Pediatric Graves' Disease

C F Mooij, T D Cheetham Pediatric Graves’ disease 11:1 e210073
et al. ETA guideline
GUIDELINES
2022 European Thyroid Association Guideline for

the management of pediatric Graves’ disease
Christiaan F Mooij1,*, Timothy D Cheetham2,3,*, Frederik A Verburg4, Anja Eckstein5, Simon H Pearce2,6,
Juliane Léger7 and A S Paul van Trotsenburg1
1Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam,
the Netherlands
2Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK
3Department of Pediatric Endocrinology, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK
4Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
5Department of Ophthalmology, University Duisburg Essen, Essen, Germany
6Endocrine Unit, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK
7Department of Pediatric Endocrinology and Diabetes, Reference Center for Rare Endocrine Growth and Development Diseases, Endo-ERN HCP,
Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, University of Paris, NeuroDiderot Institut National de la Santé et de la
Recherche Médicale (INSERM), Paris, France
Correspondence should be addressed to C F Mooij or A S P van Trotsenburg: c.mooij@amsterdamumc.nl or a.s.vantrotsenburg@amsterdamumc.nl
*(C F Mooij and T D Cheetham contributed equally to this work)
Abstract
Hyperthyroidism caused by Graves’ disease (GD) is a relatively rare disease in children.
Treatment options are the same as in adults – antithyroid drugs (ATD), radioactive Key Words
iodine (RAI) or thyroid surgery, but the risks and benefits of each modality are different. ff Graves’ disease
The European Thyroid Association guideline provides new recommendations for the ff pediatric
management of pediatric GD with and without orbitopathy. Clinicians should be alert ff childhood
that GD may present with behavioral changes or declining academic performance ff antithyroid drugs
in children. Measurement of serum TSH receptor antibodies is recommended for all ff radioactive iodine
pediatric patients with hyperthyroidism. Management recommendations include the ff total thyroidectomy
first-line use of a prolonged course of methimazole/carbimazole ATD treatment (3 years ff management
or more), a preference for dose titration instead of block and replace ATD, and to avoid ff clinical practice guideline
propylthiouracil use. Where definitive treatment is required either total thyroidectomy

or RAI is recommended, aiming for complete thyroid ablation with a personalized RAI
activity. We recommend avoiding RAI in children under 10 years of age but favor surgery
in patients with large goiter. Pediatric endocrinologists should be involved in all cases.
Introduction
Purpose and scope of guideline in the young. The European Thyroid Association
(ETA) guideline addresses the etiology, diagnosis and
Hyperthyroidism caused by Graves’ disease (GD) is a prognosis of pediatric GD patients with and without
relatively rare disease in children. Although treatment orbitopathy and includes evidence-based treatment
options are the same as in adults – antithyroid drugs recommendations. Fetal and neonatal thyroid
(ATD), radioactive iodine (RAI) and thyroid surgery – dysfunction related to maternal GD during pregnancy is
the benefits and risks of each modality are different not discussed in this guideline.
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Methodology thrill or bruit. Manifestations of thyroid eye disease include

proptosis and lid retraction and are as common in children
A taskforce of European clinician scientists led by a
as in adults, but inflammatory features are less severe (6, 7).
chairman (ASPvT) was established. For three important
In many pediatric GD patients, there is a diagnostic delay
clinical/treatment topics in pediatric GD, a systematic
due to suspected behavioral, gastrointestinal, respiratory
literature search and evaluation were performed:
or cardiac disease.
remission rate and adverse effects associated with ATD
treatment; efficacy and safety of RAI; efficacy and safety
of thyroidectomy. For additional questions, targeted How to diagnose hyperthyroidism?
literature searches were performed. The Grading of
Recommendations, Assessment, Development and In all pediatric patients with suspected hyperthyroidism,
Evaluation (GRADE) system was used for rating the strength serum FT4, FT3 and TSH should be measured. Since GD is the
of the recommendations and the quality of the underlying most frequent cause of hyperthyroidism, anti-TSH receptor
evidence (1). We used the following coding system: ‘1’, and anti-thyroperoxidase antibodies (TSHRAb – also
strong recommendation and ‘2’, weak recommendation known as thyroid-binding inhibitory immunoglobulin or
or suggestion. The quality of the evidence is rated as level TBII – and anti-TPO, respectively) should also be measured
‘ØØØØ’ – high, level ‘ØØØO’ – moderate , level ‘ØØOO’ (4). An elevated FT3 level is a more sensitive marker of overt
– low, or level ‘ØOOO’ – very low. The drafted guideline hyperthyroidism than FT4. This biochemical evaluation
version was discussed within the task force until consensus will confirm or refute the diagnosis of pediatric GD in most
was reached. The recommendations are listed in Table 1. cases (Table 2). If the clinical picture is suggestive of GD
but thyroid antibodies are absent, they should be repeated
a few weeks later. If there are still no signs of thyroid
autoimmunity, thyroid ultrasonography, scintigraphy
Hyperthyroidism – preferably with Tc-99m-pertechnetate – and additional
laboratory investigations can be considered (Table 2).
What is hyperthyroidism?
To avoid radiation exposure, thyroid ultrasonography
Hyperthyroidism is a pathological state characterized by with Doppler blood flow assessment is preferred over
increased synthesis and secretion of thyroid hormones scintigraphy (8), but scintigraphy is better for diagnosing a
(thyroxine (T4) and triiodothyronine (T3)) by the thyroid ‘hot’ autonomous nodule and excluding low iodine uptake
gland (2). Thyrotoxicosis refers to the clinical picture thyrotoxicosis.
of thyroid hormone excess. In childhood, most cases of
hyperthyroidism are caused by underlying thyroid disease
with high serum free T4 (FT4) or free T3 (FT3) concentrations
and a fully suppressed thyrotropin (TSH; <0.1 mIU/L) Graves’ disease
(3, 4). This is known as overt primary hyperthyroidism.
What is Graves’ disease?
Subclinical hyperthyroidism – a milder form – is defined as
a low or suppressed TSH (<0.4 mIU/L), but serum free T4 GD is an autoimmune disorder characterized by the
(FT4) and free T3 (FT3) within the reference interval. presence of TSHRAb resulting in an overactive thyroid
In children, hyperthyroidism is mostly caused by GD gland (Graves’ hyperthyroidism), ocular abnormalities
and is usually biochemically overt and clinically severe (Graves’ orbitopathy, GO) and – very rarely – localized
(4). The characteristics of GD and other possible causes dermopathy (pretibial myxoedema, PTM) (9). TSHRAb act
of hyperthyroidism and thyrotoxicosis in children are as agonist, induce excessive thyroid hormone secretion
shown in Table 2. Signs and symptoms of hyperthyroidism and uncouple the thyroid from pituitary control (10).
in children are similar to those in adults. Childhood They also stimulate thyroid gland growth via similar, but
hyperthyroidism may also cause accelerated growth not identical, signal transduction. In the orbit, TSHRAb
and bone maturation and deterioration in academic stimulation of fibroblasts expressing TSHR induces
performance (4). In healthy children, thyroid size at hyaluronan production, potentiated by cross-talk between
physical and ultrasound examination increases with age TSHR and insulin-like growth factor 1 receptors. This is
(5), but in GD, the thyroid is frequently symmetrically accompanied by retro-orbital inflammation, extraocular
enlarged. Increased thyroidal blood flow may result in a muscle fiber disruption and tissue edema (11). Finally,
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Table 1 European Thyroid Association 2022 recommendations for the management of pediatric Graves’ disease.
Medical treatment of hyperthyroidism caused by Graves’ disease (GD)

