Pheochromocytoma in cyanotic congenital heart disease: a case report

¹Endocrinology and Diabetology Department, Fifth Medical and Surgical Centre of the Royal Armed Forces, Errachidia, Faculty of Medicine and Pharmacy, Mohammed V University Souissi, Rabat, Morocco, ²Endocrinology and Diabetology Department, Avicenne Military Hospital, Faculty of Medicine and Pharmacy of Marrakech, Cadi Ayyad University, Marrakech, Morocco, ³Radiology Department, Fifth Medical and Surgical Centre of the Royal Armed Forces, Errachidia, Faculty of Medicine and Pharmacy, Mohammed V University Souissi, Rabat, Morocco, ⁴Cardiology Department, Moulay Ismail Military Hospital, Meknes, Morocco

^&Corresponding author
Yassine Errahali, Endocrinology and Diabetology Department, Fifth Medical and Surgical Centre of the Royal Armed Forces, Errachidia, Faculty of Medicine and Pharmacy, Mohammed V University Souissi, Rabat, Morocco

Introduction    

Congenital heart diseases encompass a diverse spectrum of structural cardiac malformations present at birth, displaying marked heterogeneity in their anatomical characteristics, clinical manifestations, therapeutic approaches, and long-term outcomes. Among these conditions, cyanotic congenital heart diseases represent approximately 10% of cases and are characterized by chronic systemic hypoxemia, typically resulting from right-to-left intracardiac shunting or from complex structural abnormalities that impair effective pulmonary circulation [1].

Pheochromocytoma is a rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla and characterized by excessive catecholamine secretion. Its estimated annual incidence ranges between 2 and 8 cases per million inhabitants [2].

The association between pheochromocytoma and cyanotic congenital heart disease remains uncommon, although several cases have been reported in the literature [3]. Recent evidence suggests that chronic hypoxia may promote the proliferation of chromaffin cells through activation of molecular pathways involved in the cellular response to hypoxia [3,4].

We report the case of a pheochromocytoma diagnosed in a patient with cyanotic congenital heart disease and single-ventricle physiology and discuss the potential pathophysiological mechanisms underlying this association based on data from the literature. Particular emphasis is placed on the diagnostic, hemodynamic, and therapeutic challenges raised by the coexistence of catecholamine excess and complex cyanotic congenital heart disease.

Patient and observation     

Patient information: a 27-year-old patient had been followed since childhood for a complex cyanotic congenital heart disease characterized by a left-dominant single-ventricle physiology with a hypoplastic right ventricle and tricuspid atresia. During childhood, the patient underwent staged palliative surgical management, including a superior cavopulmonary anastomosis (Figure 1).

During routine clinical follow-up, persistent arterial hypertension was detected, prompting further investigation for secondary causes of hypertension. At baseline, the patient had resting oxygen saturation between 70% and 74% in room air, consistent with longstanding cyanotic physiology.

Clinical findings: the patient presented with persistent arterial hypertension with paroxysmal peaks, in the absence of symptoms suggestive of catecholamine excess. The highest documented blood pressure value was 213/112 mmHg. Baseline heart rate ranged between 70 and 90 beats/min. Physical examination revealed findings consistent with longstanding cyanotic congenital heart disease, including severe growth retardation (-3 standard deviations compared with age and target height), peripheral cyanosis, and digital clubbing.

Timeline: to provide a clearer overview of the diagnostic and therapeutic sequence, the main clinical events are summarized chronologically in Table 1.

Diagnostic assessment: biochemical evaluation demonstrated elevated urinary methoxylated derivatives with a predominance of normetanephrines, suggesting the diagnosis of pheochromocytoma. The measurements were obtained from a 24-hour urine collection: urinary metanephrines were 2.17 μmol/24 h (reference range, 0.20-1.00), urinary normetanephrines were 7.86 μmol/24 h (reference range, 0.40-2.10), and 24-hour urinary creatinine was 5.65 mmol/24 h (reference range, 4.2-10), supporting the adequacy of the urine collection. Plasma free metanephrine testing was not performed because the 24-hour urinary assessment was available and already clearly positive.

Abdominal computed tomography revealed a right adrenal mass measuring approximately 70 x 52 mm, in close anatomical contact with the inferior vena cava, without definite radiological evidence of vascular invasion on available computed tomography (CT) images (Figure 2). This close anatomical relationship with the inferior vena cava was considered a major element in surgical risk assessment. MIBG scintigraphy demonstrated intense uptake in the right adrenal region, with no abnormal uptake elsewhere on whole-body imaging. These findings supported a localized right adrenal pheochromocytoma and did not show evidence of multifocal or extra-adrenal disease on MIBG assessment. Dedicated magnetic resonance imaging (MRI) and positron emission tomography (PET)-based imaging were not available at this stage; this limitation was acknowledged in the follow-up strategy, particularly because multifocal disease has been reported in hypoxia-associated pheochromocytoma/paraganglioma.

