Pediatric Graves Disease: Updates on Signs, Symptoms, Diagnosis, and Management

The prevalence of pediatric Graves disease (GD) varies worldwide, from a rate of 1 per 10,000 in the United States (US) compared with a rate of 1 per 100,000 in the United Kingdom.^1-3 Regardless of worldwide variance, the incidence of pediatric GD is thought to be on the rise and currently accounts for 10%-15% of thyroid disorders among children and is more common in girls than in boys.^1,4

Pediatricians and pediatric specialists should be aware of potential signs and symptoms of Graves disease in order to provide their patients with optimal care. A review, published in JAMA Otolaryngology-Head & Neck Surgery, discussed the current state of pediatric GD management and suggested it may be time for new approaches to the disease.⁵

Graves disease triggers thyrotropin receptor-stimulating antibodies (TRAb) to promote thyroid hormone synthesis and secretion, increasing thyroid vascularity and fostering follicular cell growth.⁴ The cause of GD is thought to be a complex interaction between several medical and environmental factors. The immune system of a child with GD and their genetic background may play a role in the development of the disorder. Children with a family history of autoimmune thyroid disease and other autoimmune conditions such as type 1 diabetes, Hashimoto thyroiditis, rheumatoid arthritis and celiac disease appear to be more susceptible to developing GD. Additionally, children with a genetic syndrome predisposed to Di George syndrome, Down syndrome, and Turner syndrome may also be more susceptible to the disorder. These factors combined are likely contributing to the differing rates worldwide.⁵

Children with GD can have highly variable alterations to their thyroid gland, but patients typically present with a symmetrically enlarged, nontender, firm thyroid. Unlike adult GD, children rarely present with true thyroid storm^6,7 or atrial fibrillation.⁸  Children with pediatric GD can present with a wide range of symptoms which, coupled with its rarity, can confound a proper and timely diagnosis.⁵

 “It’s so challenging to diagnose GD in kiddos because, first of all, it’s hard for them to express exactly what they’re feeling, and second of all, there’s just so many symptoms that people sometimes attribute to other causes. Some think [their child is] probably experiencing growing pains or that they have some psychological issue, such as anxiety. In kids, [GD] can appear in many different ways and it can mimic other diseases,” Lourdes Quintanilla-Dieck, MD, Pediatric Otolaryngologist and Assistant Professor of Otolaryngology at the Oregon Health and Science University and lead author of the review said..

Symptoms can include palpitations, tachycardia, headache, tremor, increased appetite, weight change, excessive perspiration, sleep disturbance, diarrhea, increased stool frequency, ophthalmologic changes, and behavioral symptoms such as irritability, emotional lability, and nervousness, among others.^1,5,9 In part due to the heterogenous symptomology of GD, care for these patients requires a multidisciplinary team involving pediatric specialists in the endocrinology, radiology, nuclear medicine, ophthalmology, and surgery fields.⁵

Children suspected of having GD should undergo a physical examination.  Those presenting with an abnormal, enlarged, or asymmetric thyroid gland, should also have a laboratory evaluation. The profile of a patient with GD can include^5:

• Suppressed thyrotropin
• Elevated free thyroxine
• Elevated total triiodothyronine
• Positive for thyroid-stimulating immunoglobulin
• Positive for thyrotropin-binding inhibitory immunoglobulin/TRAb
• Negative for thyroid peroxidase antibody
• Negative for antithyroglobulin antibody

When making clinical decisions, the specific treatment avenue should consider the patient’s age, clinical status, and likelihood of achieving clinical remission, however, patients typically start treatment with medication.⁵

Typical pharmacological approaches for pediatric GD include antithyroid drugs (ATD) such as methimazole or carbimazole. If indicated, b-blockers can be used for temporary symptom management of thyroid hormone levels. After one year of ATD therapy, the dosage can be titrated up if the patient has not had any major adverse effects. After two years, ATD can be continued or weaned depending on the patient’s status. For children who experience persistent thyrotoxicosis or relapse, radioactive iodine (RAI) therapy or surgery should be considered. Only a minority of patients are able to achieve durable remission with pharmacologic approaches alone, and most patients will progress to receiving RAI or surgery.⁵

“It’s important to keep in mind what the status of the patient’s quality of life is. It’s a big deal for a child to have to be really strict with taking medicine every day and for some, it’s just not going to work. These things should be taken into consideration both when deciding what the best treatment for a specific patient will be and when counseling a family. Make sure you explore both RAI and surgery in detail with patients to make sure they know about all options,” said Dr Quintanilla-Dieck.

The indications for RAI are patients over 5 years of age with ¹²³I activity <10 mCi, a gland size <80 g, and no contraindications. Surgery is recommended for children with contraindications for RAI, such as moderate to severe GD orbitopathy, a very large gland for those with thyroid nodules, and those who prefer surgery over RAI. The review authors recommended for children to undergo surgery at high-volume centers to reduce the risk for complications.⁵

Dr Quintanilla-Dieck concluded, “Medicine is not a cookbook. You should consider each patient differently. It’s important to carefully examine each patient scenario and to have that long conversation where you discuss all of the options and really come up with the [treatment plan] that’s going to be right for each patient.”

References

1. Léger J, Oliver I, Rodrigue D, Lambert AS, Coutant R. Graves’ disease in children. Ann Endocrinol. 2018;79(6):647-655. doi:10.1016/j.ando.2018.08.001

2. Williamson S, Greene SA. Incidence of thyrotoxicosis in childhood: a national population-based study in the UK and Ireland. Clin Endocrinol. 2010;72(3):358-363. doi:10.1111/j.1365-2265.2009.03717.x

3. Hanley P, Lord K, Bauer AJ. Thyroid disorders in children and adolescents: a review. JAMA Pediatr. 2016;170(10):1008-1019. doi:10.1001/jamapediatrics.2016.0486

4. Lee HS, Hwang JS. The treatment of Graves’ disease in children and adolescents. Ann Pediatr Endocrinol Metab. 2014;19(3):122-126. doi:10.6065/apem.2014.19.3.122

5. Quintanilla-Dieck L, Khalatbari HK, Dinauer CA, et al. Management of Pediatric Graves Disease: A Review. JAMA Otolaryngol Head Neck Surg. 2021;147(12):1110-1118. doi:10.1001/jamaoto.2021.2715

6. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: thyroid storm. Endocrinol Metab Clin North Am. 1993;22(2):263-277. doi:10.1016/S0889-8529(18)30165-8

7. Akamizu T, Satoh T, Isozaki O, et al. Japan Thyroid Association. Diagnostic criteria, clinical features, and incidence of thyroid storm based on nationwide surveys. Thyroid. 2012;22(7):661-679. doi:10.1089/thy.20

8. Srinivasan S, Misra M. Hyperthyroidism in children. Pediatr Rev. 2015;36(6):239-248. doi:10.1542/pir.36-6-239

9. Okawa ER, Grant FD, Smith JR. Pediatric Graves’ disease: decisions regarding therapy. Curr Opin Pediatr. 2015;27(4):442-447. doi:10.1097/MOP.0000000000000241