• Patients with GD require prompt treatment (1,ØØØØ).
• Either carbimazole (CBZ) or its active metabolite methimazole (MMI) should be used in young people with GD. Propylthiouracil
should not be used (1,ØØØØ).
• The initial antithyroid drug (ATD) dose is between 0.15 and 0.5 mg/kg of MMI or between 0.25 and 0.75 mg/kg of CBZ daily.
Both drugs are given once daily (1,ØØØO).
• Dose titration (DT) approach: with a DT approach, a starting dose of 0.15–0.3 mg/kg MMI or 0.25–0.5 mg/kg CBZ will normalize
thyroid hormone concentrations in most patients within the first 4–6 weeks. The dose is then reduced by 25–50% according
to prevailing thyroid function tests. Larger doses of ATD up to 0.5 mg/kg MMI or 0.75 mg/kg CBZ can be administered in more
severe, symptomatic cases (1,ØØØO).
• The treatment regimen may not require adjustment if FT4 or FT3 is relatively high but TSH is normal (1,ØOOO).
• Education about GD and especially its treatment is essential to optimize compliance, with attention to the developmental
age (1,ØØOO).
• Block and replace (BR) approach: a dose of 0.3–0.5 mg/kg MMI or 0.5–0.75 mg/kg CBZ will prevent endogenous thyroid
hormone production in most patients. Levothyroxine can be introduced in an age and weight-appropriate replacement dose
as the FT3 falls into the reference range. Higher doses of ATD can be used (for example 1.0 mg/kg MMI or 1.3 mg/kg CBZ) if
thyroid hormone concentrations, especially FT3, do not fall as expected (1,ØØØO).
• DT is the preferred means of ATD treatment in most cases (1,ØØØØ).
• Beta-adrenergic blockade is recommended in patients presenting with marked signs of thyroid hormone excess. This can be
stopped once the patient is biochemically euthyroid (1,ØØØO).
• Patients with untreated GD can be severely unwell with marked signs of thyroid hormone excess. Such patients should be
managed on a high dependency or intensive care unit (1,ØØØO).
• Patients managed with DT or BR should be seen approximately every 4 weeks for the first 3 months, moving to 2 and then
3 monthly assessments thereafter depending on the clinical course (1,ØØØO).
• A white cell count including neutrophil count and liver function tests should be checked at baseline because both can be
affected by the underlying disease process and ATD therapy (1,ØØØO).
• Thyroid hormone concentrations (FT4 and FT3) should normalize in most patients in the first 6 weeks with a noticeable
improvement in the first 4 weeks. TSH can remain suppressed for several months (1,ØØØO).
• Families should be warned about susceptibility to excessive weight gain while on ATD therapy (1,ØØØO).
• Minor ATD side effects occur in 10 to 20% of patients and are usually transient. Serious side-effects that warrant stopping ATD
are rare (2–3 per 100,000) (1,ØØØO).
• Patients and families should be counseled about ATD side effects and the criteria for stopping the drug and seeking health
professional guidance (1,ØØØØ).
• Alternative treatment with surgery or RAI should be discussed in patients who are thyrotoxic despite large doses of CBZ
(≥1.3 mg/kg/day) or MMI (≥1 mg/kg/day) (1,ØØØO).
• Definitive treatment (total thyroidectomy or RAI) should be considered in patients who develop severe neutropenia, signifi-
cant liver dysfunction or troublesome side-effects that fail to resolve. Definitive treatment may also be appropriate when
patients cannot accurately report potential ATD side effects, refractory compliance issues or when prolonged ATD therapy has
not resulted in remission (1,ØØØØ).
• TSH receptor antibodies (TSHRAb) can be used to predict the likelihood of remission. If TSHRAb are elevated then remission is
unlikely and ATD should not be stopped (1,ØØØO).
• ATD is normally administered for at least 3 years and only stopped when TSHRAb levels have been low for several months.
Longer courses of ATD (≥5 years) should be considered if the likelihood of remission is low on the basis of disease
characteristics at presentation (1,ØØØO).
• The overall remission rate after ATD treatment in pediatric GD patients is between 20 and 30% after 2 years of ATD treatment
and may increase with continuous ATD duration (1,ØØØØ).
• The signs of thyroid hormone excess should be discussed when ATD is stopped and a pathway for thyroid function testing
agreed (1,ØØØO).
• Patients who relapse following a course of ATD have the option of returning to ATD or choosing definitive treatment. The
decision may be influenced by factors such as age or stage of education (1,ØØØO).
• There is no established role for immune modulation with new agents such as biologics in the young person with GD (1,ØØØO).
Definitive treatment in pediatric GD – radioiodine (RAI)
• The objective of RAI (I-131) treatment is complete thyroid ablation. This is to prevent relapse and future development of
thyroid cancer (1,ØØOO).
• RAI should be avoided in patients younger than 5 years and only used in the age group 5–10 years when surgery is not a
realistic option. There is no contraindication to RAI use in patients older than 10 years/post-pubertal children (1,ØØOO).
• RAI activity should ideally be personalized using an activity of 15 MBq (0.4 miCi) per gram thyroid tissue when dosimetry is
difficult to organize or should aim at delivering at least 300 Gy to the thyroid gland when dosimetry is used. For the purpose of
I-131 dose calculation, thyroid weight is best estimated by ultrasound (2,ØØØO).
• Before RAI, ATD should be stopped for 3–7 days (1,ØØØO).
• RAI therapy should be avoided in the presence of active Graves’ orbitopathy (GO). In the case of inactive GO, a course of
steroids should be given concurrently in order to prevent relapse/exacerbation (1,ØØØØ).
(Continued)
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Table 1 Continued.
Definitive treatment in pediatric Graves’ disease – thyroidectomy