An etiological workup aimed at identifying a syndromic form, particularly multiple endocrine neoplasia, was negative. However, no germline genetic testing or somatic tumor analysis was performed, including EPAS1 testing, because of limited local availability and financial constraints. Therefore, the association with HIF-2α/EPAS1-related pseudohypoxia pathways cannot be demonstrated in this patient and should be interpreted as a literature-supported mechanistic hypothesis rather than direct molecular evidence.

Therapeutic intervention: the indication for adrenalectomy was discussed during a multidisciplinary team meeting. However, due to the high anesthetic risk related to the underlying complex congenital heart disease and the close anatomical relationship between the tumor and the inferior vena cava, surgical resection was considered high risk. The decision to defer surgery was not based solely on tumor size, but on the balance between the risk of catecholamine-driven perioperative instability, single-ventricle physiology, chronic severe hypoxemia, and the vascular complexity related to the inferior vena cava.

Medical therapy with an alpha-adrenergic blocker was therefore initiated, followed by the introduction of a beta-blocker, resulting in improved blood pressure control and clinical stabilization. Doxazosin was introduced progressively and titrated according to blood pressure tolerance. Escalation of alpha-blockade was accompanied by an increase in heart rate, with values exceeding 100 beats/min and reaching approximately 110 beats/min. After cardiology assessment, low-dose propranolol was introduced at 10 mg twice daily to control tachycardia after alpha-blockade had been established. This choice was guided by local availability, clinical tolerance, and cardiology input, with careful monitoring for signs of reduced systemic flow or heart failure.

Follow-up and outcomes: under medical treatment, significant clinical and hemodynamic improvement was observed, allowing a conservative management strategy to be adopted in the short term. Blood pressure control improved without clinically evident worsening of cyanosis, overt heart failure, or documented thromboembolic events. Oxygen saturation remained within the patient's usual baseline range of 70%-74% on room air.

During follow-up, the patient subsequently developed secondary diabetes mellitus, which was managed with lifestyle and dietary measures and achieved satisfactory glycemic control. Importantly, diabetes had been diagnosed before the introduction of beta-blocker therapy, with an initial HbA1c of 7.6% and fasting plasma glucose of 1.37 g/L. Therefore, propranolol was unlikely to be the primary trigger of dysglycemia. Catecholamine excess may have contributed through inhibition of insulin secretion and increased insulin resistance. The patient was managed with lifestyle and dietary measures alone, with favorable evolution and a most recent HbA1c of 6.9%.

The patient also presented with secondary polycythemia related to chronic hypoxia, which remained stable, with hemoglobin levels ranging between 18 and 20 g/dL. There were no symptoms of hyperviscosity and no history of thromboembolic events. The patient was maintained on antiplatelet therapy with acetylsalicylic acid 160 mg/day. Because pheochromocytoma may theoretically contribute to erythropoietic stimulation in selected cases, hemoglobin levels and symptoms of hyperviscosity were included in the surveillance plan.

The long-term management plan consists of close multidisciplinary follow-up (Table 2) involving endocrinology, cardiology, radiology, anesthesia, and surgery. Tumor volume, blood pressure profile, catecholamine burden, glycemic status, hemoglobin level, symptoms suggestive of hyperviscosity, and cardiopulmonary tolerance will be reassessed periodically. Repeat cross-sectional imaging is planned to monitor tumor growth and vascular relationships. Surgical re-evaluation would be reconsidered if there is rapid tumor enlargement, radiological suspicion of local invasion, metastatic disease, worsening biochemical secretion, refractory hypertension, or clinical deterioration despite optimized medical therapy.

Patient perspective: the patient was informed about the diagnosis, the surgical risks related to his underlying cardiac condition, and the rationale for conservative management. He reported reassurance after improvement in blood pressure control and agreed to regular multidisciplinary follow-up.

Patient consent: written informed consent was obtained from the patient for publication of this case report and accompanying images.

Discussion     

The association between pheochromocytoma/paraganglioma and cyanotic congenital heart disease (CCHD) is rare but increasingly recognized. The earliest reports date back to the 1960s, when pheochromocytomas were described in patients with complex cyanotic cardiac malformations, suggesting a possible pathogenic role of chronic hypoxia [5]. Subsequent reports involving tetralogy of Fallot, Eisenmenger syndrome, single-ventricle physiology, and extra-adrenal paragangliomas further supported this association [6]. In the multicenter study by Opotowsky et al. patients with CCHD had a significantly higher prevalence of pheochromocytoma/paraganglioma than those without cyanotic heart disease, with an adjusted odds ratio of 6.0. These tumors were often diagnosed in young adults after prolonged exposure to cyanosis and were frequently multiple or recurrent [7].

The most plausible mechanism involves chronic activation of hypoxia-inducible pathways. Persistent hypoxemia may promote chromaffin-cell proliferation through HIF signaling, particularly HIF-2α, paralleling the pseudohypoxia model described in pheochromocytoma/paraganglioma associated with VHL, SDHx, and related mutations [3,4]. Molecular studies have strengthened this hypothesis. Vaidya et al. reported EPAS1 mutations in paragangliomas occurring in patients with CCHD, while Ogasawara et al. identified EPAS1 mutations in 15 of 16 lesions from seven affected patients [1,8]. In the present case, however, neither germline EPAS1 testing nor somatic tumor sequencing was available; therefore, the HIF-2α/EPAS1 pathway remains a plausible but unproven mechanism at the individual level.

