Isolated Recurrent Syncope as the Initial Presentation of Pheochromocytoma: A Case Report of a Hidden Catecholamine-Secreting Tumor

Abstract

Syncope is a common clinical presentation, yet a substantial proportion of cases remain unexplained despite guideline-directed evaluation. Pheochromocytoma, although a well-recognized catecholamine-secreting tumor, rarely presents with syncope, particularly in the absence of classical adrenergic symptoms, leading to diagnostic delay. We report a 60-year-old previously healthy female with recurrent episodes of transient loss of consciousness over two months, characterized by abrupt onset, brief duration, and complete spontaneous recovery without prodromal or postictal features. Despite repeated emergency presentations and an extensive negative workup including serial electrocardiograms, continuous cardiac monitoring, transthoracic echocardiography, orthostatic testing, tilt-table testing, carotid sinus massage, neurological evaluation, brain imaging, and laboratory studies, no cause was identified. Electrocardiography was normal and D-dimer testing excluded pulmonary embolism. Diagnosis was ultimately suggested by physical examination revealing a right flank mass, with abdominal computed tomography demonstrating a 5.6 cm adrenal lesion and biochemical testing confirming markedly elevated plasma free metanephrine (3.8 nmol/L; reference <0.50 nmol/L) and normetanephrine (9.6 nmol/L; reference <0.90 nmol/L), consistent with pheochromocytoma. Following appropriate preoperative preparation and surgical resection, the patient experienced complete resolution of syncope. This case highlights pheochromocytoma as a rare but reversible cause of recurrent unexplained syncope and underscores a potential diagnostic limitation of standard syncope workup, where intermittent catecholamine surges may evade detection, reinforcing the continued value of thorough physical examination in refractory cases.

Introduction

Syncope is defined as a transient loss of consciousness due to global cerebral hypoperfusion, characterized by rapid onset, short duration, and spontaneous complete recovery. ¹ Current guidelines recommend an initial evaluation consisting of a detailed history, physical examination including orthostatic blood pressure measurements, and electrocardiography, followed by targeted investigations such as echocardiography, ambulatory rhythm monitoring, brain imaging, tilt-table testing, or laboratory studies according to clinical suspicion. ¹ Despite extensive diagnostic evaluation, a substantial proportion of patients remain without an identifiable cause, posing a significant diagnostic challenge. Pheochromocytoma is a rare catecholamine-producing neuroendocrine tumor arising from chromaffin cells of the adrenal medulla, with an estimated incidence ranging from 0.04 to 0.95 cases per 100,000 persons annually. ² The classic clinical triad consists of headache, palpitations, and diaphoresis, frequently accompanied by sustained or paroxysmal hypertension. ³ However, the clinical presentation is highly variable and depends on the quantity and pattern of catecholamine secretion, receptor sensitivity, and the development of adrenergic receptor desensitization. ² Consequently, pheochromocytoma may mimic a wide range of cardiovascular, neurological, endocrine, and psychiatric disorders, often leading to delayed diagnosis. Although cardiovascular manifestations such as hypertension, arrhythmias, cardiomyopathy, myocardial infarction, and heart failure are well recognized, syncope remains an uncommon presentation of pheochromocytoma. ⁴ Previously reported cases have attributed syncope to orthostatic hypotension, neurally mediated reflexes, blood pressure instability, prolonged QT interval, ventricular tachyarrhythmias, or autonomic dysfunction.^5-7 As a result, pheochromocytoma is rarely considered during the routine evaluation of recurrent syncope, particularly when cardiac and neurologic investigations are unrevealing.

We report a case of recurrent unexplained syncope in a patient with a completely negative cardiac and neurologic workup and without the classical manifestations of catecholamine excess. The diagnosis was ultimately established following the detection of a palpable abdominal mass on physical examination, which led to imaging and biochemical confirmation of pheochromocytoma. This case highlights pheochromocytoma as a rare but potentially curable cause of recurrent unexplained syncope and emphasizes the enduring value of meticulous physical examination in patients with persistent diagnostic uncertainty.

Case Presentation

A 60-year-old previously healthy female presented with recurrent episodes of transient loss of consciousness over a 2-month period. The syncopal episodes were sudden in onset, of brief duration, and followed by spontaneous and complete recovery without postictal confusion, convulsions, or focal neurological deficits. The events occurred unpredictably, both at rest and during routine daily activities, and were not consistently preceded by prodromal symptoms such as chest pain, palpitations, diaphoresis, or visual disturbances. There was no clear orthostatic trigger, and no features suggestive of seizure activity or mechanical trauma.

