A Young Patient with Undiagnosed Polycythemia-Paraganglioma Syndrome: A Case Report

Background

Polycythemia is a disorder defined as an increase in red blood cell mass, represented by increased hemoglobin and hematocrit levels [1]. The elevated red blood cell mass leads to increased blood viscosity associated with decreased blood flow and an increased risk of thrombotic events [1]. Clinical features include facial flushing, headaches, dizziness, erythromelalgia, and pruritus [2]. Polycythemia can be classified into syndromes with primary and secondary causes. Primary causes of polycythemia include disorders such as polycythemia rubra vera (PRV) and familial/congenital polycythemia. Secondary causes of polycythemia include high altitude, chronic obstructive pulmonary disease, cyanotic heart disease, elevated carboxyhemoglobin, and conditions that cause low renal blood flow, such as renal artery stenosis and hydronephrosis [3]. Other secondary causes of erythrocytosis include hemoglobinopathies, erythropoietin (EPO) administration, and EPO-secreting tumors [3].

The diagnosis of polycythemia involves a detailed medical history and appropriate diagnostic measures. Serum EPO levels are measured initially to differentiate between primary and secondary polycythemia. Low EPO levels are suggestive of primary polycythemia, and subsequent investigations are geared towards detecting PRV. JAK2 V617F or exon-12 mutations are diagnostic for PRV and are positive in 97% of cases [4]. Measurement of serum ferritin and folic acid levels are also done, as low serum ferritin and folate levels tend to be associated with primary polycythemia [1]. Conversely, high EPO levels indicate a secondary cause of polycythemia. Initial investigations for secondary polycythemia include arterial oxygen saturation levels, carboxyhemoglobin/methemoglobin levels, renal function tests, liver function tests, and abdominal ultra-sound [1]. Further evaluations with chest x-ray, lung function tests, and/or bone marrow biopsy can be performed when the initial tests do not lead to a diagnosis [1].

Paraganglioma-induced EPO-associated erythrocytosis, also known as polycythemia-paraganglioma syndrome (PPS), is a rare occurrence, with only 32 cases reported in the literature. Most reports of this syndrome have been linked with HIF2A or prolyl hydroxylase domain mutations, and there are fewer than 10 reported cases with no identifiable mutations [5]. Therefore, we present the clinical description, as well as the radiological images, of a 14-year-old female patient presenting to the clinic with polycythemia-paraganglioma syndrome with no identifiable mutations.

Case Report

PATHOLOGY:

Macroscopic examination of the largest bladder lesion revealed a round brown nodule, measuring 20×15×10 mm. It was intramural and partially surrounded by fibrofatty tissue. Microscopically, hematoxylin-eosin staining revealed eosinophilic chromaffin cells with prominent, round nuclei, and the surgical margins were negative for the tumor. The chromaffin cells stained positive for synaptophysin, chromogranin, S100, and GATA3. Collectively, these findings confirm the diagnosis of bladder paraganglioma. No urothelium was noted and the deep muscularis propria was present with no tumor invasion. One month after excision, the patient’s hemoglobin and blood pressure levels returned to normal. The patient also reported complete relief of symptoms.

Discussion

Paragangliomas are very rare, with studies reporting a prevalence rate of 0.1% in patients with sustained hypertension [2]. Bladder paragangliomas are even more rare, accounting for less than 0.05% of bladder tumors and 1% of all paragangliomas [6]. Patients with non-functional paragangliomas are often asymptomatic, and the masses are only discovered incidentally [7]. Recent studies have reported cases of metastatic paragangliomas with polycythemias, termed PPS [5]. As in our case, symptoms of PPS are often underevaluated or misdiagnosed, leading to a delay in the management of the disease. Contrary to polycythemia, symptoms of paragangliomas often result from an increase in catecholamine secretion, including hypertensive urgency, sweating, headache, and pallor [2]. These symptoms are unique from the hyperviscosity symptoms seen in patients with JAK2-positive PRV.

