# Pacak–Zhuang syndrome
## Overview

Pacak-Zhuang syndrome is a rare sporadically occurring disorder that, to date, has been predominantly found in women. The syndrome, which is caused by gain-of-function variants in EPAS1 (encoding hypoxia-inducible factor-2a or HIF-2α), was first reported by Prof. Karel Pacak, MD, PhD, DSc, FACE, Dhc, and Prof. Zhenping Zhuang, MD, PhD, in the New England Journal of Medicine. This report characterized the first two cases of a clinical triad of multiple paragangliomas, polycythemia, and, in one case, duodenal somatostatinomas with confirmation of the somatic mosaic variants in the neuroendocrine tumors.
While the syndrome is still considered rare, having been found in ~30 individuals to date, its discovery is important for several reasons.
First, while hypoxia signaling has been believed to be critical to tumorigenesis and cancer disease progression, Pacak-Zhuang syndrome is the first identified neoplastic syndrome caused by variants in HIF-2α providing direct evidence for its involvement in cancer development. Second, while other related neoplastic syndromes, such as von Hippel-Lindau syndrome, are related both clinically and mechanistically, Pacak-Zhuang syndrome differs from Von Hippel-Lindau syndrome and other previously described classical neoplastic syndromes in that it is non-heritable and sporadically occurring, highlighting the likely underappreciated role of genetic mosaicism in causing sporadic disease.
While Pacak-Zhuang syndrome was initially described by primarily abdominal or retroperitoneal PGL and duodenal somatostatinoma, continued investigations in individuals with Pacak-Zhuang syndrome and the corresponding mouse model have found additional features such as pheochromocytoma, head and neck PGL, abnormal bone formation, and vascular and ocular malformations.

## Pathophysiology

Pacak-Zhuang syndrome is caused by variants in HIF-2α centered within the oxygen degradation domain (ODD). These gain-of-function variants result in increased stabilization of HIF-2α by preventing its hydroxylation by prolyl-hydroxylase containing domain protein 2 (PHD2) and subsequent Von Hippel Lindau syndrome-mediated degradation. Thus, the physiologic response to changes in oxygen tension is altered at the tissue level. This pseudo-hypoxic response leads to constitutive hypoxia signaling and activation of downstream signaling pathways regulating angiogenesis and tumorigenesis in affected tissues.

## Clinical Features

Individuals with Pacak-Zhuang syndrome most often have noradrenergic PGL. As such, these individuals typically present with symptoms caused by overproduction and hypersecretion of norepinephrine including hypertension, palpitations, headaches, and sweating. Tumors associated with this syndrome often exhibit multiplicity with a high risk of metastasis compared to sporadic and hereditary pheochromocytomas and paragangliomas.
* Polycythemia: Individuals with Pacak-Zhuang syndrome often have early-onset polycythemia, sometimes present from birth, often requiring lifelong phlebotomies. Physical signs include red cheeks, flushing, and swelling of extremities. Elevated erythropoietin levels confirm the diagnosis.
* Tumors: Individuals with Pacak-Zhuang syndrome may develop pheochromocytoma or PGL, which may occur in the abdomen, retroperitoneum, or head and neck. These tumors produce catecholamines that are responsible for presenting signs and symptoms including hypertension, palpitations, and anxiety. These individuals may also develop duodenal somatostatinomas, which may cause diabetes and cholecystitis. Diagnostic confirmation involves biochemical testing (blood and urine samples) and functional and anatomical imaging.
* Other Findings: Individuals with Pacak-Zhuang syndrome often have concomitant congenital abnormalities such as morning glory anomaly and a variety of vascular malformations. The ocular malformations may be associated with poor vision. Other vascular abnormalities have been noticed, such as dilated capillary loops at the nail bed, which can aid in the diagnosis.

## Genetics

Pacak-Zhuang syndrome is characterized by gain-of-function variants in the ODD of HIF-2α, stabilizing the protein and increasing transcriptional activity of HIF-regulated genes.

## Diagnosis

Diagnosis involves a combination of clinical, biochemical, and genetic evaluations.
* Biochemical Testing: Elevated plasma or urinary metanephrines and in some patients also 3-methoxytyramine levels. Pacak-Zhuang syndrome typically has a noradrenergic biochemical phenotype.
* Imaging: Functional imaging modalities, such as 18F-fluorodopa, 18F-fluorodopamine, or 68Ga-DOTATATE PET, are critical for identifying primary, multifocal, recurrent, and metastatic lesions.
* Genetic Testing: Pathogenic variants in the ODD of EPAS1 gene confirm the diagnosis and guide proper clinical follow-up. The somatic mosaic variants are found in low variant allele frequency in unaffected tissue. The frequency is much higher in affected or tumor tissue. Detection in unaffected tissue may require more sensitive techniques such as ddPCR, but this requires specific probes.

## Management

Management requires a multidisciplinary approach tailored to the syndrome’s complex manifestations.
* Surgical Resection: Primary tumors are treated with adrenalectomy or tumor excision.
* Pharmacological Therapy: Alpha-adrenoceptor blockade followed by beta-adrenoceptor blockade is used to manage catecholamine excess. In cases where catecholamine levels are very elevated, metyrosine can be helpful, but often limited by its price, availability and side effect. Emerging therapies, such as HIF-2α inhibitors like belzutifan, show great promise. Belzutifan may help in stabilizing and decreasing tumor growth, limit the need for phlebotomy and normalize hemoglobin levels, and, importantly, help lower catecholamine levels within hours, thus normalizing blood pressure and heart rate.
* Treatment of Secondary Polycythemia: Phlebotomy is commonly used to manage symptoms of elevated erythropoietin levels.
* Surveillance: Lifelong follow-up with biochemical and imaging studies ensures early detection of recurrence or new lesions.

## Prognosis

Prognosis varies depending on tumor burden, metastatic potential, and timely intervention. Advances in diagnostic tools, surgical techniques, and targeted therapies have significantly improved outcomes. However, the risk of recurrence and malignant transformation necessitates vigilant, lifelong surveillance.

## Research and Future Directions

Ongoing research seeks to unravel the molecular mechanisms of Pacak-Zhuang syndrome, particularly the interplay between hypoxia signaling and tumorigenesis. Efforts focus on developing novel therapeutics targeting the HIF pathway and refining diagnostic tools for earlier detection. Collaborative international studies, including contributions from The Cancer Genome Atlas (TCGA) and other international studies, continue to expand knowledge of the syndrome’s genetic and clinical spectrum of the involvement of other organs in this syndrome.