Hrev_master Abstract The Thyroid Storm (TS) is the severest form of thyrotoxicosis and is associated with a high mortality rate. TS presents with fever, tachycardia, gastrointestinal symptoms, and central nervous sys- tem dysfunction and may be overlooked if patients do not present thyrotoxic symptoms or have precipitating factors. We reported a pediatric case of TS with mild proptosis but no obvious precipitat- ing factors in a previously healthy child. A 9-year-old, female patient with a history of attention-deficit hyperactivity disorder presented with the complaint of frequent vomiting. She was alert but lethargic with fever and tachycardia. Physical examination was unremarkable except for coolness in the extremities and a delayed capillary refill time of two seconds. Fluid resuscitation was inef- fective in alleviating the tachycardia. Additional history-taking revealed a one-month history of mild proptosis but no other thyro- toxic findings or precipitating factors were found. Markedly ele- vated thyroxine and triiodothyronine and suppressed thyroid-stim- ulating hormone on thyroid function tests led to a diagnosis of TS. Methimazole, potassium iodine, bisoprolol, and hydrocortisone were administered. Her vital signs and thyroid functions gradually improved, and she was discharged 18 days after admission without any serious complications. She is currently euthyroid and clinically stable on 5 mg of methimazole at three months after admission. When tachycardia that is resistant to usual resuscitation is found, careful history-taking and physical examination targeting thyroid disorders should be performed to assess for TS. Introduction Thyrotoxicosis is rare, having an incidence of only 0.7- 6.5/100,000 in children.1 Its most severe manifestation is the Thyroid Storm (TS), which triggers a variety of complications. The incidence of TS is around 0.2/100,000 per year in hospitalized patients, and the associated mortality rate is �10% although there are no data on pediatric patients with this condition.2 TS can man- ifest a wide variety of symptoms, including fever, tachycardia, Gastrointestinal (GI) symptoms, and Central Nervous System (CNS) dysfunctions associated with thyrotoxicosis, such as goiter, proptosis, and palpitation. However, the various combinations of these common symptoms often make diagnosis challenging espe- cially if the patient neither presents thyrotoxic symptoms nor has a history of a thyroid disorder.2 Furthermore, TS is often triggered by the discontinuation of anti-thyroid medication, surgery or infec- tion, and in the absence of such triggers, diagnosis may be diffi- cult.2 We herein report a pediatric case of TS without any triggers in a prepubertal child with no previous history of a thyroid disor- der. Case Report A 9-year-old female patient with a history of attention-deficit Emergency Care Journal 2022; volume 18:10165 Correspondence: Takaaki Mori, Division of Pediatric Emergency Medicine, Department of Pediatric Emergency and Critical Care Medicine, Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo 183-8561, Japan. Tel.: +81.43.300.5111; Fax: +81.43.312.8130. E-mail: takaakimori001019@gmail.com Key words: Thyroid storm; healthy child; precipitating factors. Acknowledgements: We thank Mr. James R. Valera for his assistance with editing this manuscript. Contributions: TM conceptualized and designed the study, collected data, and drafted the initial manuscript. MMK and YHag coordinated and supervised the data collection and critically reviewed the manu- script for important intellectual content. YHas critically reviewed the manuscript for important intellectual content. All the authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Conflict of interests: The Authors declare no conflict of interest. Availability of data and materials: All data underlying the findings are fully available. Ethics approval and consent to participate: No ethical committee approval was required for this case report by the Department, because this article does not contain any studies with human participants or ani- mals. Informed consent was obtained from the patient included in this study. Consent for publication: The patient’s guardian gave her written consent to use the patient’s personal data for the publication of this case report and any accompanying images. Received for publication: 2 October 2021. Revision received: 10 January 2022. Accepted for publication: 11 January 2022. