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Graves' disease in children

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 Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 233–243

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Graves’ disease in children

Juliane Léger, MD, Professor of Pediatrics a, b, c, *,
Florentia Kaguelidou, MD, PhD, Assistant Professor of Clinical
Pharmacology a, d, Corinne Alberti, MD, PhD, Professor of
Epidemiology a, e, Jean Claude Carel, MD, Professor of
Pediatrics a, b, c
a
Univ Paris Diderot, Sorbonne Paris Cité, F-75019 Paris, France
b
AP-HP, Hôpital Robert Debré, Service d’Endocrinologie Diabétologie Pédiatrique et Centre de Référence des
Maladies Endocriniennes Rares de la Croissance, F-75019 Paris, France
c
Institut National de la Santé et de la Recherche Médicale, UMR 676, F-75019 Paris, France
d
AP-HP, Hopital Robert Debré, Unité de Pharmacologie Pédiatrique, INSERM CIC9202, 75019 Paris, France
e
AP-HP, Hopital Robert Debré, Unité d’Epidémiologie Clinique, INSERM CIC-EC CIE5, 75019 Paris, France

Keywords:
Graves’ disease is an autoimmune disorder resulting from thyro-
hyperthyroidism tropin receptor stimulation by autoantibodies. It may occur at any
childhood age during childhood, but its frequency increases with age, peaking
Graves’ disease during adolescence. Symptoms and signs are often recognizable and
proportional to the increase in serum free thyroid hormone levels.
Antithyroid drug treatment with methimazole (or carbimazole) is
recommended for initial treatment, but relapse rates are high, with
remission achieved in only 30% of children after a first course of
treatment for about two years. More prolonged medical treatment
may increase the remission rate to up to 50%. Alternative treatments,
such as radioactive iodine or thyroidectomy, are considered in cases
of relapse, lack of compliance or antithyroid drug toxicity. Relapse
risk decreases with increasing duration of the first course of anti-
thyroid drug treatment. The identification of other predictive fac-
tors, such as severe biochemical hyperthyroidism at diagnosis,
young age and the absence of other autoimmune conditions, has
made it possible to stratify patients according to the risk of relapse,
leading to improvements in patient management, by facilitating the
identification of patients requiring long-term antithyroid drug
treatment or early alternative therapy.
Ó 2013 Elsevier Ltd. All rights reserved.

* Corresponding author. Pediatric Endocrinology Department, Centre de Référence Maladies Endocriniennes de la Croissance,
INSERM U 676, Hôpital Robert Debré, 48 Bd Sérurier, 75019 Paris, France. Tel.: þ33 1 40 03 23 54; Fax: þ33 1 40 03 24 29.
E-mail address: juliane.leger@rdb.aphp.fr (J. Léger).

1521-690X/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.beem.2013.08.008
234 J. Léger et al. / Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 233–243

Practice points

 Graves’ disease is the most frequent cause of hyperthyroidism in children.

 Antithyroid drug treatment (ATD; methimazole or carbimazole) is usually recommended as
the initial treatment for GD and is generally well tolerated.
 The risk of adverse events due to ATD is dose-dependent.
 The overall frequency of relapse is higher in children than in adults. About 30% of children
achieve lasting remission after about 24 months of ATD.
 Indications for radical treatment (mostly radioactive iodine, rather than thyroidectomy)
include relapse after an appropriate course of ATD, a lack of compliance and ATD toxicity.

Research agenda

Future research on the management of patients should focus on:

 The impact of long-term drug treatment on remission rate and the factors predicting the
likelihood of remission.
 Improving compliance with drug treatment through educational strategies.
 Long-term effects on thyroid gland morphology and function, potential future pregnancies
and quality of life.
 A better understanding of the physiopathology of this disorder, leading to improvements in
patient management and the development of new modes of curative treatment.

Graves’ disease: Introduction

Graves’ disease (GD), an autoimmune disorder resulting from thyrotropin (TSH) receptor stimula-
tion by autoantibodies, is an uncommon disease in children, who account for only 1–5% of all patients
with GD [1]. In adults, this disease affects approximately 2% of women and 0.2% of men [2]. It accounts
for about 15% of thyroid disorders during childhood and, like most other thyroid disorders in both
adults and children, GD is much more frequent in female than in male subjects. It may occur at any age
during childhood, but its frequency increases with age, peaking during adolescence. The incidence of
GD is thought to be rising and is currently about 0.1 per 100,000 person-years in young children to 3
per 100,000 person-years in adolescents [3]. The estimated prevalence varies between countries, from
1/10,000 in the United States to 1/100,000 person-years (for children aged 0–15 years) in the UK and
Ireland [4]. A frequency of up to 14 per 100,000 patient-years has been reported in Hong Kong, and
differences in the frequency of this condition do not seem to depend on dietary iodine intake [5,6]. GD
is more frequent in children with other autoimmune conditions (Table 1), and in children with a fa-
milial history of autoimmune thyroid disease [7–10].