Given the recurrent presentations to the emergency department, the patient underwent an extensive diagnostic workup to exclude cardiac, neurological, metabolic, and reflex causes of syncope. A 12-lead electrocardiogram was performed and was normal (Figure 1). Continuous cardiac monitoring using a holter ECG for 7 days and transthoracic echocardiography were also unremarkable. Carotid sinus massage and tilt-table testing were performed and did not reproduce symptoms or reveal diagnostic abnormalities. On presentation, the patient’s blood pressure was 120/70 mmHg with a heart rate of 65 beats/min. No episodes of sustained or paroxysmal hypertension were documented during hospitalization. Orthostatic blood pressure assessment remained within normal limits (standing blood pressure 110/70 mmHg) without associated symptoms. Cardiovascular examination revealed a regular rate and rhythm without murmurs, while respiratory and neurological examinations were unremarkable, with no focal neurological deficits. Abdominal examination, however, disclosed a firm, well-defined, non-tender palpable mass in the right flank without overlying skin changes or signs of peritoneal irritation. This unexpected finding prompted further abdominal imaging. Laboratory investigations, including complete blood count and serum electrolytes, were normal. Exercise stress test was done to rule out chronotropic incompetence and was normal. Cardiac biomarkers, including serial troponin measurements, were negative. D-dimer testing was not suggestive of pulmonary embolism, further excluding an acute thromboembolic etiology. Brain imaging including a CT scan of brain and MRI of the brain and neurological examination were also unrevealing. An Electroencephalogram (EEG) was performed showing no evidence of seizure. Despite this broad and repeated evaluation across multiple admissions, no definitive cause of syncope was identified. Abdominal computed tomography revealed a well-defined right adrenal mass measuring approximately 5.6 cm in greatest diameter (Figures 2 and 3), suspicious for a catecholamine-secreting tumor. Biochemical testing confirmed the diagnosis. Plasma free metanephrine was markedly elevated at 3.8 nmol/L (reference: <0.50 nmol/L), and plasma free normetanephrine was 9.6 nmol/L (reference: <0.90 nmol/L). Twenty-four-hour urinary fractionated metanephrines were also significantly elevated at 2,450 µg/24 h (reference: <350 µg/24 h), with elevated urinary catecholamines of 310 µg/24 h (reference: <100 µg/24 h), consistent with pheochromocytoma. Chromogranin A was not measured because the diagnosis was established using markedly elevated plasma free and urinary fractionated metanephrines. The patient subsequently underwent appropriate preoperative preparation followed by successful surgical laparoscopic adrenalectomy (Figure 4). Histopathological examination confirmed pheochromocytoma, demonstrating the characteristic zellballen pattern composed of nests of polygonal cells with abundant granular eosinophilic cytoplasm. Immunohistochemical staining showed tumor cell positivity for chromogranin A and synaptophysin, with S100-positive sustentacular cells, confirming neuroendocrine origin. No malignant features, including significant mitotic activity, necrosis, or local invasion, were identified. Given the recognized hereditary predisposition associated with pheochromocytoma, germline genetic testing using a pheochromocytoma–paraganglioma (PPGL) gene panel was performed and did not identify any pathogenic or likely pathogenic variants. Postoperatively, she experienced complete resolution of syncopal episodes. Biochemical evaluation revealed normal plasma free metanephrine and normetanephrine levels of 0.4 nmol/L and 0.65 nmol/L, respectively. Twenty-four-hour urine fractionated metanephrine was 214 µg/24 hours, while urinary catecholamine measurement was 54 µg/24 hours, both within the reference ranges. At follow-up, she remained asymptomatic with normalization of biochemical markers and no recurrence of syncope.

Figure 1.

Electrocardiogram (ECG) showing normal sinus rhythm without atrioventricular or bundle branch block, arrhythmia, significant ST-segment abnormalities, or QT prolongation

Figure 2.

Abdominal computed tomography (CT) images demonstrating a well-defined right adrenal mass measuring 56.0 × 37.7 mm

Figure 3.

Abdominal computed tomography (CT) images demonstrating a well-defined right adrenal mass measuring 56.0 × 37.7 mm

Figure 4.

