UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Clinical manifestations and diagnosis of hyperthyroidism in children and adolescents

Author
Stephen LaFranchi, MD
Section Editor
Mitchell E Geffner, MD
Deputy Editor
Alison G Hoppin, MD

INTRODUCTION

The clinical manifestations of hyperthyroidism in children and adolescents are similar to those seen in adults. In addition, the disorder has unique effects on growth and development. The clinical features of hyperthyroidism are largely independent of the cause. While the terms hyperthyroidism and thyrotoxicosis are often used interchangeably, in this topic thyrotoxicosis refers to the clinical symptomatology resulting from excess thyroid hormone, either of endogenous or exogenous origin. Hyperthyroidism refers specifically to excessive synthesis and secretion of endogenous thyroid hormone. Although there are several potential causes of hyperthyroidism in children, Graves' disease is by far the most common etiology.

In addition to causing hyperthyroidism, Graves' disease causes unique problems that are not related to the high serum thyroid hormone concentrations. They include Graves' ophthalmopathy and infiltrative dermopathy (localized or pretibial myxedema). Graves' ophthalmopathy is common in children, but less severe than in adults; dermopathy is almost never found in children. Most patients with Graves' hyperthyroidism have a diffuse goiter, but so do patients with other, less common causes of hyperthyroidism, such as "Hashitoxicosis" (silent or painless thyroiditis), subacute thyroiditis, or forms of nonautoimmune hyperthyroidism. These disorders are discussed briefly in this topic review. (See 'Destructive thyroiditis' below.)

The clinical presentation and laboratory evaluation of children with hyperthyroidism and thyrotoxicosis are discussed here. Treatment of hyperthyroidism is discussed separately. Hyperthyroidism presenting during the neonatal period also is discussed separately. (See "Treatment and prognosis of Graves' disease in children and adolescents" and "Evaluation and management of neonatal Graves' disease".)

INCIDENCE

Graves' disease is by far the most common cause of hyperthyroidism in children and adolescents. In a national population-based study of thyrotoxicosis from the United Kingdom and Ireland in 2004, the annual incidence was 0.9 per 100,000 children <15 years of age, with Graves' disease accounting for 96 percent of cases [1]. A nationwide study from Denmark reported an incidence of 0.79 per 100,000 in children <15 years of age in the time period of 1982 to 1988, with a doubling to 1.58 per 100,000 in the years 1998 to 2012 [2]. A report using data from the US National Health and Nutritional Examination Surveys (NHANES) analyzing adolescents and young adults found that thyrotoxicosis was more common in non-Hispanic blacks than Mexican-Americans, in whom it was more common than non-Hispanic whites [3]. Overall, the prevalence of Graves' hyperthyroidism in children is approximately 0.02 percent (1:5000), mostly in the 11- to 15-year age group [4]. In a report of 143 children with Graves' disease, 38 percent were prepubertal at diagnosis [5]. Girls are affected more commonly than boys, at a ratio of about 5:1. The ratio is considerably lower among younger children, suggesting that estrogen secretion in some way affects the occurrence of Graves' disease.

PATHOGENESIS

The proximate cause of Graves' hyperthyroidism in children and adolescents, as in adults, is thyrotropin (TSH) receptor-stimulating antibodies (TSHR-Ab), which activate the TSH receptor. A population-based study of Danish twins suggested that approximately 80 percent of the risk of Graves' disease is attributable to genetic factors [6] (see "Pathogenesis of Graves' disease"). The development of Graves’ disease has also been reported in children after hematopoietic stem cell transplantation, so-called Graves’ immune reconstitution inflammatory syndrome (IRIS) [7]. The mechanism is believed to be immunological dysregulation during T-cell engraftment with subsequent production of TSHR-Ab by B-cells.