Pathogenesis

The cause of GD remains unclear, but it is believed to result from a complex interaction between
genetic background (heredity), environmental factors and the immune system. For unknown reasons,
the immune system produces an antibody (thyroid-stimulating hormone receptor antibody) that
stimulates the thyroid gland to produce excess thyroid hormone. Genetic susceptibility to the disease is
thought to be polygenic. GD has been reported to be associated with the human leukocyte antigen
(HLA) gene on chromosome 6p, the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene on chromosome
2q33 and the PTPN22 (lymphoid tyrosine phosphatase) gene on chromosome 1p13. Data from twin
studies and the higher prevalence of Graves’ disease in first-degree relatives of patients with this
 J. Léger et al. / Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 233–243 235

Table 1
Most common associations for GD in children with other auto immune disorders.

Type I diabetes
Hashimoto’s thyroiditis
Turner’s syndrome
Down’s syndrome
Di George syndrome
Rheumatoid arthritis

disease than in controls suggest that about 80% of the susceptibility to GD is determined by genetic
factors, whereas the other 20% is associated with environmental influences [11–13].
The thyroid-stimulating immunoglobulin (TSI) binds to and stimulates the thyroid-stimulating
hormone (TSH) receptor on the thyroid cell membrane, resulting in follicular cell growth, an in-
crease in vascularity and the excessive synthesis and secretion of thyroid hormone. The thyroid gland
typically displays lymphocytic infiltration, with T-lymphocyte abnormalities and an absence of
follicular destruction. T cells activate local inflammation and tissue remodeling, by producing and
releasing cytokines, leading to B-cell dysregulation and an increase in autoantibody production. An
imbalance between pathogenic and regulatory T cells is thought to be involved in both the develop-
ment of Graves’ disease (GD) and its severity [14].

Clinical manifestations

Most patients present the classic symptoms and signs of hyperthyroidism (Table 2). The early
symptoms are often subtle, with changes in behavior, irritability, emotional lability, fatigue,
nervousness, palpitations, tremor, sleep disturbance with insomnia, excessive perspiration, an increase
in appetite accompanied by no weight gain or even weight loss, and diarrhea. A decline in academic
performance and a deterioration of attention are often associated.
The size of the thyroid gland is highly variable and the goiter may go unnoticed in patients with a
slightly enlarged thyroid gland. The thyroid gland is usually symmetrically enlarged, firm, uniformly
smooth and not tender. A palpable thrill may be present, reflecting the increase in blood flow through
the gland. Ophthalmic abnormalities are less severe in children than in adults, with staring eyes, soft
tissue involvement, proptosis, with retraction of the upper lid, and a wide palpebral aperture [15,16].
True exophthalmos is rare in children. Thyrotoxic crisis is also an extremely rare event in childhood
[17]. Other major signs include tachycardia, an increase in blood pressure, precordial thrill, and an
ejection murmur due to functional insufficiency of the mitral valve. Increases in height velocity, with
advanced bone age, are related to the duration of hyperthyroidism. Neurological symptoms are rare
[18]. As in adults, children with GD may have a lower than normal bone mass, but bone mass is often
restored to normal levels after two years of a euthyroid state on ATD treatment [19]. Pretibial myx-
oedema is rare. Various symptoms are observed, and children may initially be referred to cardiologists,
ophthalmologists, neurologists, psychiatrists and/or gastroenterologists before being referred to an
endocrinologist.