Gross specimen demonstrating the resected adrenal gland and the tumor

Discussion

Syncope is defined as a transient loss of consciousness resulting from global cerebral hypoperfusion, characterized by rapid onset, short duration, and spontaneous complete recovery. ¹ The differential diagnosis is broad and includes reflex (neurally mediated) syncope, orthostatic hypotension, cardiac arrhythmias, structural cardiovascular disease, neurological disorders, metabolic disturbances, and less commonly endocrine etiologies. Current guidelines recommend an initial evaluation consisting of a detailed history, physical examination, orthostatic blood pressure measurements, and a 12-lead electrocardiogram, as these investigations provide the highest diagnostic yield. ¹ Despite a systematic and guideline-directed approach, approximately 20–40% of patients remain classified as having unexplained syncope after comprehensive evaluation, necessitating consideration of uncommon causes beyond the routine cardiac and neurological differential diagnoses.^1,8

Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors arising from chromaffin cells of the adrenal medulla, whereas extra-adrenal catecholamine-secreting tumors are classified as paragangliomas.^2,9 Although uncommon, these tumors may produce diverse cardiovascular, neurological, metabolic, and gastrointestinal manifestations through excessive catecholamine secretion. While the classic triad of headache, palpitations, and diaphoresis in association with hypertension remains the most recognized presentation, contemporary studies have demonstrated that clinical manifestations are highly variable and may depend on tumor size, secretory phenotype, catecholamine profile, receptor sensitivity, and the degree of chronic adrenergic receptor desensitization.^2,4 Consequently, pheochromocytomas have been described as “great masqueraders,” capable of mimicking numerous cardiovascular, neurological, gastrointestinal, psychiatric, and endocrine disorders.

Several mechanisms have been proposed to explain syncope in patients with pheochromocytoma. Chronic catecholamine excess can induce persistent vasoconstriction and pressure natriuresis, resulting in intravascular volume depletion and impaired cerebral perfusion. ⁶ Long-standing exposure to elevated catecholamine concentrations may also lead to adrenergic receptor downregulation and reduced vascular responsiveness, rendering patients susceptible to transient hypotensive episodes.^6,10 Additionally, fluctuations in catecholamine release may produce marked hemodynamic instability through competing $\alpha$ -adrenergic vasoconstrictive and ${\beta }_2$ -mediated vasodilatory effects, potentially resulting in abrupt changes in blood pressure sufficient to provoke syncope. ⁵ Another proposed mechanism is neurally mediated syncope. Cotias et al described a patient with pheochromocytoma and recurrent syncope in whom tilt-table testing demonstrated vasodepressor neurally mediated syncope, suggesting that excessive adrenergic stimulation may paradoxically trigger reflex withdrawal of sympathetic tone and enhanced vagal activation. ⁵ This mechanism may be particularly relevant in patients without documented arrhythmia or persistent hypotension.

Cardiac rhythm disturbances represent another important cause of syncope in pheochromocytoma. Previous reports have described prolonged QT intervals, polymorphic ventricular tachycardia, torsades de pointes, and bradyarrhythmia resulting from catecholamine excess.^3,7,11 However, unlike many published cases, our patient had a normal electrocardiogram and echocardiogram, making an arrhythmogenic mechanism less evident. Several reports have documented recurrent syncope as the initial manifestation of pheochromocytoma.^3,5,6,10 Nevertheless, many of these cases demonstrated identifiable mechanisms such as hypotension, autonomic dysfunction, QT prolongation, or ventricular arrhythmias. In our patient, the absence of these characteristic findings made the diagnosis particularly challenging and suggests that intermittent catecholamine-mediated hemodynamic instability was the most likely mechanism underlying the recurrent syncope.

Recent evidence has highlighted the considerable phenotypic heterogeneity of pheochromocytoma, with an increasing recognition that a substantial proportion of patients lack the classical triad of headache, palpitations, and diaphoresis or sustained hypertension.^2,9 Consequently, clinicians should maintain a high index of suspicion in patients with recurrent unexplained symptoms after common cardiovascular and neurological causes have been excluded. In such patients, targeted biochemical evaluation for catecholamine excess may facilitate an earlier diagnosis and prevent potentially life-threatening complications.