• Pediatric patients undergoing thyroidectomy should be operated on by a high-volume thyroid surgeon (1,ØØØØ).
• Total thyroidectomy is the operation of choice (1,ØØØO).
• The pediatric GD patient should be biochemically euthyroid prior to surgery. Pre-operative treatment with ATDs and, if
necessary, iodine, a beta-blocker and glucocorticoid may be needed (1,ØØØØ).
• Pre-operative treatment with vitamin D reduces the risk of post-operative transient hypocalcemia in those who are not
vitamin D replete (2,ØØOO).
• Levothyroxine treatment should be started soon after thyroidectomy (1,ØØOO).
Management of pediatric Graves’ orbitopathy
• Children with eye symptoms should be seen by an orbital specialist, preferably in combined (ophthalmologist/physician)
thyroid eye clinics (1,ØØØO).
• Mild GO symptoms without inflammatory features can be followed expectantly or, if indicated, with selenium supplementation
(2,ØØOO).
• Rare cases of moderate to severe active GO cases can be treated with anti-inflammatory drugs (e.g. i.v. corticosteroids)
(1,ØØOO).
• Chronic inactive stable GO, which may reduce quality of life, can be treated surgically as in adults; however, except for
decompression surgery this should be postponed until the facial skull has fully grown (1,ØØOO).
Management of an increased thyroid cancer risk
• Young patients with GD may, like adults, have a slightly higher risk of developing differentiated thyroid cancer (2,ØØOO).
• Children and adolescents with GD who have a palpable thyroid nodule should be managed by a pediatric endocrinologist in
collaboration with a pertinent multi-disciplinary team (2,ØOOO).
• Young patients with a thyroid nodule/nodules should either be evaluated by thyroid ultrasound, and proceed to cytological
evaluation if indicated from the sonographic findings, or undergo total thyroidectomy (2,ØØOO).
Prognosis
• Young people diagnosed with GD, diagnosed and treated in childhood, may have a lower quality of life than healthy peers.
This should be kept in mind and, where necessary, appropriate steps are taken to address this (1,ØØOO).
TSHR stimulation induces fibroblasts to differentiate into incidence is lower: 1 to 2.91/100,000 per year. GD is 3.4 times
adipocytes, resulting in tissue expansion in the orbit (12). more common in girls than boys (21). Before age 5 years, the
The etiopathogenesis of GD is not fully understood. prevalence is about ten times lower, with a girls-to-boys ratio
Genetically determined immunological susceptibility of 1.4. This ratio increases markedly with age, particularly
appears to interact with environmental insults (e.g. in the second decade of life (21, 22). GD incidence varies
cigarette use, infection, stress and gut microbiota). between countries and may be rising (23, 24).
Genetic susceptibility is linked to the HLA locus and other
immune-related genes (e.g. CTLA4, IL-2RA and PTPN22)
and thyroid-specific genes (e.g. TG and TSHR) (13, 14,
15). HCP5 polymorphisms have been associated with a Treatment of hyperthyroidism caused by
younger age at GD onset (16, 17). GD is associated with the Graves’ disease
occurrence of other autoimmune disorders such as type
General considerations
I diabetes mellitus, celiac disease and vitiligo and is more
common in Down syndrome (4, 18). In approximately 15% Because of deleterious effects of excess thyroid hormone on
of cases, there is a first-degree relative with autoimmune multiple organ systems, children with GD require prompt
thyroid disease. GD can also occur following bone marrow treatment. Occasional, evolving ‘mild’ cases, including
transplantation and HIV therapies (19). subclinical hyperthyroidism with minimal clinical and
biochemical disturbance, may benefit from a period of
surveillance to clarify the need for treatment.
What is the incidence and prevalence of GD
In general, initial treatment is medical. When this
in children?
fails or is not possible, a definitive treatment should be
Childhood GD accounts for 5% of all GD cases throughout considered. The proposed approach to treatment and
life (20). The overall incidence in children and adolescents follow-up is a general one and – depending on specific
is around 4.58/100,000 per year, but before age 15 years, the patient characteristics – can be individualized.
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Table 2 Causes of pediatric hyperthyroidism/thyroid hormone excessa.
Cause Etiology Clinical signs and symptoms, findings at ultrasonography Biochemical characteristics
Thyroid gland
Autoimmune
Graves’ disease Autoimmune disease characterized Changes in behavior, attention span, school performance, Elevated serum (F)T4 and (F)T3 levels;
by the presence of TSHRAb anxiety, disturbed sleep, fatigue, palpitations, tremor, suppressed TSH level; elevated TSHRAb
stimulating the thyroid gland. heat intolerance, sweating, tremor, diarrhea and weight
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May arise following interventions loss; symmetrical thyroid enlargement; sometimes
such as bone marrow accelerated growth and bone maturation; at US, the
transplantation thyroid is often enlarged and can be hyperechoic, with
heterogeneous echotexture and hypervascularity
Hyperthyroid phase of Autoimmune disease characterized Clinical signs and symptoms are typically milder and Elevated (F)T4 and (F)T3 levels;
Hashimoto’s disease by chronic lymphocytic thyroiditis self-limiting in contrast to GD; at US, a diffusely enlarged suppressed TSH level; elevated
with destruction of thyroid follicles thyroid with a heterogeneous echotexture, a anti-TPO or anti-Tg antibodies; negative
et al.
causing supraphysiological release pseudo-nodular pattern, vascularity can be decreased, TSHRAb

of thyroid hormone normal or increased
Infectious
Subacute thyroiditis Post-viral Painful or tender firm thyroid; fever; asymptomatic or Biochemical hyperthyroidism with
(de Quervain thyroiditis) mild signs of thyrotoxicosis in most pediatric cases elevated ESR/CRP
Acute infectious Bacterial infection (in most cases) Fever, severe pain, often unilateral swelling of the thyroid Elevated infectious parameters (CRP and
thyroiditis (usually left-sided); at US, a heterogenous enlarged ESR); usually no thyroid hormone
thyroid lobe with central necrosis excess, but cases of thyrotoxicosis
C F Mooij, T D Cheetham
have been reported
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© 2022 European Thyroid Association
Nodule(s)/neoplasm
Autonomous functioning Somatic activating mutation in Mild symptoms of hyperthyroidism; asymmetric thyroid Elevated (F)T4 and (F)T3 levels;
nodule TSHR, GNAS or EZH1, sporadic toxic gland or thyroid nodule at palpation or US suppressed TSH level; negative TSHRAb
adenoma, hyperfunctioning
papillary or follicular carcinoma
McCune–Albright Mutation in GNAS causing an often Symptoms of hyperthyroidism; asymmetric thyroid gland Elevated (F)T4 and(F)T3 levels;
syndrome (multi)nodular toxic goiter or thyroid nodules at palpation or ultrasound; café au suppressed TSH level; negative TSHRAb
ETA guideline
(post-zygotic mosaic) lait macule, polyostotic fibrous dysplasia and other