Biochemical confirmation of Graves’ disease

The diagnosis is confirmed by thyroid hormone determinations. TSH is undetectable in the serum
(<0.3 mU/l) in all patients. Most children with hyperthyroidism have very high serum FT4 and FT3
concentrations. However, some patients may have normal FT4 concentrations and high FT3 concen-
trations d a condition known as T3 toxicosis, which may be observed at diagnosis or during relapses
occurring in the course of the disease. In some patients with mild hyperthyroidism and serum FT4 and
FT3 levels close to the upper limit of normal values, thyrotropin-releasing hormone (TRH) tests may be
carried out. In this test, the inhibition of TSH release in response to TRH stimulation confirms the
diagnosis of hyperthyroidism.
Thyroid-stimulating hormone receptor antibodies (TRAbs) are specific to GD. They are detected in
most patients, with highly variable titers. There is a positive correlation between serum TRAb and FT4
236 J. Léger et al. / Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 233–243

Table 2
Clinical characteristics at diagnosis of a cohort of children and adolescents with GD (adapted from ref. 20).

Percentage or median
(25th–75th perc.)
Sex Female 77
Male 23
Age 5 or younger 11
Older than 5 yr 89
Pubertal development Prepubertal 42
Pubertal (Tanner 2–5) 58
Ethnicity Caucasian 80
Non-caucasian 20
Personal history of autoimmunity and susceptibility factors 14
Family history of hyperthyroidism 24
Severe initial clinical presentationa 78
Ophthalmic abnormalities 59
Tachycardia 83
Hypertension 17
Loss of weight 59
Goiter Small or absent 46
Moderate or large 54
Height SDS 1.45 (0.37–2.35)
Body mass index SDS 0.50 (1.20 - 0.30)
FT4 (pmol/l) 52 (40.2–70.5)
FT3 (pmol/l) 26 (17–31)
TSH receptor autoantibodies positivity 4 (1.5–8.6)
(multiple of normal upper limit)
a
Severe initial clinical presentation is defined by the presence of at least 2 of the following features: tachycardia, hyper-
tension, initial weight loss, ophthalmic abnormalities.

levels. Serum TRAb levels are significantly higher in young (5 years of age) than in older (>5 years of
age) patients, and in patients with a severe initial clinical presentation than in those with a milder
clinical presentation [20]. Determination of the levels of circulating antibodies against thyroperoxidase
and, in some cases, thyroglobulin, may be useful for the confirmation of thyroid autoimmune disease.

Thyroid imaging

Thyroid imaging with radioisotopes is not required for the diagnosis of GD and has been replaced by
ultrasound scans. The thyroid gland is diffusely enlarged, and often homogeneous. The gland may
display normal echogenicity or may be hypoechogenic, as in thyroiditis. Diffuse parenchymal hyper-
vascularity is observed. High-grade hypervascularization is not observed to the same extent in patients
with chronic autoimmune thyroiditis. Goiter size is variable, and the goiter may be small, medium-
sized or large [21]. In 10% of patients, thyroid volume is normal.

Management

Antithyroid drug (ATD) treatment is usually recommended as the initial treatment for hyperthy-
roidism in children and adolescents. The optimal treatment of GD in childhood remains a matter of
debate [17,22–26], and prospective randomized long-term clinical studies are required to compare
treatment failure frequencies and the short- and long-term side effects of the various treatment op-
tions. Current treatment options include antithyroid drugs, subtotal or near total thyroidectomy and
radioactive iodine (iodine-131). There is no specific cure for the disease and each treatment option is
associated with complications. Most patients are initially treated with antithyroid drugs, and the main
cause of treatment failure in these patients is non-compliance. However, it is difficult to achieve long-
term compliance and the relapse rate is high. Surgical removal of the thyroid gland or destruction of the
gland by radioiodine treatment is therefore often used as an alternative. Indications for radical
treatment in children include relapse after an appropriate course of drug treatment, a lack of
 J. Léger et al. / Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 233–243 237

compliance on the part of the patient or the parents and ATD toxicity. As in many rare diseases, there is
currently no evidence-based strategy for the management of this disease in children, by contrast to the
situation in adults, in whom the disease is more frequent [27,28]. GD treatment policy varies consid-
erably within and between countries and depends on local traditions and resources, the age and
preference of the patient, the size of the goiter and the severity of the disease.
Additional treatment with b blockers (except in patients with asthma or cardiac failure) during the
first two weeks of management may help to reduce the patient’s symptoms. This treatment can be
given orally twice daily, at a dose of 2 mg/kg/day, and stopped when the patient becomes euthyroid.