The diagnosis of pheochromocytoma and paraganglioma (PPGL) relies on biochemical confirmation of catecholamine excess followed by anatomical and functional localization of the tumor. Current guidelines recommend initial screening using plasma free fractionated metanephrines, blood fractionated catecholamines, or random urinary fractionated metanephrines, with subsequent confirmatory testing using 24-hour urinary fractionated metanephrines or catecholamines when screening thresholds are exceeded. ⁹ Biochemically, pheochromocytomas typically exhibit elevations in both adrenaline and noradrenaline, whereas paragangliomas more commonly demonstrate isolated noradrenaline excess. ⁹ Following biochemical confirmation, imaging studies are employed for tumor localization. Computed tomography remains the preferred initial imaging modality because of its excellent spatial resolution and ability to detect both primary tumors and metastatic lesions, although its specificity is limited. ⁹

Once diagnosed, pheochromocytoma requires preoperative medical optimization with $\alpha$ -adrenergic blockade and volume expansion to reduce perioperative hemodynamic instability. Current guidelines recommend initiation of $\alpha$ -adrenergic blockade as the cornerstone of preoperative therapy, typically for 7–14 days before surgery. $\beta$ -blockers may subsequently be introduced for persistent tachycardia but only after adequate $\alpha$ -blockade to avoid unopposed $\alpha$ -adrenergic stimulation.^4,9

An important aspect of contemporary pheochromocytoma management is the recognition of its strong genetic basis. Historically regarded as predominantly sporadic tumors, current evidence indicates that up to 30–40% of pheochromocytomas and paragangliomas harbor germline pathogenic variants, making them among the most heritable neoplasms in clinical medicine.^2,9 The most implicated susceptibility genes include those associated with hereditary syndromes such as Multiple Endocrine Neoplasia type 2 (RET), Von Hippel–Linda syndrome (VHL), Neurofibromatosis type 1 (NF1), and succinate dehydrogenase complex mutations (SDHA, SDHB, SDHC, SDHD, and SDHAF2). Genetic testing is increasingly recommended for all patients with pheochromocytoma or paraganglioma regardless of age or family history, as the identification of a pathogenic mutation may influence surveillance strategies, recurrence risk assessment, metastatic potential, and screening of at-risk family members. ⁹

Long-term surveillance is a critical component of pheochromocytoma and paraganglioma (PPGL) management. ⁹ Current recommendations advise postoperative biochemical assessment within^2-6 weeks of resection to confirm normalization of catecholamine secretion, followed by periodic biochemical and radiological monitoring. At least 10 years of follow-up is recommended for all patients, while lifelong surveillance should be considered in those at increased risk of recurrence or metastasis, including younger patients, individuals with paragangliomas, tumors measuring $\ge 5 \text{cm}$ , noradrenergic biochemical phenotypes, or those harboring pathogenic germline mutations. ⁹ In our patient, germline testing using a PPGL gene panel was negative for pathogenic variants, making a hereditary syndrome less likely. Nevertheless, long-term clinical and biochemical surveillance remains warranted, as recurrence may occur even in apparently sporadic cases.

Our case contributes to the limited but growing body of literature describing pheochromocytoma presenting as recurrent unexplained syncope and adds several distinctive clinical insights. Unlike most previously reported cases (Table 1) in which syncope was mechanistically linked to documented arrhythmias, orthostatic hypotension, QT prolongation, or overt hemodynamic instability, our patient had a completely unrevealing cardiac and neurological evaluation, including normal electrocardiography and echocardiography, and no documented orthostatic hypotension or rhythm disturbances. This rendered the diagnosis particularly challenging and initially placed the patient within the category of unexplained syncope despite extensive guideline-directed assessment. In addition, the absence of classical symptoms of excess catecholamine such as sustained or paroxysmal hypertension, headache, palpitations, and diaphoresis further obscured clinical suspicion and delayed consideration of an endocrine etiology.

Table 1.

Published cases of pheochromocytoma presenting with syncope compared with the present case

Author (Year)	Age/Sex	Syncope mechanism	Classical symptoms	Outcome
Zweiker et al (1997)	Adult male	Bradyarrhythmia secondary to pheochromocytoma	Not typical	Resolution after adrenalectomy
Ueda et al (2005)	Adult	Orthostatic hypotension with recurrent hypotensive episodes	Absent hypertension; recurrent hypotension	Complete recovery following tumor resection
Bhat et al (2018)	Adult	Long QT syndrome with ventricular electrical instability	Catecholamine-related symptoms present	QT normalization and symptom resolution after adrenalectomy
Cotias et al (2024)	Adult	Neurally mediated syncope associated with repolarization abnormalities	Variable adrenergic symptoms	Resolution after surgical treatment
Bansal et al (2024)	Pediatric	QT prolongation with macroscopic T-wave alternans	Classical symptoms present	Complete recovery following adrenalectomy
Present case	60 year old female	Probable intermittent catecholamine-mediated hemodynamic instability	Absent (no hypertension, headache, palpitations, or diaphoresis)	Complete resolution of syncope following laparoscopic adrenalectomy