                            

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Tue Oct 11 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Williamson S, Greene SA. Incidence of thyrotoxicosis in childhood: a national population based study in the UK and Ireland. Clin Endocrinol (Oxf) 2010; 72:358.
  2. Havgaard Kjær R, Smedegård Andersen M, Hansen D. Increasing Incidence of Juvenile Thyrotoxicosis in Denmark: A Nationwide Study, 1998-2012. Horm Res Paediatr 2015; 84:102.
  3. McLeod DS, Cooper DS, Ladenson PW, et al. Race/Ethnicity and the prevalence of thyrotoxicosis in young Americans. Thyroid 2015; 25:621.
  4. Barnes HV, Blizzard RM. Antithyroid drug therapy for toxic diffuse goiter (Graves disease): thirty years experience in children and adolescents. J Pediatr 1977; 91:313.
  5. Poyrazoğlu S, Saka N, Bas F, et al. Evaluation of diagnosis and treatment results in children with Graves' disease with emphasis on the pubertal status of patients. J Pediatr Endocrinol Metab 2008; 21:745.
  6. Brix TH, Kyvik KO, Christensen K, Hegedüs L. Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts. J Clin Endocrinol Metab 2001; 86:930.
  7. Sinha A, Abinun M, Gennery AR, et al. Graves' immune reconstitution inflammatory syndrome in childhood. Thyroid 2013; 23:1010.
  8. Bahn RS, Heufelder AE. Pathogenesis of Graves' ophthalmopathy. N Engl J Med 1993; 329:1468.
  9. Acuna OM, Athannassaki I, Paysse EA. Association between thyroid-stimulating immunoglobulin levels and ocular findings in pediatric patients with Graves disease. Trans Am Ophthalmol Soc 2007; 105:146.
  10. Shulman DI, Muhar I, Jorgensen EV, et al. Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy. Thyroid 1997; 7:755.
  11. Mankaï A, Chadli-Chaieb M, Saad F, et al. Screening for celiac disease in Tunisian patients with Graves' disease using anti-endomysium and anti-tissue transglutaminase antibodies. Gastroenterol Clin Biol 2006; 30:961.
  12. Koves IH, Cameron FJ, Kornberg AJ. Ocular myasthenia gravis and Graves disease in a 10-year-old child. J Child Neurol 2009; 24:615.
  13. Dost A, Rohrer TR, Fröhlich-Reiterer E, et al. Hyperthyroidism in 276 Children and Adolescents with Type 1 Diabetes from Germany and Austria. Horm Res Paediatr 2015; 84:190.
  14. Panamonta O, Sumethkul V, Radinahmed P, et al. Propylthiouracil associated antineutrophil cytoplasmic antibodies (ANCA) in patients with childhood onset Graves' disease. J Pediatr Endocrinol Metab 2008; 21:539.
  15. Friedman JM, Fialkow PJ. The genetics of Graves' disease. Clin Endocrinol Metab 1978; 7:47.
  16. Goday-Arno A, Cerda-Esteva M, Flores-Le-Roux JA, et al. Hyperthyroidism in a population with Down syndrome (DS). Clin Endocrinol (Oxf) 2009; 71:110.
  17. De Luca F, Corrias A, Salerno M, et al. Peculiarities of Graves' disease in children and adolescents with Down's syndrome. Eur J Endocrinol 2010; 162:591.
  18. Wasniewska M, Corrias A, Messina MF, et al. Graves' disease prevalence in a young population with Turner syndrome. J Endocrinol Invest 2010; 33:69.
  19. Zimmerman D, Gan-Gaisano M. Hyperthyroidism in children and adolescents. Pediatr Clin North Am 1990; 37:1273.
  20. Bossowski AT, Reddy V, Perry LA, et al. Clinical and endocrine features and long-term outcome of Graves' disease in early childhood. J Endocrinol Invest 2007; 30:388.
  21. Cassio A, Corrias A, Gualandi S, et al. Influence of gender and pubertal stage at diagnosis on growth outcome in childhood thyrotoxicosis: results of a collaborative study. Clin Endocrinol (Oxf) 2006; 64:53.