Antithyroid drug therapy

Drugs and tolerance

The most commonly used ATDs are carbimazole and its active metabolite, methimazole (MMI), and
propylthiouracil (PTU). These drugs inhibit thyroid hormone synthesis by interfering with the thyroid
peroxidase-mediated iodination of the tyrosine residues of thyroglobulin. PTU can also block the
conversion of thyroxine to triiodothyronine, whereas MMI cannot. Both MMI and PTU are associated
with minor reactions (rash, urticaria, arthralgia, gastrointestinal problems) in about 5%–25% of cases.
The frequency of agranulocytosis, the most severe side effect, is between 0.2 and 0.5% for both drugs.
Other major side effects are rare and are observed mostly with PTU; they include drug-induced hep-
atitis and the production of cytoplasmic anti-neutrophil antibodies. Antibody-positive vasculitis occurs
only in exceptional cases. Patients and families should be informed of the potential side effects of ATD,
and should inform their physician if they develop pruritic rash, jaundice, acholic stools or dark urine,
arthralgia, abdominal pain, nausea, fatigue, fever or pharyngitis [29]. However, most of the side effects
occur only rarely and many are minor and transient.
The use of PTU as a first-line treatment should be avoided, because of the high risk of PTU-induced
severe hepatitis. Only MMI (or carbimazole) should be used in children [29–31]. The frequency of side
effects may be dose-related and is very low for severe side effects in patients receiving MMI at a dose of
less than 10 mg/day [28]. Adverse events on MMI treatment generally occur during the first six months
of therapy [32]. MMI is also more effective than PTU in the short term [33] and presents a major
advantage over PTU in terms of compliance, as MMI has a longer half-life and is effective when given as
a single daily dose.

Management of drug treatment

The initial starting dose of MMI (or carbimazole) is 0.5–1 mg/kg/day, with a maximal dose of 30 mg
per day. After two to four weeks, when thyroid hormone secretion is effectively blocked and thyroid
hormone levels have normalized, the initial dose is gradually reduced by 30–50% [28]. However, two
possible approaches have been discussed: the block and replace (BR) approach and the dose titration
(DT) regimen. The BR approach involves the use of a high dose of antithyroid medication with the
addition of levothyroxine, whereas the DT approach involves adjusting the dose of ATD to achieve
euthyroidism, improving compliance. Compliance may also be a particularly difficult issue in adoles-
cent patients, who may find it easier to take one drug (ATD) rather than two (ATD and levothyroxine).
In most children, no additional benefit accrues from the maintenance of a high dose of ATD together
with replacement doses of L-thyroxine. Recent studies have even suggested that high-dose treatment
may be harmful, because the frequency of side effects is dose-dependent. There is also currently no
rationale for the use of L-thyroxine in combination with ATDs to enhance remission rates [28], and
recent American Thyroid Association (ATA) guidelines suggest that the BR regimen should be avoided
[29].
ATD treatment usually leads to improvements in metabolic rates, growth velocity and body weight
within three months, with some patients gaining more weight than expected on the basis of weight
loss at presentation [34]. It also leads to a normalization of serum thyroid hormone levels within one
month, with TSH becoming detectable in the serum, usually within two to four months. Thyroid
function should initially be assessed every three to six weeks, because hypothyroidism may occur if
ATD dose is not reduced as serum FT4 levels normalize. Once the ATD dose has been reduced,
biochemical evaluations should be carried out every three to four months. However, about 10% of
238 J. Léger et al. / Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 233–243

patients, with T3-predominant Graves’ disease, have high serum T3 concentrations after serum T4
concentrations have normalized or even become low. These patients therefore have a high free T3 to
free T4 ratio, making it necessary to determine serum free T3 concentrations in patients with serum
TSH concentrations remaining undetectable in the long term, to identify cases with this presentation.
These patients have larger thyroid glands and high serum titers of anti-TSH receptor antibody [35,36]. A
higher dose of ATD may be required to overcome the resistance to ATD, and the BR regimen may also be
useful in these cases.
GD remission on ATD treatment is linked to the restoration of euthyroidism rather than the
immunosuppressive effects of the drugs. Hyperthyroidism itself has been shown to worsen the
autoimmune aberration, and autoimmunity leads to the generation of more TSH receptor antibodies
and a worsening of hyperthyroidism. Once this cycle is broken by ATD treatment rendering the patient
euthyroid (or by radical treatment), the patient may experience gradual remission of the disease [37]
(Fig. 1). More prolonged use of ATD (at least 2–6 years, depending on initial severity of the disease) may
be required to achieve remission in children than in adults [38]. Compliance is therefore an important
issue in the management of these children and should be improved by educational strategies. However,
the inhibition of autoantibodies achieved on treatment is difficult to predict, probably because the
treatment does not target B cells or autoantibodies directly. B lymphocytes are important self-antigen-
presenting cells and precursors of antibody-secreting plasma cells. Temporary B-lymphocyte depletion
with the monoclonal antibody rituximab may therefore efficiently decrease or abolish the production
of TRAb antibodies. Progress has also been made in the production of TSHR antagonists. Large clinical
trials of such treatment are currently required [39–41].
Less than 30% of children achieve lasting remission after about 24 months of ATD [21,42–45]. Near-
total thyroidectomy or radioiodine therapy may be used for definitive treatment, but both carry a high