From a clinical perspective, diagnosis may be difficult because symptoms of catecholamine excess can be absent or masked by the underlying cardiac disease. In the Opotowsky cohort, presentations were often cardiovascular or neuropsychiatric rather than classically catecholaminergic [7]. Our patient similarly presented mainly with persistent and paroxysmal hypertension, without typical headache, palpitations, or sweating. The predominantly noradrenergic biochemical profile, with marked elevation of urinary normetanephrines, supports the need for systematic biochemical screening for pheochromocytoma/paraganglioma in patients with CCHD and unexplained hypertension. In this case, MIBG scintigraphy provided functional confirmation of right adrenal localization and did not demonstrate additional pathological uptake on whole-body imaging. However, the absence of abnormal extra-adrenal uptake does not fully exclude microscopic, small-volume, or MIBG-negative multifocal disease, particularly in hypoxia-associated pheochromocytoma/paraganglioma; therefore, structured radiological and biochemical surveillance remains warranted.

Management is particularly challenging in patients with complex cyanotic heart disease. Although surgical resection remains the standard treatment for pheochromocytoma, anesthetic and hemodynamic risks may be substantial in single-ventricle physiology, especially during induction, tumor manipulation, and venous clamping [9]. In our patient, immediate surgery was deferred because of severe chronic hypoxemia, baseline oxygen saturation of 70%-74%, single-ventricle physiology, and close anatomical contact between the tumor and the inferior vena cava. Conservative treatment was therefore adopted as a temporizing strategy, with progressive alpha-blockade followed by low-dose propranolol after cardiology consultation. No clinical worsening of cyanosis, heart failure, or systemic flow was observed during follow-up [7,10].

The metabolic and hematologic findings also require integrated follow-up. Diabetes was documented before beta-blocker initiation, making propranolol unlikely to be the primary cause. Catecholamine excess may have contributed through impaired insulin secretion and increased insulin resistance. The patient also had chronic secondary polycythemia, with hemoglobin levels between 18 and 20 g/dL, without hyperviscosity symptoms or thromboembolic events. Although cyanosis remains the most likely explanation, pheochromocytoma-related erythropoietic stimulation may contribute in selected cases.

The main limitations of this report include the absence of EPAS1 or broader germline genetic testing, the lack of somatic tumor analysis, and the unavailability of complementary MRI or PET-based imaging to further characterize the lesion and exclude microscopic, small-volume, or MIBG-negative multifocal disease. Nevertheless, this case is clinically relevant because it highlights a practical diagnostic and therapeutic challenge increasingly encountered as survival improves among patients with complex CCHD. Persistent or paroxysmal hypertension in this population should prompt evaluation for pheochromocytoma/paraganglioma, and when surgery is deferred, conservative management must be supported by structured multidisciplinary follow-up.

Conclusion     

Pheochromocytoma is a rare but important cause of secondary hypertension in patients with cyanotic congenital heart disease. As survival improves among patients with complex CCHD, this diagnosis should be considered in cases of persistent or paroxysmal hypertension, unexplained hemodynamic deterioration, or functional decline. Early recognition requires a high index of clinical suspicion and close collaboration between endocrinologists, cardiologists, radiologists, anesthesiologists, and surgeons. When surgery is deferred because of prohibitive cardiac or anesthetic risk, conservative treatment should be considered a temporizing or individualized risk-adapted strategy, requiring structured multidisciplinary follow-up, including serial imaging, biochemical reassessment, cardiovascular evaluation, and repeated review of surgical feasibility.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Yassine Errahali contributed to patient management, conception of the manuscript, drafting, and critical revision; Ikhlass Lakssir contributed to clinical data collection and manuscript revision; Yassine Zerhari and Soukaina Zaimi contributed to radiological interpretation and figure preparation; Najlae Elyounoussi contributed to cardiological assessment and manuscript revision. All the authors read and approved the final version of this manuscript.

Tables and figures     

Table 1: timeline of the main clinical, diagnostic, and therapeutic events

Table 2: suggested structured follow-up protocol for the patient

Figure 1: transthoracic echocardiography demonstrating the underlying cyanotic congenital heart disease: A) apical four-chamber view showing tricuspid atresia with a hypoplastic right ventricle and a dominant left ventricle, consistent with left-dominant single-ventricle physiology; B) four-chamber view illustrating the previous superior cavopulmonary anastomosis performed as part of staged surgical palliation (RV: right ventricle, LV: left ventricle, RA: right atrium, LA: left atrium)

Figure 2: contrast-enhanced abdominal computed tomography demonstrating a right adrenal pheochromocytoma: A) axial computed tomography (CT) image showing a right adrenal mass measuring approximately 70 x 52 mm; B) coronal reconstruction demonstrating the spatial relationship between the tumor and the inferior vena cava; C) sagittal reconstruction illustrating the extent of the mass and its vascular relationships

References