  22. Koutras DA. Disturbances of menstruation in thyroid disease. Ann N Y Acad Sci 1997; 816:280.
  23. Bilezikian JP, Loeb JN. The influence of hyperthyroidism and hypothyroidism on alpha- and beta-adrenergic receptor systems and adrenergic responsiveness. Endocr Rev 1983; 4:378.
  24. Nordyke RA, Gilbert FI Jr, Harada AS. Graves' disease. Influence of age on clinical findings. Arch Intern Med 1988; 148:626.
  25. Chan W, Wong GW, Fan DS, et al. Ophthalmopathy in childhood Graves' disease. Br J Ophthalmol 2002; 86:740.
  26. Goldstein SM, Katowitz WR, Moshang T, Katowitz JA. Pediatric thyroid-associated orbitopathy: the Children's Hospital of Philadelphia experience and literature review. Thyroid 2008; 18:997.
  27. Holt H, Hunter DG, Smith J, Dagi LR. Pediatric Graves' ophthalmopathy: the pre- and postpubertal experience. J AAPOS 2008; 12:357.
  28. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system: from theory to practice. J Clin Endocrinol Metab 1994; 78:1026.
  29. Channick BJ, Adlin EV, Marks AD, et al. Hyperthyroidism and mitral-valve prolapse. N Engl J Med 1981; 305:497.
  30. O'Brien T, Katz K, Hodge D, et al. The effect of the treatment of hypothyroidism and hyperthyroidism on plasma lipids and apolipoproteins AI, AII and E. Clin Endocrinol (Oxf) 1997; 46:17.
  31. Crocker MK, Kaplowitz P. Treatment of paediatric hyperthyroidism but not hypothyroidism has a significant effect on weight. Clin Endocrinol (Oxf) 2010; 73:752.
  32. van Veenendaal NR, Rivkees SA. Treatment of pediatric Graves' disease is associated with excessive weight gain. J Clin Endocrinol Metab 2011; 96:3257.
  33. Berti I, Trevisiol C, Tommasini A, et al. Usefulness of screening program for celiac disease in autoimmune thyroiditis. Dig Dis Sci 2000; 45:403.
  34. Shah SA, Peppercorn MA, Pallotta JA. Autoimmune (Hashimoto's) thyroiditis associated with Crohn's disease. J Clin Gastroenterol 1998; 26:117.
  35. Zürcher RM, Horber FF, Grünig BE, Frey FJ. Effect of thyroid dysfunction on thigh muscle efficiency. J Clin Endocrinol Metab 1989; 69:1082.
  36. Ross DS. Hyperthyroidism, thyroid hormone therapy, and bone. Thyroid 1994; 4:319.
  37. Seeherunvong T, Diamantopoulos S, Berkovitz GD. A nine year old girl with thyrotoxicosis, ataxia, and chorea. Brain Dev 2007; 29:660.
  38. Merkenschlager A, Ehrt O, Müller-Felber W, et al. Reversible benign intracranial hypertension in a child with hyperthyroidism. J Pediatr Endocrinol Metab 2008; 21:1099.
  39. Sohal AP, Dasarathi M, Lodh R, et al. Speech and language delay in two children: an unusual presentation of hyperthyroidism. J Pediatr Endocrinol Metab 2013; 26:1171.
  40. Loomba-Albrecht LA, Bremer AA, Styne DM, Glaser NS. High frequency of cardiac and behavioral complaints as presenting symptoms of hyperthyroidism in children. J Pediatr Endocrinol Metab 2011; 24:209.
  41. Segni M, Leonardi E, Mazzoncini B, et al. Special features of Graves' disease in early childhood. Thyroid 1999; 9:871.
  42. Hazen EP, Sherry NA, Parangi S, et al. Case records of the Massachusetts General Hospital. Case 10-2015. A 15-year-old girl with Graves’ disease and psychotic symptoms. N Engl J Med 2015; 372:1250.
  43. Sasaki T, Nogawa S, Amano T. Co-morbidity of moyamoya disease with Graves' disease. report of three cases and a review of the literature. Intern Med 2006; 45:649.
  44. Noh BH, Cho SW, Ahn SY. Simultaneous occurrence of diabetic ketoacidosis, thyroid storm, and multiple cerebral infarctions due to Moyamoya disease. J Pediatr Endocrinol Metab 2016; 29:221.
  45. Heymann WR. Cutaneous manifestations of thyroid disease. J Am Acad Dermatol 1992; 26:885.