Autoimmune
aberration
TRAb

Vicious cycle of Graves’ disease

Hyperthyroidism

Autoimmune
aberration
TRAb

Treatment of
hyperthyroidism
rendering the patient
euthyroid

GRADUAL
REMISSION
Fig. 1. Schematic diagram illustrating the hypothesis that the gradual remission of GD is linked to maintenance in the euthyroid
state for a long period of time. Hyperthyroidism itself has been shown to worsen the autoimmune aberration, and autoimmunity
leads to the generation of more TSH receptor antibodies and a worsening of hyperthyroidism. Once this cycle is broken by ATD
treatment, rendering the patient euthyroid (or by radical treatment), the patient may experience gradual remission of the disease.
The figure is adapted from ref [37].
 J. Léger et al. / Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 233–243 239

risk of permanent hypothyroidism. However, hypothyroidism is preferable to hyperthyroidism as it is

easier to treat and hyperthyroidism is associated with serious morbidities, such as cardiovascular
diseases and osteopenia. Unfortunately, prospective randomized trials are still lacking for evaluation of
the efficacy of short- and long-term ATD therapy for increasing the remission rate in children, and
further studies are required to increase our knowledge of ATD treatment in children.

Surgical treatment

Total (or near total) thyroidectomy is currently often preferred to subtotal (or partial) thyroidec-
tomy, to reduce the risk of recurrent hyperthyroidism [23]. The vascularity of the gland is decreased by
adding iodine to ATD (5–10 drops of Lugol’s solution) for one week before surgery [46]. L-thyroxine
replacement therapy should be initiated within days of surgery and the patient should undergo long-
term follow-up. Complications, such as hypoparathyroidism, vocal cord palsy due to recurrent laryn-
geal nerve injury and keloid formation, are rare for operations performed by pediatric surgeons with
extensive experience and have an estimated incidence of about 15% [47]. For patients with recurrent
hyperthyroidism after surgery, radioactive iodine (RAI) treatment is recommended, because the risk of
complications is higher for a second operation [23].

Iodine treatment

Radioiodine is more frequently used than surgery as a first-line radical option, and is often rec-
ommended in patients with a large goiter or with ophthalmopathy.
RAI treatment is effective in children with hyperthyroidism due to GD, and most patients can be
successfully treated with a single oral dose. Low doses are often used to cure hyperthyroidism without
causing hypothyroidism, but this strategy results in a high relapse rate. Consequently, larger doses
(usually 220–275 mCi/g, corresponding to about 250 Gy) should be preferred over smaller doses of 131-I
[48]. Patients should be preferably be rendered euthyroid by ATD treatment before proceeding with
RAI treatment. Hypothyroidism is likely to occur after treatment, and appropriate doses of L-thyroxine
must therefore be administered throughout the patient’s life. If hyperthyroidism persists three to six
months after treatment, retreatment with 131-I is indicated. There is no evidence of reproductive
dysfunction or higher frequencies of abnormalities in the offspring of treated patients [49]. RAI is
absolutely contraindicated during pregnancy and breastfeeding, and should also be avoided in very
young children, because of an increased potential risk of neoplasia. Concerns about potential thyroid
malignancy, hyperparathyroidism and mortality rates have highlighted the need for a large, ran-
domized control study with long-term follow-up, to settle this issue definitively [50].

Long-term outcome

Less than 30% of children treated with ATDs for a mean of two years achieve remission lasting at
least two years, whereas ATD treatment results in long-term remission in about 40–60% of adult pa-
tients [21,42–45,51]. Consequently, the overall frequency of relapse after a first course of about two
years of ATD treatment is higher in children than in adults, potentially reaching 70–80%. About 75% of
patients relapse within six months of the end of drug treatment, whereas only 10% relapse after 18
months. Methods for identifying patients for whom remission is unlikely to be achieved after drug

Table 3
Predictors of remission of GD in children.