endocrinopathies (e.g. precocious puberty)
Pituitary gland
TSH-secreting pituitary TSH overproduction Symptoms of hyperthyroidism; often diffuse goiter at Elevated (F)T4 and / or (F)T3 levels; normal
Pediatric Graves’ disease
adenoma physical examination; headache, visual field defects or or mildly elevated TSH levels; high serum
galactorrhea may be present alpha subunit concentration
Other
Genetic
Familial non-autoimmune Germline-activating TSHR mutation Goiter, progressive hyperthyroidism from early life Elevated (F)T4 and (F)T3 levels;
hyperthyroidism (autosomal dominant) suppressed TSH level
Thyroid hormone Inactivating mutation in THRB Attention deficit, tachycardia, goiter and potential short Elevated FT4 and FT3 levels; normal or
resistance stature; sometimes asymptomatic elevated TSH level
11:1
Exogenous
Iodine-induced Treatment with iodineb, radiocontrast Symptoms of hyperthyroidism Elevated (F)T4 and (F)T3 levels; suppressed
hyperthyroidism agents or amiodarone TSH level; high urinary iodine
Factitious thyrotoxicosis Excessive intake of thyroid Symptoms of hyperthyroidism; at physical examination Elevated (F)T4 or (F)T3 levels; suppressed
hormone (T4 or T3) no visible or palpable thyroid abnormalities TSH levels; low serum Tg
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e210073
aAn important diagnostic pitfall is the false biochemical picture of hyperthyroidism due to interference with laboratory testing, for example, by biotin.
bDeliberate or inadvertent (e.g. as a component of multivitamin supplement).
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FT3, free triiodothyronine; FT4, free thyroxine; GD, Graves’ disease; T3, tri-iodothyronine; T4, thyroxine; Tg, thyroglobulin; TSH,
thyrotropin; TSHRAb, TSH receptor antibodies; TSI, thyroid-stimulating immunoglobulins; TPO, thyroid peroxidase; US, ultrasonography.
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Medical treatment – antithyroid drugs supervenes. Higher ATD doses (e.g. 1.0 mg/kg MMZ or
1.3 mg/kg CBZ) can be used initially in severe disease or if
Which antithyroid drug(s) (ATD) can be used in thyroid hormone concentrations do not fall as expected.
children?
The thionamide carbimazole (CBZ) or its active metabolite What is the preferred approach, DT or BR?
methimazole (MMI; also known as thiamazole) can be
A recent RCT showed no difference in biochemical control
used to treat hyperthyroidism. Propylthiouracil (PTU)
between DT and BR, but more adverse events in BR (31).
should not be used because of the risk of hepatic failure
Therefore, in most cases, DT is preferred. Earlier studies
(25). Thionamides act as a preferential substrate for thyroid
can be interpreted as demonstrating greater biochemical
peroxidase (TPO), thereby preventing tyrosine iodination in
stability with BR (32, 33, 34), and there may be occasions
the thyroglobulin molecule and blocking thyroid hormone
when the pediatric endocrinologist discusses the
synthesis. Although a direct immunomodulatory action
theoretical advantages of BR with families.
has been proposed (26), rendering the patient euthyroid
has a beneficial effect on autoimmunity in itself (27).
What are the indications for beta-

What is the (optimal) ATD starting dose? adrenergic blockade?
ATD can be titrated against thyroid function tests A beta-blocker (e.g. propranolol or atenolol) should be
(dose titration, DT) or administered in a larger dose to administered in an age- or weight-appropriate dose when
prevent endogenous thyroid hormone production, with there are signs of moderate to severe thyroid hormone
levothyroxine (LT4) added later in a replacement dose excess (35) but are contraindicated in patients with asthma.
(block and replace, BR). The ATD starting dose will depend The beta-blocker can be stopped once thyroid hormone
on weight, signs, symptoms and biochemical severity. levels normalize.
MMZ of 0.6 mg is approximately equivalent to 1.0 mg
CBZ. MMZ of 0.5 mg/kg or CBZ of 0.75 mg/kg will block
Thyroid storm
thyroid hormone production in the majority of patients.
A lower starting dose of 0.15 mg/kg of MMZ or 0.25 mg/kg Occasionally, patients with GD present with a thyroid
≤ 35 pmol/L or FT3 ≤ 12 pmol/L). MMZ/CBZ can be