  46. Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011; 21:593.
  47. Botero D, Brown RS. Bioassay of thyrotropin receptor antibodies with Chinese hamster ovary cells transfected with recombinant human thyrotropin receptor: clinical utility in children and adolescents with Graves disease. J Pediatr 1998; 132:612.
  48. Diana T, Brown RS, Bossowski A, et al. Clinical relevance of thyroid-stimulating autoantibodies in pediatric graves' disease-a multicenter study. J Clin Endocrinol Metab 2014; 99:1648.
  49. Rahhal SN, Eugster EA. Thyroid stimulating immunoglobulin is often negative in children with Graves' disease. J Pediatr Endocrinol Metab 2008; 21:1085.
  50. Williams JL, Paul D, Bisset G 3rd. Thyroid disease in children: part 2 : State-of-the-art imaging in pediatric hyperthyroidism. Pediatr Radiol 2013; 43:1254.
  51. Kummer S, Hermsen D, Distelmaier F. Biotin Treatment Mimicking Graves' Disease. N Engl J Med 2016; 375:704.
  52. Kwok JS, Chan IH, Chan MH. Biotin interference on TSH and free thyroid hormone measurement. Pathology 2012; 44:278.
  53. Nabhan ZM, Kreher NC, Eugster EA. Hashitoxicosis in children: clinical features and natural history. J Pediatr 2005; 146:533.
  54. Wasniewska M, Corrias A, Arrigo T, et al. Frequency of Hashimoto's thyroiditis antecedents in the history of children and adolescents with graves' disease. Horm Res Paediatr 2010; 73:473.
  55. Panamonta O, Panombualert S, Panamonta M, Apinives C. Acute suppurative thyroiditis with thyrotoxicosis. J Med Assoc Thai 2009; 92:1370.
  56. Polak M. Hyperthyroidism in early infancy: pathogenesis, clinical features and diagnosis with a focus on neonatal hyperthyroidism. Thyroid 1998; 8:1171.
  57. Duprez L, Parma J, Van Sande J, et al. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet 1994; 7:396.
  58. Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991; 325:1688.
  59. Hacihamdioğlu B, Berberoğlu M, Siklar Z, et al. Amiodarone-induced thyrotoxicosis in children and adolescents is a possible outcome in patients with low iodine intake. J Pediatr Endocrinol Metab 2010; 23:363.
  60. Kasagi K, Hattori H. A case of destructive thyrotoxicosis induced by neck trauma. Thyroid 2008; 18:1333.
  61. Chow EJ, Friedman DL, Stovall M, et al. Risk of thyroid dysfunction and subsequent thyroid cancer among survivors of acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2009; 53:432.
  62. Nakayama Y, Jinguji S, Kumakura S, et al. Thyroid-stimulating hormone (thyrotropin)-secretion pituitary adenoma in an 8-year-old boy: case report. Pituitary 2012; 15:110.
  63. Rabbiosi S, Peroni E, Tronconi GM, et al. Asymptomatic thyrotropin-secreting pituitary macroadenoma in a 13-year-old girl: successful first-line treatment with somatostatin analogs. Thyroid 2012; 22:1076.
  64. Mazerkina N, Trunin Y, Gorelyshev S, et al. Thyrotropin-secreting pituitary adenoma in an 11-year-old boy with type 1 autoimmune polyglandular syndrome. J Pediatr Endocrinol Metab 2016; 29:237.
  65. Teng X, Jin T, Brent GA, et al. A Patient With a Thyrotropin-Secreting Microadenoma and Resistance to Thyroid Hormone (P453T). J Clin Endocrinol Metab 2015; 100:2511.
  66. Refetoff S. Resistance to thyroid hormone: an historical overview. Thyroid 1994; 4:345.
  67. Pohlenz J, Weiss RE, Macchia PE, et al. Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene. J Clin Endocrinol Metab 1999; 84:3919.
  68. Vaidyanathan P, Kaplowitz PB. Evaluation and follow-up of clinically euthyroid children with normal free T4 and suppressed TSH. J Pediatr Endocrinol Metab 2010; 23:993.