Unfavorable Favorable
Biochemical severity Presence of other autoimmune conditions
Younger age Older age
Large goiter Duration of ATD treatment (>2 years)
Non-caucasians
Non-compliance to ATD
240 J. Léger et al. / Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 233–243

treatment would greatly improve patient management, by making it easier to identify patients
requiring long-term ATD or early radical treatment. Previous studies have evaluated age, goiter size,
decrease in body mass index and severity of biochemical hyperthyroidism at onset, TRAb levels at onset
and at the end of treatment, and duration of medical treatment as predictive markers of GD relapse
during childhood [21,45,52–56]. However, these studies all had limitation, all but one [56] being
retrospective, and none has led to widespread changes in clinical practice. Our prospective study [20]
showed that the risk of relapse after a first course of ATD for about two years was higher in very young
patients and patients of non-Caucasian origin, and that this risk increased with disease severity at
diagnosis as assessed on the basis of serum TRAb and free thyroid hormone levels (high levels being
associated with severity). Conversely, relapse risk decreases with increasing duration of the first course
of ATD, as each additional year of treatment is associated with a decrease in relapse rate. These results
highlight the positive impact on outcome of a long period of primary ATD treatment, to minimize
thyroid autoimmunity and disease recurrence. In this study, a prognostic score was generated, allowing
the identification of three different risk groups at diagnosis. This score could greatly improve the
counseling of patients and favor the taking of appropriate decisions concerning treatment [20].
However, little is known about long-term outcome, because there have been few studies of the

Assessment
of thyrotoxicosis
symptoms

- Determinations of TSH, free T4, (+/- free T3)

- Thyroid- stimulating hormone receptor antibiodies
- +/- Antithyroid peroxydase antibiodies
- Thyroid ultrasound
- Identification of possibly extrathyroidal manifestations of Graves disease

Treatment with antithyroid drug (Carbimazole or Methilmazole)

for 2-6 years (continuously) depending on initial severity

Severe side effects Trial off medication

or non-compliance
with drug

Recurrence Remission

Definitive treatment: radioiodine

(or thyroidectomy)

Drug treatment
of hypothyroidism

Long term surveillance

(particularly during pregnancy)

Fig. 2. Algorithm for diagnosis and management of GD in children.

 J. Léger et al. / Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 233–243 241

relationship between ATD treatment duration and remission rate or relapse risk in pediatric patients. It
is widely accepted that there is a need to prescribe longer courses of treatment than in adult patients.
Our recent prospective study investigated the effect of ATD treatment duration after three consecutive
courses, each lasting for about two years [38]. With a median study period of 10.4 years, about half the
patients achieved remission after the discontinuation of carbimazole. Less severe forms of hyperthy-
roidism at diagnosis or the presence of other associated autoimmune conditions was associated with
an increase (by a factor of about 2.2) in the predicted remission rate achieved with ATD treatment
(Table 3). This study suggests that children with GD displaying good compliance with treatment and
without major adverse effects of ATD medication may be offered several years of medical treatment
with ATD before definitive treatment is envisaged [38]. However, continuous treatment, rather than
treatment cycles of two years, should be considered in future clinical trials (Fig. 2). Long-term treat-
ment should also be optimized by educational strategies, to improve compliance with treatment and
medical care, particularly during the transition from pediatric to adult services. Other factors, such as
genetic background, sex, iodine intake and smoking are thought to modulate individual responsiveness
in adults [51,57–59]. Large prospective randomized studies are required to address these issues in
children.

Future management during adulthood

Negative consequences for the patients’ health-related quality of life during and after treatment,
even after 14–21 years, particularly as concerns mental performance and “vitality”, have been
demonstrated in adult patients with GD. These problems do not seem to be accounted for by the
patient’s thyroid hormone status during follow-up. However, the mode of treatment, whether drug-
based, surgical or based on the use of radioiodine, has been shown to have little impact on health-
related quality of life in the long term [60]. These aspects have not been studied in children, but it
would seem prudent to monitor subjects with hyperthyroidism in childhood in the longer term, not
only for thyroid function and “eventual” persistence of the disease, even after radical treatment, given
the importance of TRAb determination for the management of future pregnancies [29], but also for
neuropsychological, emotional and/or behavioral functioning.

Funding

None declared.

Conflict of interest

JL, FK, CA and JCC have no conflict of interest to declare.

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