropin; IFN-alpha: interferon alfa; IL-2: interleukin-2; ESR: erythrocyte sedimentation rate.
* TSHR-Ab can be measured by either a TSI or TBII. In many labs this is now ordered as "TSH receptor antibody"
test (TSHR-Ab or simply TRAb). A positive TSI confirms the presence of a stimulating antibody and a diagnosis of
Graves disease. A positive TBII (or TSHR-Ab) confirms that there is an antibody that competes with TSH binding
to its receptor, but does not provide information about whether it is a stimulating or blocking antibody. A positive
TBII (or TSHR-Ab) in a patient with clinical thyrotoxicosis is most likely indicative of Graves disease.

Graphic 58890 Version 12.0

Contributor Disclosures
Stephen LaFranchi, MD Nothing to disclose Mitchell E Geffner, MD Grant/Research/Clinical Trial
Support: Novo Nordisk [Growth (Somatropin)]. Consultant/Advisory Boards: Daiichi-Sankyo [Type 2
diabetes (Colesevelam)]; Novo Nordisk [Growth (Somatropin)]; Nutritional Growth Solutions [Growth];
Pfizer [Growth (Somatropin)]; Spruce Biosciences [Congenital adrenal hyperplasia]. Other Financial
Interest: McGraw-Hill [Pediatric endocrinology (Textbook royalties)]; Ascendis [Data safety monitoring
board; Growth (Somatropin)]; Tolmar [Data safety monitoring board; Precocious puberty (GnRH
analog)]; Millendo [Data safety monitoring board; Prader-Willi syndrome]. Alison G Hoppin,
MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
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