Pacak–Zhuang Syndrome

Overview

Pacak–Zhuang syndrome is an extremely rare hereditary disorder characterized by a unique combination of paragangliomas, somatostatinomas, and polycythemia. This syndrome was first described by Drs. Karel Pacak and Zhengping Zhuang, and it is now considered a novel paraganglioma syndrome with an identifiable genetic basis. Individuals with Pacak–Zhuang syndrome often present with tumors arising from paraganglia—neuroendocrine tissues located throughout the body—and show signs of excessive red blood cell production. The condition is autosomal dominant in inheritance and involves mutations affecting hypoxia-related pathways, particularly those involving the HIF2A gene (also known as EPAS1).

Causes

The primary cause of Pacak–Zhuang syndrome is somatic gain-of-function mutations in the EPAS1 gene, which encodes the transcription factor HIF-2α (hypoxia-inducible factor 2 alpha). These mutations are typically mosaic, meaning they occur after fertilization and affect only a subset of the body’s cells. The EPAS1 gene plays a central role in the body’s response to oxygen levels. Mutations lead to increased stability and activity of HIF-2α, even under normal oxygen conditions, resulting in excessive production of erythropoietin and abnormal growth of neuroendocrine cells. This ultimately contributes to the development of paragangliomas, somatostatinomas, and secondary polycythemia.

Symptoms

Symptoms of Pacak–Zhuang syndrome are primarily related to the tumor types and elevated red blood cell count associated with the condition. Common clinical features include:

Paragangliomas: These can occur in the head, neck, thorax, abdomen, or pelvis, often leading to symptoms like hypertension, palpitations, and headaches due to catecholamine secretion.
Somatostatinomas: These rare neuroendocrine tumors may produce somatostatin, leading to gastrointestinal disturbances such as diarrhea, weight loss, or gallstones.
Polycythemia: Elevated red blood cell levels result in symptoms such as headaches, dizziness, facial redness, and an increased risk of thrombosis.
Other symptoms: Fatigue, sweating, and anxiety are possible due to the hormonal effects of the tumors.

Diagnosis

Diagnosis of Pacak–Zhuang syndrome requires a combination of clinical, biochemical, radiological, and genetic investigations. Steps include:

Blood tests: Elevated hemoglobin and hematocrit levels suggest polycythemia. Elevated catecholamines or metanephrines indicate functional paragangliomas.
Imaging: CT, MRI, or PET scans help localize paragangliomas and somatostatinomas.
Histology: Biopsy of tumor tissues may confirm diagnosis and assess tumor type.
Genetic testing: Detection of somatic mosaic mutations in EPAS1 is critical. Tumor DNA is often needed for accurate identification of mutations.

Treatment

Treatment for Pacak–Zhuang syndrome is multidisciplinary, aimed at managing tumors and controlling polycythemia:

Surgical resection: Primary treatment for localized paragangliomas and somatostatinomas.
Phlebotomy: Used to control polycythemia and reduce hematocrit levels.
Medical therapy: Alpha-blockers or other antihypertensives may be used to manage symptoms related to catecholamine secretion.
Targeted therapy: Ongoing research into HIF pathway inhibitors may offer future treatment options.
Surveillance: Lifelong follow-up with imaging and bloodwork is essential due to risk of tumor recurrence or development of new tumors.

Prognosis

The prognosis of Pacak–Zhuang syndrome depends on early detection, effective management of tumors, and control of polycythemia. Surgical removal of tumors can be curative in some cases, especially when diagnosed early. However, the presence of mosaic mutations and potential for multiple or recurrent tumors requires ongoing monitoring. With appropriate surveillance and treatment, individuals can have a good quality of life. Nonetheless, complications such as metastatic disease, thromboembolic events due to polycythemia, and treatment-related side effects may impact long-term outcomes.