The case

A 7-year-old female with a history of receptive-expressive speech disorder presents with her father to establish care. She complains of dull headaches that occur 3 to 4 times per month to her central forehead over the past few months that improve with acetaminophen, ibuprofen, and closing her eyes. They occur in any setting and do not have any clear trigger.

Father also describes an episode of chest pain 2 days prior to presentation. She was getting ready to leave for school when she felt her heart racing and father witnessed her fall to the floor. This episode lasted 2 minutes before self-resolving. Father denied dyspnea, loss-of-consciousness, or cyanosis with this event. No previous episodes like this were reported, though father reports that she has had more anxious episodes recently that could be panic attacks. Family history was notable for hypertension in father, neuroendocrine tumor in paternal grandmother, as well as hyperlipidemia and heart disease in paternal grandfather. The initial exam was notable for an elevated automatic blood pressure of 125/88 mmHg, heart rate of 113 beats per minute (BPM), height of 125.6cm (64th percentile), and weight of 26.7kg (75th percentile).

Evaluation

An outpatient EKG was ordered (although not completed), referral placed to psychology for anxiety, and follow-up arranged for 3 weeks at her well-child check with plan to recheck her blood pressure.

Three weeks later, at her well-child check, she complained of sweating with "beads running down her face" and soaking through her clothes even in the cold and at night through sheets.

Headaches continued 3 to 4 times per month, although she reported increasingly severe pain, which caused her to sob on the floor. She denied photo- and phonophobia.

Her physical exam was notable for fundoscopy without papilledema and an anxious effect, automatic blood pressure of 114/71 mmHg (repeat 110/70), heart rate of 111 BPM and weight of 25.9kg (69th percentile) (Figure 1).

Figure 1

Growth chart

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She was diagnosed with failure-to-thrive and ordered for a urinalysis, complete blood count (CBC) with manual differential, comprehensive metabolic panel (CMP), erythrocyte sedimentation rate, hemoglobin A_1C (HgA_1C), thyroid studies, celiac screening, as well as a brain MRI for her headaches. She was scheduled for follow-up in 2 weeks. Labs are remarkable for CBC with anemia to hemoglobin 11.4 g/dL and thrombocytosis, HgA_1c of 6.0%, and ESR of 123 mm/hr.

Two weeks later at her follow-up, she began to complain of fatigue. She continued with intermittent headaches now associated with dizziness. She endorsed bilateral thigh and lower leg pain worsened with walking over 6 months. She has had no further palpitations and review of systems was otherwise negative. She awaited her MRI, scheduled for the following week.

The exam was notable for an automatic blood pressure of 120/81 mmHg (repeat 127/82, manual 120/76), normal fundoscopy, heart rate of 132 beats/min, and weight down to 25.5kg. Her urine had ketones, protein, and was sent for further testing. She was directed to the emergency department, where an EKG shows sinus tachycardia with heart rate of 124 beats/min, nonspecific intraventricular conduction delay, T-wave abnormality, and left axis deviation (Figure 2). Her blood pressure was 163/127 mmHg and she receives IV hydralazine. The chest x-ray was within normal limits and a complete abdominal ultrasound with doppler was initially interpreted as unremarkable (Figure 3). She was admitted to the nephrology service for further management of her hypertensive crisis. Further imaging and laboratory findings confirm her diagnosis.

Figure 2 - Electrocardiograms

Left image displays EKG abnormalities on admission while the right shows normalized EKG at discharge.

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Figure 3 - Complete Abdominal Ultrasound with Doppler

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Discussion

This patient had several presenting symptoms evolve throughout her outpatient workup including increasingly severe headaches awakening her from sleep, episodic anxiety, profuse diaphoresis, palpitations, and fatigue. In the setting of the parent’s report of anxiety, suspicion for panic attacks was elevated; however medical causes must be ruled out before relying on mental health diagnoses. She also had objective findings including incidental hypertension, tachycardia, and weight loss, all of which could have been explained by a unifying diagnosis or separate etiologies, warranting a broad diagnostic work-up.

The diagnosis of hypertension in pediatrics was complicated by the need for a period of observation. The 2017 American Academy of Pediatrics clinical practice guidelines for management of hypertension recommend annual blood pressure measurement in all >3 years old, ambulatory blood pressure monitoring (ABPM) in patients with elevated measurements over 1 year, and a formal diagnosis of hypertension for auscultatory confirmed measurements >95th percentile at 3 different visits followed by confirmatory ABPM.¹ The 95th percentile for this patient’s size was 112/73 mmHg, which she exceeded, however she did not meet criteria for hypertension until her third visit when she was directed to the emergency department for urgent imaging.

The differential for pediatric secondary hypertension can be organized by system into renal (e.g. glomerulonephritis, polycystic kidney disease, chronic kidney disease), cardiovascular (aortic coarctation, renal artery stenosis), endocrine (e.g. primary hyperaldosteronism, congenital adrenal hyperplasia, malignancy, hyperthyroidism, diabetes mellitus), pharmacological (e.g. stimulants, oral contraceptives, corticosteroids), and monogenic (e.g. Liddle Syndrome, Gordon Syndrome) etiologies (Table 1). Additionally, her weight loss raised concern for autoimmune processes including IBD and celiac disease, while her severe headaches with the red flag of awakening her from sleep further raised concern for an intracranial process, prompting brain imaging.