CBZ can be used in mild to moderate disease (e.g. FT4 crisis or ‘storm’. The associated clinical picture includes
tachycardia, heart failure, hyperthermia, extreme anxiety,
administered once daily (28, 29, 30). altered mental state and gastrointestinal upset. This may
arise in untreated GD or be precipitated by additional
Dose titration factors such as infection, surgery or RAI therapy. In these
A starting dose of 0.15–0.3 mg/kg MMZ or 0.25–0.5 mg/kg circumstances, euthyroidism can be reached more rapidly
CBZ will normalize thyroid hormone concentrations by administering iodine (e.g. potassium iodide solution)
in most patients with the dose then reduced to prevent and a glucocorticoid, in addition to ATD and a beta-
hypothyroidism. Larger ATD doses (0.5 mg/kg MMI or 0.75 blocker. ATD and iodine (ATD an hour before iodine to
mg/kg CBZ) can be administered in more severe cases where stop the release of preformed thyroid hormone) are used
a more rapid reduction in thyroid hormone concentrations is to block thyroid hormone synthesis and secretion, while
desirable. The ATD dose required to maintain euthyroidism glucocorticoids inhibit the peripheral conversion of the
will depend on disease severity. TSHRAb concentrations fall (inactive) prohormone T4 to metabolically active T3. Beta-
during ATD therapy and so the ATD dose can sometimes be blockers attenuate the peripheral adrenergic actions of
reduced to 2.5–5 mg MMZ or CBZ daily in the longer term. the thyroid hormone. Patients in thyroid storm should be
managed in a high or intensive care setting. The possibility
Block and replace that iodine administration may complicate RAI treatment
A dose of 0.3–0.5 mg/kg MMZ or 0.5–0.75 mg/kg CBZ will or result in hyperthyroidism at a later stage needs to be
usually result in hypothyroidism. LT4 in an age and weight- considered. In general, GD patients should avoid excess
appropriate replacement dose should be started when nutritional iodine intake because this may aggravate
thyroid hormone levels normalize/before hypothyroidism hyperthyroidism.
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How should the patient’s thyroid status be monitored Table 4 Framework for managing patients with block and
while on ATD treatment? replace.
Tables 3 and 4 describe frameworks for managing patients Objective of treatment: maintain thyroid hormone
with DT and BR, respectively. Patients can be seen and concentrations within the laboratory reference range with a
TSH that is also within the normal laboratory range (neither
thyroid status can be assessed every 4 weeks for the elevated nor suppressed).
first 3 months, moving to 2- to 3-monthly assessments Start of treatment: MMI is commenced in a dose of
thereafter. 0.5 mg/kg/day (0.75 mg/kg/day CBZ).
Thereafter:
• This ATD dose will block endogenous thyroid hormone
release in most patients. If thyroid hormone
What other tests are required besides thyroid concentrations remain elevated at 3–4 months into
treatment with a suppressed TSH, then discuss compliance
function tests? and consider increasing the dose of ATD by 25%.
• As thyroid hormones (FT4/FT3) normalize, start LT4 in a
Hyperthyroidism can, like ATD, be associated with a low relatively low dose (age and weight appropriate). Bear in
white cell count and hepatic dysfunction (36, 37). A full mind that FT3 will take longer to normalize than FT4.
blood count (FBC) and liver function should therefore be • If TSH is suppressed, but FT4/FT3 is low or in the bottom
part of the normal range in the initial phase of treatment
assessed pre-treatment so that subsequent investigations (the first 4 months), then LT4 should still be commenced.
can be placed into context. The timing of FBC/liver • After initiation of LT4 replacement treatment, dose titrate
function assessments while on ATD is discussed in more LT4 guided by biochemistry (FT4) every 4–6 weeks until
stable values are achieved.
detail below. • If the patient becomes thyrotoxic with a suppressed TSH
when the biochemistry (FT4 and FT3) normalized at an
earlier stage, then check compliance, make sure iodine
intake has not increased substantially and consider
increasing the ATD dose. Review TSHRAb titers.
• Discuss the importance of compliance to ATD therapy on
Table 3 Framework for managing patients with dose titration.
a regular basis, revisiting the importance of stopping ATD
therapy in the event of a sore throat or fever
Objective of treatment: maintain thyroid hormone concentrations
within the laboratory reference range with a detectable TSH that
ATD, antithyroid drug; CBZ, carbimazole; FT3, free triiodothyronine; FT4,
is below the upper limit of the reference range.
free thyroxine; LT4, levothyroxine; MMI, methimazole; TSH, thyrotropin;
Start of treatment: MMI is commenced in a dose of
TSHRAb, TSH receptor antibodies.
0.5 mg/kg/day (0.75 mg/kg/day CBZ) until thyroid hormone
levels fall toward or into the local laboratory normal range. A
lower starting dose of ATD can be used in the case of mild to
moderate hyperthyroidism. What is the response to ATD, what can the physician
Thereafter: and patient expect?
• As the patient becomes euthyroid or hypothyroid, then
the MMI/CBZ (ATD) dose can be reduced by approximately Short term
25–50% (euthyroid) or 50% (hypothyroid). Most patients will be biochemically euthyroid within
• If the patient remains hyperthyroid, then the ATD dose can
be increased by approximately 25% or more if the
4–6 weeks, although the timeline will depend on disease
hyperthyroidism is severe. severity, ATD dose and compliance. Patients with higher
• Be guided by thyroid hormone concentrations (not TSH) in baseline thyroid hormone concentrations may take a
the first 4–6 months after diagnosis.
• Be guided by thyroid hormone concentrations as well as
longer time to normalize. Moreover, ATDs build up in the
TSH concentrations beyond 4–6 months; if TSH thyroid over a few weeks, and improvement in symptoms
concentrations remain persistently suppressed in the may not be immediate.
presence of a normal FT4, this may reflect elevated FT3;
consider increasing the dose of ATD a little.
• Discuss the importance of compliance on a regular basis Longer term
as well as the importance of stopping ATD therapy in the Although most patients have a BMI SD score within normal
event of a sore throat or fever with agranulocytosis.
• A raised TSH above the local laboratory normal range
limits at diagnosis, excessive weight gain can occur after
despite a minimum daily dose of ATD (e.g. 2.5 mg of MMI euthyroidism is restored (38).
or CBZ daily) together with normal TSHRAb suggests that
the patient is in remission or has evolving thyroid gland
failure and that ATD can potentially be stopped.
What are the side effects of ATD treatment?
ATD, antithyroid drug; CBZ, carbimazole; FT3, free triiodothyronine; FT4,
free thyroxine; kg, kilogram; MMI, methimazole; TSH, thyrotropin; Around 15% of pediatric GD patients on ATD (mainly
TSHRAb, TSH receptor antibodies. MMI/CBZ) develop at least one side effect/adverse event
via free access
(AE) (Supplementary Table 1, see section on supplementary (MMI) or 1.3 mg/kg/day (CBZ), it is appropriate to discuss
materials given at the end of this article). The most frequent the role of surgery or RAI with families as well (45).
urticaria; ≈10%). Hepatitis/liver dysfunction with CBZ/

minor side effect is a cutaneous reaction (pruritic rash and
What are the criteria for definitive treatment while