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2022 Licensee PAGEPress, Italy Emergency Care Journal 2022; 18:10165 doi:10.4081/ecj.2022.10165 [Emergency Care Journal 2022; 18:10165] [page 1] Thyroid storm without precipitating factors in a previous healthy child: A case report Takaaki Mori,1 Marie Mitani-Konno,2 Yusuke Hagiwara,1 Yukihiro Hasegawa2 1Division of Pediatric Emergency Medicine, Department of Pediatric Emergency and Critical Care Medicine; 2Division of Endocrinology and Metabolism, Tokyo Metropolitan Children’s Medical Center, Fuchu Tokyo, Japan Non -co mmerc ial us e o nly hyperactivity disorder presented with frequent non-bilious vomit- ing of 22 hours’ duration. On arrival, she was alert but lethargic with a respiratory rate of 16 breaths/minute, a heart rate of 140 beats/minute, oxygen saturation of 99% on room air, a blood pres- sure of 141/65 mmHg, and a body temperature of 37.0°C. Her weight was 27.0 kg (-0.8 SD), and her height was 133.5 cm (-0.2 SD). She denied any other symptoms, such as abdominal pain and diarrhea. On physical examination, her lungs were clear. Her heart sounds were normal with no heart murmurs or gallop rhythm. Hepatosplenomegaly was denied. She had coolness in her extrem- ities and a delayed Capillary Refill Time (CRT) of two seconds. Ultrasonography demonstrated adequate left ventricular contrac- tion, and a chest radiography and electrocardiogram revealed no remarkable findings except for sinus tachycardia. Venous blood gas analysis showed metabolic acidosis with hypoglycemia and positive urinary ketone bodies (Table 1). Fluid resuscitation with 20mL/kg of normal saline and 40mL of 20% glucose was initially performed for hypovolemic compensated shock due to frequent vomiting. After fluid resuscitation, her heart rate remained at around 150 beats/minutes despite warmth in the extremities and normal CRT. Additional history-taking revealed that her mother had noticed a slight protrusion of the patient’s eyes one month ago despite the absence of any family history of thyroid disorders. Repeated exam- inations failed to find a goiter but revealed slight exophthalmos in comparison to a photograph taken two months ago. Her body tem- perature rose to 38.8°C although the other vital signs and physical examination findings showed no significant change. Laboratory tests (Table 1) found Thyroid-Stimulating Hormone (TSH) sup- pressed to <0.005µU/mL (normal range: 0.67-4.52µU/mL), Free Thyroxine (FT4) elevated to >7.77ng/dL (normal range: 0.96- 1.60ng/dL), and Free Triiodothyronine (FT3) elevated to 22.31pg/mL (normal range: 3.10-4.87pg/mL). Anti-TSH-receptor antibodies and thyroid-stimulating antibody were markedly elevat- ed at 35.2 IU/L, and 2392%, respectively, as seen in Graves’ dis- ease. Other laboratory tests demonstrated normal creatinine and elevated urea nitrogen, aspartate aminotransferase, alanine amino- transferase, and total bilirubin. Nasopharyngeal swab, blood, stool, and urine cultures were negative (Table 1). Graves’ disease was diagnosed based on the clinical findings and test findings. TS was confirmed by the Burch-Wartofsky Point Scale and the Japanese Thyroid Association criteria. The patient was admitted to a pediatric intensive care unit for cardiovascular monitoring and anti-thyroid treatment. Methimazole (MMI) 60mg/day, potassium iodide (KI) 150mg/day, bisoprolol 1.4 mg/day, and Hydrocortisone (HDC) 200 mg/day were soon begun in accordance with the guidelines for the treatment of childhood- onset Graves’ disease in Japan and the 2016 guidelines for the management of thyroid storm of the Japan Thyroid Association and the Japan Endocrine Society. After treatment, the patient’s vital signs and thyroid function tests slowly improved as shown in Figure 1. Thyroid ultrasonography on day 2 showed an enlarge- ment in the right and left lobe to 6.5mL and 5.8mL, respectively, and increased vascularity (upper limit: 4.4mL and 3.6mL) despite the gland being clinically impalpable. KI and HDC were tapered, then discontinued on hospitaliza- tion day 16. MMI was also tapered in accordance with the thyroid function test findings, and the patient was discharged with a pre- scription for MMI 30 mg and bisoprolol 1.4mg without serious complications, such as severe liver dysfunction or agranulocytosis, 18 days after admission. After discharge, bisoprolol was terminat- ed on day 74. The patient is currently euthyroid and clinically sta- ble with 5 mg of methimazole at three months after admission. Discussion In the present case, the presence of tachycardia resistant to the initial treatment raised suspicion of a thyroid disorder. Tachycardia in children can be caused by any one of a variety of conditions, including sympathetic hyperactivity triggered by fever, anxiety or exercise; life-threatening conditions, such as sepsis, hypovolemic shock or intoxication; and thyrotoxicosis.3 