A 12-year-old girl presents with fatigue, palpitations, and inability to sleep. She has been an excellent student in school but has had increasing difficulty concentrating in class and difficulty focusing her eyes. Family history was significant for thyroid disease in her mother (hypothyroid) and maternal aunt (Graves’ disease [GD]). On examination, her pulse is 105 beats per minute, blood pressure 112/60 mm Hg, and she is mildly underweight with a BMI of 15. She has a mild resting tremor, proptosis (R >L), and her thyroid exam reveals a slightly enlarged but symmetric gland (Figure 192-1). You obtain blood work that reveals a low thyroid-stimulating hormone (TSH) and an elevated free thyroxin level (T4). A thyroid scan and uptake shows a diffusely increased intake of 54 percent with no nodules (Figure 192-2). The patient was diagnosed with GD and the therapeutic options are presented to the family.

GD is an autoimmune thyroid disorder characterized by circulating antibodies that stimulate the thyroid-stimulating hormone (TSH) receptor and resulting in hyperthyroidism.¹

Thyrotoxicosis (clinical state resulting from inappropriately high thyroid hormone levels); hyperthyroidism (thyrotoxicosis caused by elevated synthesis and secretion of thyroid hormone), autoimmune hyperthyroidism, von Basedow’s disease (in Europe).

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  GD is the most common cause of thyrotoxicosis in children (up to 95 percent of cases), with a prevalence in children and adolescents of between 1:2000 and 1:10,000 and an incidence between 0.1 and 3 per 100,000.^2,3 The incidence peaks in adolescence; only 1 to 5 percent of cases of childhood hyperthyroidism begin before the age of 16 years.⁴

  
  
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  Similar to adults, there is a female predominance of between 3:1 to 5:1.⁴

  
  
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  Autoimmune hyperthyroidism can occurs in about 2 percent of infants born to mothers with GD, but is usually transient (resolving in 3 to 12 weeks).^4,5 Cases of persistent congenital hyperthyroidism and non-autoimmune familial hyperthyroidism due to mutations in the TSH-receptor gene have been reported.⁴

  
  
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  Rare forms of hyperthyroidism in children include pituitary adenomas, functioning thyroid nodules, pituitary resistance to thyroid hormones, and ingestion thyroid hormone or iodine.⁴ Thyrotoxicosis of variable duration can also occur as part of Hashimoto thyroiditis (see Chapter 191, Hypothyroidism). Authors of one small case series (N = 14) reported resolution of hyperthyroidism by 8.3 ± 6.3 months after diagnosis (range 3 to 23 months); duration was positively correlated with thyroid peroxidase autoantibody level at presentation.⁶

  
  
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  Graves’ ophthalmopathy (see the following section “Clinical Features”) occurs in more than 80 percent of patients within 18 months of diagnosis of GD. The ophthalmopathy is clinically apparent in 30 to 50 percent of patients, including children.^4,7

  
  
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  Untreated hyperthyroidism can lead to osteoporosis, atrial fibrillation, cardiomyopathy, and congestive heart failure; thyrotoxicosis (thyroid storm) has an associated mortality rate of 20 to 50 percent.⁸ In newborns, untreated hyperthyroidism can cause irreversible nervous system damage and developmental delay.⁴

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  The hyperthyroidism of GD results from circulating immunoglobulin (Ig) G antibodies that stimulate the TSH receptor.⁷ These antibodies are synthesized in the thyroid gland, bone marrow, and lymph nodes. Activation of the TSH receptor stimulates follicular hypertrophy and hyperplasia causing thyroid enlargement (goiter) and an increase in thyroid hormone production with an increased fraction of triiodothyronine (T3) relative to T4 (from approximately 20 to up to 30 percent).⁷

  
  
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  The etiology is seen as a combination of genetic (polygenetic, including human leukocyte antigen-D related [HLA-DR] and cytotoxic (T-lymphocyte antigen 4 [CTLA-4] polymorphisms) and environmental factors, including physical and emotional stress (e.g., infection, childbirth, life events).^4,7 In addition, insulin-like growth factor-1 receptor (IGF-1R)-bearing fibroblasts and B-cells exhibiting the IGF-1R(+) phenotype may be involved in the connective tissue manifestations.⁹ Siblings have a higher incidence of both GD and Hashimoto thyroiditis (Chapter 191, Hypothyroidism).

  
  
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  The ophthalmopathy is believed to result from an autoimmune response directed toward an antigen shared by the thyroid and the eye’s orbit. There is infiltration of the extraocular muscles by activated T cells, which release cytokines, activating fibroblasts (fibrosis can lead to diplopia) and increasing the synthesis of glycosaminoglycans (water trapping causes swelling).⁷

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  Family history of thyroid disease, especially in maternal relatives.

  
  
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  Smoking (a strong risk factor for Graves ophthalmopathy).

  
  
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  Children with McCune-Albright syndrome are at higher risk of hyperthyroidism and nodular goiter.¹⁰

  
  
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  Type 1 diabetes mellitus does not appear to confer an increased risk of GD.³

Clinical Features

Symptoms depend on the severity of thyrotoxicosis, duration of disease (initial symptoms can be nonspecific), and age. Children with congenital hyperthyroidism may be born prematurely and postnatally can display restlessness, irritability, failure to thrive, and tachycardia; premature craniosynostosis can occur if diagnosis is delayed.⁴ Common symptoms of Graves’ disease are:^4,7

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  Nervousness.

  
  
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  Fatigue.

  
  
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  Weight loss.

  
  
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  Increased appetite.

  
  
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  Diarrhea.

  
  
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  Behavioral changes including poor school performance, insomnia, restlessness and irritability, and nocturia.

Signs of disease include:

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  Tachycardia.

  
  
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  Goiter—Listening over the goiter with a stethoscope may reveal a thyroid bruit (Figures 192-3 to 192-5).

  
  
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  Resting tremor.

  
  
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  Hyperreflexia

  
  
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  Skin changes include:

  
  
  
  
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    Warm, erythematous, moist skin (from increased peripheral circulation).

    
    
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    Palmer erythema.

  
  
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  Eye involvement can occur before hyperthyroidism (in 20% of patients) and gradually progresses with only mild discomfort (a gritty sensation with increased tearing is the earliest manifestation). The eye findings in GD are less severe in children and include:^4,7,11

  
  
  
  
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    Lid retraction (drawing back of the eyelid allowing more sclera to be visible; Figures 192-1 and 192-5).

    
    
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    Frank proptosis (displacement of the eye in the anterior direction; Figures 192-1 and 192-5).

    
    
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    It is possible to have unilateral or asymmetric eye involvement with Graves ophthalmopathy (Figure 192-1).

    
    
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    Extraocular muscle dysfunction (e.g., diplopia), severe strabismus, and optic neuropathy are rare in children.