Sarah, a 12-year-old female, presents to the pediatric endocrinology clinic with complaints of weight loss, increased appetite, and difficulty concentrating in school. Her parents report that she has become increasingly irritable and anxious over the past three months. They've also noticed that Sarah seems to be sweating more than usual, even in cool environments.

On physical examination, the following findings are noted:

• Height: 75th percentile
• Weight: 25th percentile (down from 50th percentile 6 months ago)
• Heart rate: 110 bpm
• Blood pressure: 130/80 mmHg
• Skin: warm and moist
• Thyroid: diffusely enlarged, approximately 40 grams
• Eyes: mild proptosis
• Hands: fine tremor

Laboratory tests reveal:

• TSH: <0.01 mIU/L (normal range: 0.4-4.0)
• Free T4: 3.8 ng/dL (normal range: 0.8-1.8)
• Free T3: 12 pg/mL (normal range: 2.3-4.2)
• TSH receptor antibodies: positive

Based on these findings, Sarah is diagnosed with Graves' disease, the most common cause of hyperthyroidism in children. She is started on methimazole and propranolol, with close follow-up scheduled to monitor her response to treatment and adjust medication as needed.

1. Classical Graves' Disease Presentation

   • Goiter
   • Exophthalmos (bulging eyes)
   • Tachycardia
   • Weight loss despite increased appetite
   • Heat intolerance and increased sweating
   • Tremors
   • Hyperactivity and difficulty concentrating

2. Thyrotoxic Crisis (Thyroid Storm)

   • High fever (>40°C)
   • Severe tachycardia or atrial fibrillation
   • Vomiting and diarrhea
   • Dehydration
   • Altered mental status or agitation
   • Possible congestive heart failure

3. Prepubertal Presentation

   • Accelerated growth and bone maturation
   • Early onset of puberty
   • Attention deficit and poor school performance
   • Mild weight loss or failure to gain weight appropriately

4. Neonatal Graves' Disease

   • Prematurity
   • Intrauterine growth restriction
   • Goiter
   • Tachycardia
   • Hepatosplenomegaly
   • Thrombocytopenia
   • Craniosynostosis

5. Apathetic Hyperthyroidism

   • Fatigue and weakness
   • Depression
   • Weight loss
   • Minimal to no goiter
   • Subtle eye signs

6. Thyrotoxic Periodic Paralysis

   • Sudden onset of muscle weakness or paralysis
   • Hypokalemia
   • More common in adolescent males of Asian descent

7. Ocular Predominant Presentation

   • Severe exophthalmos
   • Periorbital edema
   • Corneal ulceration
   • Optic nerve compression
   • Minimal systemic symptoms

1. Q: What is the most common cause of hyperthyroidism in children?

   A: The most common cause of hyperthyroidism in children is Graves' disease, an autoimmune disorder accounting for approximately 95% of pediatric hyperthyroidism cases.

2. Q: What is the pathophysiology of Graves' disease?

   A: Graves' disease is caused by autoantibodies (thyroid-stimulating immunoglobulins) that bind to and stimulate the TSH receptor on thyroid follicular cells. This leads to increased thyroid hormone production and secretion, as well as thyroid gland hyperplasia.

3. Q: How does the incidence of Graves' disease vary with age and sex in children?

   A: Graves' disease is rare in children under 5 years old. Its incidence increases with age, peaking in adolescence. It is more common in females, with a female-to-male ratio of approximately 5:1 in adolescents.

4. Q: What are the key clinical features of hyperthyroidism in children?

   A: Key clinical features include goiter, tachycardia, weight loss despite increased appetite, heat intolerance, tremors, hyperactivity, and difficulty concentrating. In prepubertal children, accelerated growth and bone maturation may be observed.

5. Q: How does hyperthyroidism affect growth and development in children?

   A: Hyperthyroidism can lead to accelerated linear growth and advanced bone age. However, if left untreated, it may result in premature closure of growth plates and ultimately reduced adult height.

6. Q: What eye signs are associated with Graves' disease in children?

   A: Eye signs may include proptosis (exophthalmos), lid lag, lid retraction, periorbital edema, and in severe cases, optic nerve compression or corneal ulceration.

7. Q: What laboratory tests are used to diagnose hyperthyroidism in children?

   A: Key tests include serum TSH (suppressed), free T4 and free T3 (elevated), and TSH receptor antibodies (positive in Graves' disease). Additional tests may include thyroid ultrasound and radioactive iodine uptake scan.

8. Q: What is the significance of TSH receptor antibodies in pediatric Graves' disease?

   A: TSH receptor antibodies are diagnostic for Graves' disease. They can cross the placenta and cause neonatal thyrotoxicosis. Their levels may also be used to predict the likelihood of remission or relapse.