The combination of fever, frequent vomiting and tachycardia initially pointed to hypo- Case Report Figure 1. Time course of patient’s thyroid hormone levels (FT4 indicated by dashed line and FT3 indicated by solid line). MMI: methi- mazole; KI: potassium iodine; HDC: hydrocortisone; BB: beta-blocker (bisoprolol). [page 2] [Emergency Care Journal 2022; 18:10165] Non -co mmerc ial us e o nly Case Report Table 1. Laboratory test results on admission. Complete blood count Endocrinological analysis (Normal range) White blood cell 8970 /µL Free thyroxine (FT4) >7.77 ng/dL (0.96-1.60) Hemoglobin 10.4 g/dL Free triiodothyronine (FT3) 22.31 pg/mL (3.10-4.87) Platelet 297,000 /µL Thyroid stimulating hormone (TSH) <0.005 µU/mL (0.67-4.52) Cortisol 11.5 µg/dL (3-12) Biochemistry test Adrenocorticotropic hormone (ACTH) 53.6 µg/dL (7.2-63.3) Aspartate aminotransferase 61 U/l Anti-thyroid peroxidase antibody <9 IU/mL (<16) Alanine aminotransferase 80 U/l Anti-thyroglobulin antibody 10 IU/mL (<28) Total bilirubin 1.0 mg/dL Anti-TSH stimulating antibody 2392 % (<120) Direct bilirubin 0.1 mg/dL Urea nitrogen 22.6 mg/dL Blood culture Negative Creatinine 0.4 mg/dL Na 142 mEq/L Urine culture Negative K 5.5 mEq/mL Cl 104 mEq/mL Stool Culture Negative Ca 10.4 mg/dL P 7 mg/dL Nasopharyngeal swab Negative C-reactive protein 0.03 mg/dL SARS-CoV-2 Negative Adenovirus Negative Blood gas analysis (venous) Coronavirus 229E/HKU1/NL63/OC43 Negative pH 7.23 Human-metapneumovirus Negative pCO2 40.9 mmHg Rhino/Enterovirus Negative HCO3 16.5 mmol/L Influenza virus A/B Negative Base excess -10.3 mmol/L Para-influenza virus 1/2/3/4 Negative Lactate 1.9 mg/dL Respiratory syncytial virus Negative Bordetella pertussis Negative Urinalysis Chlamydia pneumoniae Negative Nitrate Negative Mycoplasma pneumoniae Negative Ketone 3+ White blood cell Negative Table 2. Pediatric cases of thyroid storm with no past history of thyroid diseases or precipitating factors. Author, year Age Gender TS Thyrotoxicosis PE Past Family Precipitating (years symptoms associated history history of factors old) symptoms of TD TD Ladd, 2020 2 Female CNS, fever, tachycardia, GI Weight loss, Goiter None Present None excessive sweating Bonfield, 2018 4 Female Tachycardia Weight loss, increased appetite, Goiter, None None None tiredness, sleep disturbance, exophthalmos, tremor Hecht, 2012 7 Female CNS, fever, tachycardia None Goiter None None None Matsubara, 2021 9 Female CNS, fever, tachycardia, GI Weight loss N.A. None None None Darby, 1962 9 Female Fever, tachycardia, CHF, GI Weight loss, heat Goiter, exophthalmos, None None None intolerance tremor Grossman, 1961 10 Female CNS, fever, tachycardia, GI Weight loss Goiter None None None Albeert, 2014 12 Female CNS, fever, tachycardia, GI Weight loss, jitteriness, anxiety Goiter None None None Present case 9 Female Fever, tachycardia, GI None Mild exophthalmos None None None GI, gastrointestinal symptoms such as nausea, vomiting, diarrhea, and increased total bilirubin level over 3.0 0mg/dL; CNS, central nervous system dysfunction including decreased consciousness, seizure, somnolence/lethargy, restlessness, delirium, mental abrasion/psychosis; CHF; congestive heart failure including pulmonary edema, moist rale in more than half of the lung field, Class by the New York Heart Association, or Class in Killip classification, or cardiogenic shock; TS, thyroid storm; TD, thyroid disease; PE, physical examination [Emergency Care Journal 2022; 18:10165] [page 3] Non -co mmerc ial us e o nly volemia caused by frequent vomiting, but fluid resuscitation was ineffective in alleviating the symptoms. According to the 2020 Pediatric Advanced Life Support Guidelines, if the initial treatment for tachycardia is unsuccessful, the patient should be re-evaluated and rare causes of tachycardia, such as thyrotoxicosis, should be considered.4 The frequent vomiting in the present patient was considered a potential symptom of TS. Hyperthermia, tachycardia, heart failure, and CNS and GI dysfunctions are the chief presenting symptoms of TS.2 In adults, TS manifests marked tachycardia and CNS impairment rather than fever, GI symptoms or heart failure.5 Although no epidemiological studies of TS in children have been published, tachycardia, fever, GI dysfunction is common symp- toms in pediatric TS cases.6-18 In the present case, the patient denied abdominal pain and diarrhea, and anti-thyroid therapy quickly alleviated the vomiting, suggesting that the latter was a symptom of TS rather than acute gastroenteritis. It is often more difficult to diagnose childhood Graves’ disease than in adults. Pediatric Graves’ disease predominantly occurs in adolescent