MMI is cholestatic and resolves when ATD is stopped (39),
under treatment?
in contrast to the hepatocellular damage seen with PTU.
Major side effects like agranulocytosis are reported very Total thyroidectomy or RAI is the treatment options
rarely in pediatric GD patients (40). The majority of AEs for patients who develop ATD side effects such as severe
occur in the first 3 months with a higher rate in younger neutropenia or significant liver dysfunction. These
children (41, 42). Severe AEs may be dose-dependent (27). treatments may also be selected if the patient or parents are
unable to report ATD side effects (e.g. learning disability), if
they have relapsed and do not want further ATD, or where
Managing ATD side effects there is long-standing poor compliance.
Patients and families should be counseled about ATD side
effects. In case of agranulocytosis/severe neutropenia, What is the role of TSHRAb measurement during
the patient should stop ATD and undergo determination ATD therapy?
of neutrophil count in the event of signs or symptoms
of infection like fever or a sore throat. ATD-associated When considering whether ATD should be stopped,
neutropenia typically develops in the first month of TSHRAb can be used to predict the likelihood of relapse.
treatment (median 30 days), although there are rare cases If the TSHRAb titer is elevated, then remission is
of patients developing neutropenia after many years on unlikely (46).
treatment (43). Management is complicated by the fact
that a low neutrophil count can reflect the disease process
What are the remission and relapse rates after ATD
or recent infection. If the neutrophil count is below 0.5
treatment?
(×109/L), then the ATD should be stopped and alternative
treatment should be initiated. A neutrophil count between The overall remission rate after 2 years of ATD treatment
0.5 and 1.5 can be monitored closely with once or twice in pediatric GD patients is 20–30% (40, 47). The remission
weekly measurements. Some ATD side effects such as rash rate increases with longer treatment duration. Remission
can be managed symptomatically knowing that they rates of 24.1, 31.0 and 43.7% are reported after treatment
usually settle spontaneously, although, in the presence of durations of 1.5–2.5, 2.5–5 and 5–6 years, respectively
mucosal blistering, which may herald Stevens–Johnson (40, 48). One study with a treatment duration of 9 years
syndrome, ATD should be stopped immediately (42, reported a remission rate of 75% (Fig. 1) (49).
44). An increased transaminase level (>three times the
upper limit of normal) during treatment warrants ATD
When should ATD be stopped?
cessation and so liver function tests should be performed
in the event of pertinent signs of liver dysfunction (4). Treatment duration should be at least 3 years and
MMI/CBZ should not be recommenced in an individual potentially 5 years or longer if the likelihood of remission
who has experienced a serious complication linked to is low based on patient characteristics at presentation
earlier MMI/CBZ administration. (Table 5). ATD can be continued for many years although
the likelihood of long-term remission if ATD were stopped
should be discussed regularly with families. Those patients
Management of patients who do not become
who are likely to remit when ATD are stopped will usually
euthyroid on a substantial dose of ATD
be on a low dose of ATD and have no detectable TSHRAbs.
Occasionally, patients remain thyrotoxic on doses of TSHRAb decline by a median of 90% after 3 years of ATD
MMI/CBZ in excess of 0.6 mg/kg/day or 1 mg/kg/day, treatment and ATD should not be stopped if TSHRAb are
respectively. Compliance and exacerbation by the use of raised (46, 50). Patients who relapse when ATD is stopped
iodine-containing supplements should be discussed. The usually do so within 12 months (47), and so treatment
risk of adverse events may increase with higher doses, and cessation should not usually be in the period leading up to
while the ATD dose can be increased to 1.0 mg/kg/day key educational milestones such as examinations.
via free access
Figure 1
Remission rates in relation to duration of medical treatment (methimazole or carbimazole) in patients with pediatric Graves’ disease. Remission rates
reported in the systematic review by van Lieshout et al. (40) (Table 2) evaluating studies on the efficacy of treatment with methimazole or carbimazole in
relation to the treatment duration in pediatric Graves’ disease. Size of the bubble reflects the size of the patient population. Prospective studies
comparing standard and long-term treatment durations are displayed twice in this figure (Azizi et al. (49) displayed in red, and Léger et al. and Kaguelidou
et al. (47, 48) displayed in green).
How should patients be followed up after 10 years or in case of symptoms or signs of