In this context, intermittent, paroxysmal catecholamine release with transient fluctuations in systemic vascular tone may represent a possible explanation for the recurrent syncopal episodes in our patient. Catecholamine excess has been proposed to cause syncope through competing α-adrenergic vasoconstrictive and β-mediated vasodilatory effects, chronic volume depletion, and altered vascular responsiveness, potentially resulting in transient cerebral hypoperfusion without sustained hypotension or persistent hemodynamic abnormalities on routine evaluation.^4-6 Another possible mechanism is a neurally mediated or baroreflex response triggered by acute catecholamine surges, as previously described in a patient with pheochromocytoma and vasodepressor syncope. ⁵ However, these mechanisms were not directly demonstrated in our patient, as no syncopal episode was captured during hemodynamic or rhythm monitoring and no corresponding hypotensive or arrhythmic event was documented. Therefore, the proposed catecholamine-mediated and reflex mechanisms remain hypothetical and should be regarded as possible explanations rather than confirmed mechanisms in this case. The episodic nature of catecholamine secretion may nevertheless account for the absence of abnormalities during interictal evaluation.

The diagnosis was ultimately prompted only by careful physical examination revealing a palpable abdominal mass, which directed targeted biochemical and imaging evaluation confirming pheochromocytoma. This sequence of findings highlights an uncommon diagnostic pathway and reinforces that pheochromocytoma may present solely with recurrent syncope even in the absence of its typical clinical and cardiovascular manifestations. To the best of our knowledge, cases in which pheochromocytoma presents with isolated recurrent syncope and a completely negative initial cardiological and neurological workup remain rare. Therefore, this case underscores two key messages: first, that pheochromocytoma should remain in the differential diagnosis of otherwise unexplained recurrent syncope regardless of the absence of classical features; and second, that meticulous physical examination continues to play a decisive role in identifying secondary causes that may be missed by extensive technological evaluation.

The main strength of this case is its unusual clinical presentation of pheochromocytoma as recurrent isolated syncope in the absence of sustained hypertension, classical adrenergic symptoms, or identifiable abnormalities on an extensive cardiac and neurological evaluation. The case also highlights the diagnostic value of meticulous physical examination, which led to the identification of the adrenal mass and subsequent biochemical confirmation. Furthermore, comparison with previously reported cases demonstrates the distinctive presentation of our patient and expands the recognized clinical spectrum of pheochromocytoma-associated syncope. This report has several limitations. First, the precise physiological mechanism underlying the syncopal episodes could not be established because no episode was captured during simultaneous hemodynamic or cardiac monitoring. The proposed catecholamine-mediated and neurally mediated mechanisms therefore remain hypothetical. Second, as a single case report, the findings cannot be generalized to all patients presenting with unexplained syncope. Finally, long-term follow-up is limited, although the patient remained asymptomatic with normalization of biochemical markers after surgical resection.

Conclusion

Pheochromocytoma is a rare but clinically important cause of syncope and should be considered in patients with recurrent unexplained episodes, even in the absence of classical adrenergic symptoms or identifiable abnormalities on initial cardiac and neurological evaluation. This case illustrates an uncommon presentation characterized by isolated syncope as the dominant manifestation, with a completely negative standard workup, where diagnosis was ultimately suggested by meticulous physical examination and confirmed biochemically and radiologically. The case emphasizes that intermittent catecholamine surges may lead to transient and unpredictable hemodynamic instability, resulting in syncope that can evade routine diagnostic testing. Early recognition of this rare presentation is essential, as timely diagnosis and surgical treatment are potentially curative and may prevent life-threatening cardiovascular complications.

ORCID iD

Antonio Al Hazzouri https://orcid.org/0009-0009-3066-993X

Ethical Considerations

Case reports are exempted from ethical approval at our institution.

Consent to Participate

A signed written informed consent was obtained from the patient prior to manuscript submission.

Data Availability Statement

Data will be made available upon request from authors.*