females and its incidence rate in prepubertal patients is around 0.4/100,000, or less than one-fifth of that in adolescent.1 The median time to diagnose from the onset of symptoms in the entire pediatric patients is three months (0-36 months).1 At least the following three factors hindered the diagnosis of TS in the present case. First, the patient had no history of Grave’s disease. Epidemiological studies in Asia have shown that more than 60% of adult TS cases occurred in patients with a history of thyroid disorder.5 However, only 15% of pediatric patients with TS reportedly have a history of thyroid disorder.8-10,12,16,17 Second, dif- ficulty in detecting the patient’s proptosis at the initial examination delayed the diagnosis of Graves’ disease. The triad of Graves’ dis- ease is goiter, tachycardia, and proptosis. However, proptosis is uncommon in childhood Grave’s disease compared with goiter and tachycardia where its incidence is around 40%,19 and it is often mild.20 Lastly, the patient had no precipitating factors of TS. In adult TS, the discontinuation of anti-thyroid medication, surgery, infection, pregnancy, and emotional stress are often recognized as precipitating factors.2 There are just several cases where pediatric patients had precipitating factors. Table 2 shows previous cases of TS in children without precipitating factors,6,7,11,13-15,18 Conclusions When patients present with marked tachycardia that is resistant to initial resuscitation, TS should be considered even if no typical thyrotoxic findings, a past history of thyroid disorder or precipitat- ing factors are found. References 1. Williamson S, Greene SA. Incidence of thyrotoxicosis in childhood: a national population based study in the UK and Ireland. Clin Endocrinol (Oxf) 2010;72:358-63. 2. Chiha M, Samarasinghe S, Kabaker AS. Thyroid storm: an updated review. J Intensive Care Med 2015;30:131-40. 3 Fleisher GR, Ludwig S, Bachur RG, et al. Textbook of pedi- atric emergency medicine. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins Health 2015. 4. Topjian AA, Raymond TT, Atkins D, et al. Part 4: Pediatric Basic and Advanced Life Support 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2020;142:S469-S523. 5. Kornelius E, Chang KL, Yang YS, et al. Epidemiology and fac- tors associated with mortality of thyroid storm in Taiwan: a nationwide population-based study. Intern Emerg Med 2021;16:601-07. 6. Albert BB, Eckersley LG, Skinner JR, et al. QT prolongation in a child with thyroid storm. BMJ Case Rep 2014;2014:bcr2013202595. 7. Bonfield A, Shenoy S. Thyrotoxic crisis as an acute clinical presentation in a child. BMJ Case Rep 2018;2018:bcr2017222850. 8. Chantra M, Limsuwan A, Mahachoklertwattana P. Low cardiac output thyroid storm in a girl with Graves’ disease. Pediatr Int 2016;58:1080-83. 9. Creo AL, Cannon BC, Pittock ST. Thyroid storm after chok- ing. J Pediatr Endocrinol Metab 2018;31:933-36. 10. Dahl IL. Thyroid crisis in a 3-year-old girl. Acta Paediatr Scand 1968;57:55-8. 11. Darby CP. Three episodes of spontaneous thyroid storm occur- ring in a nine-year-old child. Pediatrics 1962;30:927-31. 12. Galaburda M, Rosman NP, Haddow JE. Thyroid storm in an 11-year-old boy managed by propranolol. Pediatrics 1974;53:920-2. 13. Grossman A, Waldstein SS. Apathetic thyroid storm in a 10- year-old child. Pediatrics 1961;28:447-51. 14. Hecht T, Brand J, Vlaho S. Encephalopathy and sinustachycar- dia in childhood—a possible differential diagnosis. J Pediatr Endocrinol Metab 2012;25:149-51. 15. Ladd JM, Sabsabi B, von Oettingen JE. Thyroid Storm in a Toddler Presenting as a Febrile Seizure. Pediatrics 2020;145:e20191920. 16. Landgraf L, Grubina R, Chinsky J. Altered mental status in a 16-year-old girl: the calm before the storm. Clinical Pediatrics 2008;47:720-4. 17. Lawless ST, Reeves G, Bowen JR. The development of thyroid storm in a child with McCune-Albright syndrome after ortho- pedic surgery. Am J Dis Child 1992;146:1099-102. 18. Matsubara K, Kuki I, Yamamoto N, et al. Thyroid crisis mim- icking clinically mild encephalitis/encephalopathy with a reversible splenial lesion: A pediatric case report. Brain Dev 2021;43:596-600. 19. Sato H, Minamitani K, Minagawa M, et al. Clinical features at diagnosis and responses to antithyroid drugs in younger chil- dren with Graves’ disease compared with adolescent patients. J Pediatr Endocrinol Metab 2014;27:677-83. 20. Goldstein SM, Katowitz WR, Moshang T, et al. Pediatric thy- roid-associated orbitopathy: the Children’s Hospital of Philadelphia experience and literature review. Thyroid 2008;18:997-9. Case Report [page 4] [Emergency Care Journal 2022; 18:10165] Non -co mmerc ial us e o nly