Management

Definitive treatment for pheochromocytoma requires surgical excision of the adrenal tumors. Pheochromocytomas secrete excess catecholamines, which have potent autonomic activity at alpha- and beta-receptors, risking both hypertensive crisis and hemodynamic instability as resection first releases catecholamines and later cause a relative deficiency of catecholamines. However, with the development of perioperative blood pressure management, mortality has greatly decreased. At time of diagnosis, patients start on alpha blockade which was titrated with the target of normotension. Beta-blockers are later added for reflex tachycardia secondary to the alpha blockade. Alpha blockade was optimized first because beta blockade on its own can lead to unopposed alpha activity and lead to vasoconstriction with worsening of the patient’s hypertension. In select populations with mild hypertension, calcium channel blockers have been used as an alternative to alpha blockade with the benefit of avoiding reflex tachycardia.² As these patients are typically volume contracted and salt-depleted secondary to excess catecholamine exposure and their alpha-blockade results in vasodilation, pre-operative management requires fluid and salt resuscitation to mitigate risk of hypotension.² Post-operative course requires close follow up with endocrine specialists for treatment of the patient’s secondary adrenal insufficiency.

Clinical course

Upon admission to nephrology, the patient has a CT abdomen pelvis that demonstrates bilateral adrenal masses (Figure 4).

She was transferred to the oncology service followed by the PICU for telemetry monitoring after sustaining a tachycardia to the 180s beats/min concerning for risk of tachyarrhythmia. She began doxazosin for an alpha blockade and has an echocardiogram which demonstrates normal function.

Upon return to the floor, in consultation with nephrology, her doxazosin alpha blockade dosing was increased and a beta blockade with propranolol was titrated to effect. Serum metanephrines were significantly elevated, with normetanephrines and total metanephrines both resulting 10,220 pg/mL (ref ranges <148 pg/mL and <205 pg/mL, respectively), confirming the diagnosis of bilateral pheochromocytomas (Table 2).

After a 13-day admission, a repeat EKG was within normal limits and she was discharged on doxazosin 4 mgs twice daily and propranolol 8 mgs three times daily (Figure 2). She was scheduled for a bilateral cortical sparing adrenalectomy in a month and follow-up with nephrology, oncology, and primary care during the intervening weeks. Discharge instructions include to follow a high salt diet, maintain fluid intake of at least 1.6L/day, avoid strenuous activity, and maintain strict blood pressure monitoring. Her blood pressure was taken three times per day, including manually by the school and a visiting home nurse.

The surgery was completed as scheduled and followed by an uncomplicated 6-day admission. She was discharged home with no scheduled medications and instructions to restart activity as tolerated, maintain a low salt diet, and follow-up with oncology, nephrology, surgery, as well as endocrinology.

She later had genetic testing positive for heterozygous von-Hippel-Lindau (VHL) pathogenic variant c.250G>C (pVal84Leu) (Figure 5). Eight months later, a metaiodobenzylguanidine (MIBG) scan was completed with no evidence of disease (Figure 6). MRI brain and abdomen 10 months post-diagnosis also had no evidence of disease (Figure 7).

Lessons for the clinician:

• Differential for secondary hypertension can be organized by system into renal (e.g. glomerulonephritis, PCKD, CKD), cardiovascular (aortic coarctation, renal artery stenosis), endocrine (e.g. primary hyperaldosteronism, congenital adrenal hyperplasia, malignancy, hyperthyroidism, diabetes mellitus), pharmacological (e.g. stimulants, oral contraceptives, corticosteroids), and monogenic (e.g. Liddle Syndrome, Gordon Syndrome) etiologies. Approximately 1.7% of pediatric hypertension cases are secondary to pheochromocytomas.²
• Early detection of hypertension is vital in pediatrics given greater relative prevalence of secondary causes of hypertension.³

1. Diagnosis of hypertension should be made for auscultatory confirmed BP readings >/=95th percentile at 3 visits.³
2. Ambulatory blood pressure monitoring (ABPM) provides continuous rather than discrete data points, improving reliability for diagnosis of hypertension and ruling out white-coat hypertension. ABPM should be performed in pediatric patients with elevated outpatient BP measurements for 1 year or more or with stage 1 hypertension over 3 visits.¹
3. Patients with concern for white coat hypertension should undergo ABPM.¹

• High salt diet is necessary prior to adrenalectomy due to total body fluid and salt depletion secondary to chronic excessive catecholamine exposure.²
• Pheochromocytomas are associated with familial syndromes including MEN2, VHL, NF1.⁴

References:

1. Flynn JT, Urbina EM, Brady TM, et al. Ambulatory Blood Pressure Monitoring in Children and Adolescents: 2022 Update: A Scientific Statement From the American Heart Association. Hypertension. 2022;79(7):e114-e124. doi:10.1161/HYP.0000000000000215
2. Ambarsari CG, Nadhifah N, Lestari HI. Perioperative Blood Pressure Management Recommendations in Pediatric Pheochromocytoma: A 10-Year Narrative Review. Kidney Blood Press Res. 2025;50(1):61-82. doi:10.1159/000542897
3. Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Pediatrics. 2017;140(3):e20171904. doi:10.1542/peds.2017-1904
4. Korpershoek E, van Nederveen FH, Komminoth P, de Krijger RR. Familial endocrine tumours: pheochromocytomas and extra-adrenal paragangliomas – an update. Diagnostic Histopathology. 2017;23(8):335-345. doi:https://doi.org/10.1016/j.mpdhp.2017.06.001