stopping ATD? hyperthyroidism. The possibility of TSHRAb crossing
the placenta and affecting the health of the fetus years
Patients and families should be familiar with the
later should be discussed with females pre-discharge and
manifestations of thyrotoxicosis, and patients should have
reinforced by pertinent text in associated correspondence.
thyroid function checked if relapse is suspected, or every
Evaluation of thyroid function pre-conception and
3–4 months after stopping ATD in the first year, every 6
TSHRAb levels when pregnant (especially after definitive
months in the second year and annually thereafter; not
treatment for GD) is needed.
only because of the risk of relapse but also of autoimmune
hypothyroidism (see prognosis) (51). Patients can be
referred back to their family doctor after 12–24 months, What to do when a patient experiences a relapse
with advice to monitor thyroid function for at least after ATD treatment?
Table 5 Factors associated with improved likelihood of Some patients who relapse may still remit in the long term
remission following antithyroid drug treatment. depending on associated features (Table 5). This should
be taken into consideration when considering the role of
Older age (47, 99)
further ATD.
Female sexa (100)
Ethnicity (Caucasian) (47)
Small goiter size (101)
Mild biochemical derangement at diagnosis (48) Is there a role for new treatment modalities like
Lower TSHRAb titer (47) immune modulation in the treatment of pediatric GD?
History of other autoimmune conditions (48)
Duration of ATD treatment (48, 102) There are case reports and series describing the clinical
aIn
adult studies only.
course of adult patients receiving biologics like rituximab
ATD, antithyroid drug; TSHRAb, TSH receptor antibodies. or TSHR-blocking antibodies (K1-70) as a treatment for GD
via free access
(52, 53, 54, 55, 56, 57, 58). There is insufficient evidence to patients treated with RAI aiming at hypothyroidism
suggest that these agents are of benefit in pediatric GD. reported no malignancies or fertility problems with a
maximum follow-up of nearly four decades (59, 63, 64, 65).
Measures to be considered when preparing a pediatric
Definitive treatment – radioiodine or surgery patient for RAI are shown in Supplementary Table 2. ATD
should be stopped 3–7 days prior to RAI administration.
Indications for definitive treatment include relapse after Patients with active GO should receive a course of steroids
ATD treatment, serious or persistent side effects of ATD, in accordance with EUGOGO guidelines (66). RAI should
poor compliance or obstructive symptoms from a large be administered according to local radiation protection
goiter (4, 59, 60). law. After RAI, ATD treatment should be resumed 1–2 days
after I-131 administration and continued for at least 3
months if a BR strategy is used, or titrated against thyroid
Radioiodine treatment
hormone concentrations. TSH levels may not normalize for
Like iodine, RAI is taken up and metabolized by the several months after RAI treatment. Patients and parents
thyrocyte and stored within the thyroid follicle as thyroid should be warned about a small risk of thyroid crisis post
hormone. Isotope decay with the emission of beta- RAI treatment (67), although this is extremely rare in
radiation damages thyrocyte DNA resulting in apoptosis children (65). The first clinical and biochemical evaluation
and tissue necrosis. Sufficient RAI activity will destroy the by the pediatric endocrinologist should be scheduled
thyroid gland resulting in hypothyroidism. 4–6 weeks after RAI administration but can be brought
When RAI is chosen as definitive treatment, we advise forward depending on the pre-RAI treatment status. As
aiming for thyroid ablation in order to minimize the risk the objective of RAI is complete thyroid ablation, lifelong
of relapse and (future) malignant transformation of LT4 replacement is usually necessary. If hyperthyroidism
persistent, viable but radiation-damaged cells. still persists at 12 months after RAI, a second course can be
When administering RAI, there are various methods for considered.
calculating appropriate activity, including a fixed approach
with activities ranging from 200 to 800 MBq (61), limited
Total thyroidectomy
personalization in the form of (preferably) 15 MBq I-131 per
gram thyroid tissue (thyroid volume/weight estimated by Total thyroidectomy aims to remove all overactive thyroid
ultrasound) (62) or dosimetry aiming at delivering at least tissue. It is the preferred definitive treatment option for
300 Gy to the thyroid gland for functional ablation (61). GD patients younger than 10 years, for patients with
No method is demonstrably superior to others, although a (relative) contraindication for RAI treatment and for
higher activities/doses are usually associated with higher those with a large or nodular goiter. The advantage
rates of complete functional ablation. No adult or pediatric of total thyroidectomy is that it immediately cures
studies demonstrate a 100% success rate. For the greatest hyperthyroidism by removing the source of excess thyroid
chance of success, while at the same time minimizing hormone. Subsequent hypothyroidism necessitates
excessive radiation exposure, we recommend performing lifelong LT4 treatment. Total thyroidectomy is preferred
thyroid dosimetry if available. over subtotal thyroidectomy to reduce the risk of
RAI can theoretically be used in any patient with recurrent hyperthyroidism, with no reported difference in
GD, but contraindications are pregnancy (and becoming complications (68, 69).
pregnant within 6 months after RAI), breast-feeding, Prior to surgery, patients need to be biochemically
young age (<5 years; because of a greater long-term euthyroid to reduce the risk of anesthesia and thyroid
theoretical risk of malignancy) and active GO which can storm. ATD treatment should be continued until the day
be exacerbated by RAI. Relative contraindications are age of surgery. When euthyroidism cannot be achieved by
5–10 years, inactive GO and large goiter that may need ATD treatment alone, oral iodine (5–10 drops of Lugol’s
repeated treatment. solution or 1–4 drops of saturated potassium iodide
Side effects following RAI treatment in pediatric GD solution three times daily) can be administered for 1–2
patients are extremely rare, although sometimes a mild weeks prior to surgery to normalize FT3. If surgery is not
tenderness over the thyroid may be observed in the first performed in a timely manner, then the patient may
week after treatment. Observational studies in pediatric become thyrotoxic again. Pre-operative treatment with
via free access
a beta-blocker and glucocorticoid may be required (2). with GO (46, 72). The pathogenesis of GO is therefore the
Patients should be vitamin D replete prior to surgery to same in children as in adults (10).
reduce the risk of post-operative transient hypocalcemia
and if in doubt can be treated with cholecalciferol for 3
Epidemiology
days prior to surgery (60). After total thyroidectomy,
LT4 treatment should be commenced in a weight- The frequency of GO in pediatric GD patients is 27–63%
appropriate dose. and is similar to adults (47, 72, 73, 74, 75, 76, 77). In 19–69%,
Mortality post-thyroidectomy in pediatric GD family members also have thyroid dysfunction (78, 79, 80).
patients is very low (<0.1%). However, there are post- Female-to-male ratio is between 3.3 and 7.1 to 1 (75, 76, 78,
operative morbidities, including transient hypocalcemia 79, 81). The time between diagnosing thyroid dysfunction
(22.2%) and recurrent laryngeal nerve (RLN) injury (5.4%) and the onset of eye signs is usually less than 6 months.
(70). In addition, permanent hypoparathyroidism with Like in adults, independent risk factors for GO are smoking
hypocalcemia was reported in 2.5% and permanent RLN (OR = 7.098), TSHRAb (OR = 6.358), stress (OR = 6.030) and
in 0.4% of pediatric GD patients (70). Post-operative high FT4 at diagnosis (OR = 5.963) (82).
infection, hemorrhage and keloid development are rare.
Damage to the superior laryngeal nerve’s external branch Signs and symptoms
may occur after thyroidectomy and can have subtle
effects on voice projection (71). The risk of post-operative Eyelid retraction (median 72%; range 23–91%) and
morbidities is lower when thyroidectomy is performed by a proptosis (median 53%; range 4–92%), best detected by
high-volume thyroid surgeon. comparison with photographs prior to the onset of GO, are
the most frequent signs of GO in children with GD; soft
tissue inflammation is less common (median 22%; range
Radioiodine vs thyroidectomy 1–59%). In most retrospective and cross-sectional studies,
impaired motility and dysthyroid optic neuropathy are rare
The choice for RAI or total thyroidectomy is a contentious
or not reported, respectively. Accordingly, most patients
topic and will reflect local opinion and expertise. Each
have a mild course (7).
pediatric case warrants interdisciplinary consultation
including a pediatric endocrinologist, thyroid surgeon and
nuclear medicine physician specialized in thyroid disease; Treatment and prognosis of orbitopathy in pediatric
the choice of definitive treatment will involve shared GD patients
decision making with the patient and the parents/legal
In most retrospective case series and cross-sectional studies,
guardians, focusing on the advantages and disadvantages
pediatric GD patients with GO are managed conservatively
of each option.
(70–100%) because of mild underlying disease (79, 80). In
An absolute or relative contraindication for one
patients with lagophthalmos artificial tears can be offered,
modality vs another such as pregnancy or a markedly
but with good tear production and absence of meibomian
elevated risk of perioperative morbidity may direct
gland dysfunction, eye drops and ointments are rarely
treatment choice. Table 6 lists contraindications for
needed. Rare cases of moderate-to-severe active GO cases
and advantages and disadvantages of RAI and total
can be treated with anti-inflammatory drugs (e.g. i.v.
thyroidectomy.
corticosteroids) (66). Selenium (Se) supplementation can
prevent further deterioration in adults and can be offered
to children when residing in an area of limited Se intake
Pediatric Graves’ orbitopathy (83). A daily supplementation dosage of 1–2 µg/kg can be
administered for 6 months (84).
Pathogenesis
Improvement of GO with normalization of thyroid
Pediatric GO is caused by autoreactivity to TSHR. function is frequently reported (7). Few patients need
Hyperthyroid children with GD and GO have higher surgery (lid lengthening and rarely orbital decompression).
TSHRAb levels than those with only hyperthyroid GD, and Decompression surgery is best deferred until the facial skull
during ATD treatment, TSHRAb decreases less in children has fully grown. Success rates are the same as in adults (85, 86).
via free access
Table 6 Specific indications and contraindications for, and pros and cons of, definitive treatment in pediatric Graves’ disease:
radioactive iodine vs surgery/total thyroidectomy.
Radioactive iodine Total thyroidectomy
General indications Relapse after ATD treatment, serious or persistent Relapse after ATD treatment, serious or
side effects of ATDs, or poor compliance. persistent side effects of ATDs, or poor
compliance.
Indications and Absolute contraindication Indications
contraindications Pregnancy (pre-treatment pregnancy test is mandatory Obstructive symptoms from a large goiter.
from the moment of menarche) or breastfeeding. When a euthyroid state is required quickly.
Patients under 5 years of age. Patients under 5 years.
Active GO.
Relative contraindication Contraindication
Patients between 5 and 10 years of age. Essentially none, however, patients must
Inactive GO. be euthyroid or have only mild thyroid
Large goiter – second dose may be required. dysfunction at the time of surgery.
Pros and cons
Likelihood of hypothyroidism The success rate of achieving hypothyroidism 100% success rate of achieving
increases with a higher RAI activity dose. hypothyroidism when total
thyroidectomy is performed.
Treatment process Usually administered orally (capsule) on an Surgical procedure with admission.
outpatient basis.
Time to hypothyroid state Achieving hypothyroidism can take weeks or months. Rapid achievement of hypothyroidism.
Short-term logistics and risks Specific regulations need to be followed in the weeks General surgical risks and consequences,
following treatment. like bleeding, infections, scar.
Long-term risks General risks associated with ionizing radiation Risk of post-operative (transient or
including theoretical neoplasia risk. permanent) morbidities:
Hypothetical risk of genetic damage to offspring: hypoparathyroidism and/or recurrent
mandatory advice not to become pregnant within laryngeal nerve injury.
6 months after RAI.
Adolescent girls
Smaller chance of disappearance of TSHRAb
compared to total thyroidectomy, resulting in
greater risk of fetal or neonatal hyperthyroidism in
offspring (103).
Risk of thyroid cancer A histopathological diagnosis of thyroid (micro-) Histopathological examination can be
carcinoma cannot be made (if present). performed and may show thyroid (micro)
carcinoma (if present).
ATD, antithyroid drug; GO, Graves’ orbitopathy; RAI, radioactive iodine; TSHRAb, anti-TSH receptor antibodies.
Treatment of thyroid disease in presence of reflecting modern, detailed histological analysis. In some
orbitopathy but not all studies, the rate of thyroid cancer detected is
the same in adult GD patients as in those undergoing
Pediatric patients with GO are more likely to have a severe
thyroidectomy for other benign thyroid diseases (89).
course of their GD and are less likely to go into remission
However, several studies have found a slightly higher DTC
following ATDs (77). Thyroid surgery is preferable to
rate in GD patients. Cappelli et al. found a cancer rate of
RAI treatment in active GO, and if there is a poor/absent
6.5% in GD patients undergoing thyroidectomy compared
response to GO treatment, then thyroidectomy may also
to 4.4% of those with solitary toxic nodules (90), and some
reduce the risk of GO exacerbation (66, 87).
studies found that tumors in adult GD patients may behave
more aggressively (91, 92, 93). A meta-analysis of 987 GD
Thyroid cancer risk in pediatric GD patients patients with DTC confirmed the higher prevalence of
adverse prognostic features, but there was no difference in
In 2–10% of adults undergoing thyroidectomy for GD, persistent disease or mortality (94). Several mechanisms
co-existing differentiated thyroid cancer (DTC) is found have been postulated for these associations including the
in surgical specimens (88). In 80% of cases, these are stimulation of thyrocyte proliferation by TSHRAbs and
incidental microcarcinomas (<10 mm in diameter), increased vascularity.
via free access
Despite the associations found in adults with Graves’ this topic is needed, it emphasizes the need for additional
disease, there is little information on this subject in support for young people with GD, both at school and
pediatric GD patients. A retrospective analysis of young from a psychological perspective (98).
GD patients undergoing thyroidectomy at a single
North American center showed that 7 of 32 (22%) had
differentiated thyroid cancer (95). In four patients, this Conclusions
was suspected from ultrasound and cytological workup
pre-operatively, but in three, this was an incidental This ETA guideline provides new recommendations for the
finding. The young patients with GD did not appear management of pediatric GD including a longer phase of
to have a worse prognosis than age-matched patients initial medical/ATD treatment, preference for DT instead
without GD (96). of BR in most cases, complete thyroid gland ablation with
Additional work is required, but in the interim, we personalized dose determination when using RAI and
recommend that all palpable thyroid nodules in children involvement of a pediatric endocrinologist in all cases.
and adolescents with GD are subject to ultrasound
evaluation. Patients with suspicious sonographic findings
should either proceed to FNA cytological assessment Supplementary materials
or direct to total thyroidectomy. There is little role This is linked to the online version of the paper at https://doi.org/10.1530/
ETJ-21-0073.
for ‘diagnostic surgery’ in this situation with total
thyroidectomy the best treatment option.
Declaration of interest
Simon Pearce received speaker fees from Merck, Sanofi, Berlin Chemie,
Prognosis
Quidel and is member of the clinical advisory board of Apitope. The other
authors have nothing to disclose.
It is important to discuss the various possible outcomes
when managing GD. The first treatment goal is to restore
euthyroidism. The most favorable long-term outcome
is permanent functional and immunological remission Funding
The Department of Anja Eckstein received funding from Horizon
without the need for medical treatment. Unfortunately,
Therapeutics plc to conduct clinical studies on the use of Teprotumamab
many children have a less favorable outcome: persistent in GO. No financial support was received writing this guideline.
thyroid autoimmunity and thyroid stimulation by
TSHRAb necessitate lengthy medical, or definitive thyroid
destructive therapy. Hence euthyroidism is achieved by
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C F Mooij, T D Cheetham Pediatric Graves’ disease 11:1 e210073