9. Q: What are the treatment options for pediatric Graves' disease?

   A: Treatment options include antithyroid drugs (e.g., methimazole), radioactive iodine ablation, and thyroidectomy. The choice depends on the child's age, severity of disease, and family preferences.

10. Q: Why is propylthiouracil (PTU) no longer recommended as first-line therapy in children?

    A: PTU is associated with a higher risk of severe liver injury compared to methimazole. The FDA has issued a black box warning against its use as first-line treatment in children.

11. Q: What is the typical starting dose of methimazole in pediatric Graves' disease?

    A: The typical starting dose is 0.2-0.5 mg/kg/day, divided into 1-3 doses, with a usual maximum of 30 mg/day. The dose is adjusted based on clinical and biochemical response.

12. Q: What are the potential side effects of antithyroid drugs in children?

    A: Common side effects include rash, arthralgias, and gastrointestinal upset. Rare but serious side effects include agranulocytosis, hepatotoxicity, and vasculitis. Regular monitoring is essential.

13. Q: What is the role of beta-blockers in the management of pediatric hyperthyroidism?

    A: Beta-blockers (e.g., propranolol) are used to control adrenergic symptoms such as tachycardia, tremors, and anxiety. They provide symptomatic relief while waiting for antithyroid drugs to take effect.

14. Q: When is radioactive iodine therapy considered in pediatric Graves' disease?

    A: Radioactive iodine is typically considered in children over 10 years old who have failed medical therapy or have recurrent disease. It's contraindicated in very young children and those with severe ophthalmopathy.

15. Q: What are the indications for thyroidectomy in pediatric Graves' disease?

    A: Indications include large goiters causing compressive symptoms, failure of medical therapy, non-compliance with medications, and in some cases, patient/family preference for definitive treatment.

16. Q: How is thyroid storm diagnosed and managed in children?

    A: Thyroid storm is a life-threatening exacerbation of thyrotoxicosis characterized by high fever, severe tachycardia, and altered mental status. Management includes high-dose antithyroid drugs, beta-blockers, corticosteroids, and supportive care in an ICU setting.

17. Q: What is the significance of TSH receptor antibodies in pregnant women with a history of Graves' disease?

    A: TSH receptor antibodies can cross the placenta and cause fetal or neonatal thyrotoxicosis. Pregnant women with high antibody titers require close monitoring of fetal thyroid function.

18. Q: How does neonatal Graves' disease present, and how is it managed?

    A: Neonatal Graves' presents with tachycardia, goiter, and poor weight gain. It's managed with antithyroid drugs and beta-blockers. Most cases resolve within 3-6 months as maternal antibodies clear.

19. Q: What is the long-term prognosis for children with Graves' disease?

    A: With proper treatment, most children achieve good control of thyroid function. However, the remission rate with medical therapy alone is low (25-30% after 2 years). Many patients require long-term treatment or definitive therapy.

20. Q: How does hyperthyroidism affect bone health in children?

    A: Hyperthyroidism can lead to decreased bone mineral density and increased fracture risk. This is due to increased bone turnover with a net negative balance. Adequate treatment can improve bone health.

21. Q: What is the "block and replace" regimen in treating pediatric Graves' disease?

    A: The "block and replace" regimen involves using high-dose antithyroid drugs to block thyroid hormone production, combined with levothyroxine replacement. It's not routinely recommended due to higher rates of side effects without clear benefit.

22. Q: How does hyperthyroidism affect cardiac function in children?

    A: Hyperthyroidism can cause tachycardia, increased cardiac output, and in severe cases, high-output heart failure. It may also lead to atrial fibrillation in some cases, particularly in thyroid storm.

23. Q: What is Marine-Lenhart syndrome, and how does it present in children?

    A: Marine-Lenhart syndrome is the coexistence of Graves' disease with functioning thyroid nodules. It's rare in children but should be suspected if hyperthyroidism persists despite successful treatment of Graves' disease.

24. Q: How does the management of Graves' ophthalmopathy differ in children compared to adults?

    A: Graves' ophthalmopathy is generally milder in children than in adults. Management focuses on lubricants and lifestyle measures. Severe cases may require corticosteroids or orbital decompression, but this is rare in pediatric patients.

25. Q: What genetic factors are associated with an increased risk of pediatric Graves' disease?

    A: Genetic factors include polymorphisms in immune regulatory genes such as CTLA-4, PTPN22, and HLA. Family history of autoimmune thyroid disease also increases the risk.

26. Q: How should a child with Graves' disease be monitored after initiating antithyroid drug therapy?

    A: Monitoring should include clinical assessment, thyroid function tests (TSH, free T4, free T3) every 2-4 weeks initially, then every 2-3 months once stable. Complete blood count and liver function tests should be checked periodically to monitor for drug side effects.