In our case of a 14-year-old female patient with PPS, her adrenergic symptoms were mistakenly attributed to the erythrocytosis. Upon referral to hematology, she was found to have erythrocytosis with an elevated EPO level. A search for EPO-producing masses revealed multiple paragangliomas. Whole-genome sequencing revealed no mutations, leading us to believe this was a result of a somatic mutation. It is hypothesized that a gain-of-function HIF2A mutation in exon 12 may result in PPS [8]. Specifically, all reports of such mutations influence the hydroxylation domain LxxLAP, leading to nuclear accretion of HIF2A and increased transcriptional activity of EPO [8–10]. These findings confirm the importance of the LxxLAP domain for stabilizing the HIF2A protein and controlling EPO, with upregulation leading to erythrocytosis. Furthermore, some studies have described PPS due to mutations in prolyl hydroxylase domains 1 and 2, which also play a role in stabilizing the HIF2A protein [11,12]. Patients with no identifiable mutations, as in our present case, have also been reported by Janssen et al [5]. Further studies are needed to identify the causes of PPS in such patients.

The initial diagnostic workup for suspected paragangliomas should include the measurement of catecholamine levels in the patient’s blood or urine. If the analysis reveals an increase in the catecholamine levels, imaging studies can be conducted using CT or MRI [2]. Imaging in positive cases reveals oval-shaped, hypervascular bladder tumors with hypoattenuation on CT and hyperintensity on T1 and T2 MRI scans [13]. There is a lack of standardized guidelines regarding the best imaging modalities for the diagnosis of paragangliomas. Although both CT and MRI have a very high sensitivity in diagnosing paragangliomas, studies have shown that MRI scans are superior, with near 100% sensitivity [2]. In addition, 123/131 iodine-metaiodobenzylguanidine (123/131I-MIBG) and gallium-68 DOTATATE PET scans are also commonly used in the diagnostic workup of paragangliomas [14]. Compared with MIBG scintigraphy, a gallium-68 DOTATATE PET scan offers a shorter and more convenient imaging protocol with less cumbersome patient preparation. Shahrokhi et al previously found gallium-68 DOTATAE to be superior to I-MIBG scans in detecting paraganglioma lesions in all anatomical locations, particularly osseous lesions [15]. In the present case, however, the usage of the gallium-68 DOTATATE scan was limited to the location of the paraganglioma. Future studies are needed to determine whether 123/131I-MIBG scans are superior to gallium-68 DOTATATE in the diagnosis of bladder paragangliomas.

Recent studies have shown that complete resection of the paragangliomas is the only factor involved in a favorable outcome [16]. A recent article has reported that the prevalence of hypertension in children and adolescents is 3.5% [17]. Recent guidelines suggest children <6 years and non-obese children ≥6 years with stage 1 hypertension (blood pressure >130 mmHg) and no family history of hypertension should undergo further investigation to assess for secondary causes of hypertension, such as renal diseases, coarctation of the aorta, and neuroendocrine disorders [17,18]. In Saudi Arabia, the Saudi Hypertension Management Society recommends a thorough history and physical exam in children with persistent stage 1 hypertension [19]. Further investigations are only indicated if history and physical exam reveal findings suspicious for secondary hypertension. Our patient’s hypertension, however, was not investigated with an adequate history and physical exam, and upon further investigation, it was found to be due to multiple paragangliomas.

Conclusions

We hereby present the case of a 14-year-old female patient with polycythemia and severe hypertension. The patient underwent comprehensive laboratory and imaging studies, and the polycythemia and hypertension were found to be caused by multiple underlying paragangliomas. Although paragangliomas are very rare, it is essential to consider PPS as part of the differential diagnosis of young hypertensive patients presenting with sweating and palmar erythema. Early diagnosis ensures appropriate and timely patient management. We therefore emphasize the importance of conducting comprehensive clinical and imaging investigations, such as urinalysis and chemistry panels, to exclude underlying causes of hypertension in young hypertensive patients.