et al. ETA guideline

2022 European Thyroid Association Guideline for

3Department of Pediatric Endocrinology, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK

5Department of Ophthalmology, University Duisburg Essen, Essen, Germany

6Endocrine Unit, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK

Correspondence should be addressed to C F Mooij or A S P van Trotsenburg: c.mooij@amsterdamumc.nl or a.s.vantrotsenburg@amsterdamumc.nl

*(C F Mooij and T D Cheetham contributed equally to this work)

first-line use of a prolonged course of methimazole/carbimazole ATD treatment (3 years ff management

propylthiouracil use. Where definitive treatment is required either total thyroidectomy

Methodology thrill or bruit. Manifestations of thyroid eye disease include

Medical treatment of hyperthyroidism caused by Graves’ disease (GD)

Definitive treatment in pediatric Graves’ disease – thyroidectomy

causing supraphysiological release pseudo-nodular pattern, vascularity can be decreased, TSHRAb

have been reported

Published by Bioscientifica Ltd.

(post-zygotic mosaic) lait macule, polyostotic fibrous dysplasia and other

via free access

What are the indications for beta-

≤ 35 pmol/L or FT3 ≤ 12 pmol/L). MMZ/CBZ can be

urticaria; ≈10%). Hepatitis/liver dysfunction with CBZ/

What are the criteria for definitive treatment while

How should patients be followed up after 10 years or in case of symptoms or signs of

Radioactive iodine Total thyroidectomy

Received in final form 27 October 2021

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