The Pacak-Zhuang syndrome is a recently described disease manifestation in females that includes multiple

paragangliomas A paraganglioma is a rare neuroendocrine neoplasm that may develop at various body sites (including the head, neck, thorax and abdomen). When the same type of tumor is found in the adrenal gland, they are referred to as a pheochromocytoma. They ar ...

or pheochromocytomas and somatostatinomas (in some), both neuroendocrine tumors, and secondary polycythemia associated with high

erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...

levels. Paragangliomas in these patients are mainly localized to the abdomen whereas somatostatinomas are found in the second portion of the

duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...

, as shown by imaging or biochemistry.Pacak K, Jochmanova I, Prodanov T, et al: New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol, 31(13):1690-1698, 2013. This syndrome is of special interest as finding more than one type of neuroendocrine tumor in one individual is unusual. Such co-occurrences are usually seen in patients carrying hereditary syndromes like multiple endocrine neoplasia (MEN), neurofibromatosis 1 (NF1), or von Hippel-Lindau (VHL) disease.

Genetic pathway

Mutations in the genes encoding alpha subunits of hypoxia-inducible factors (HIF-alpha) have not previously been identified in any cancer. In the Pacak–Zhuang syndrome, patients have somatic gain of function mutations in the genes encoding for ''HIF2A'', leading to prolonged HIF-2α activity and, thus, an increase in its half-life. While each patient has different nucleic acid changes, all patients are found to have a point mutation near the prolyl-sensing residue site, responsible for HIF-2α hydroxylation.

Diagnosis

Polycythemia

Patients with this syndrome usually have early onset of secondary polycythemia, most of them at birth. They are diagnosed with typical physical characteristics (red cheeks, flushing, swelling of the extremities), which are then confirmed through lab results that show abnormally increased

levels.

Tumors

Patients are initially suspicious for paragangliomas when they present with symptoms like

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

, heart

palpitations Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart. Symptoms include a rapi ...

, headaches, and anxiety; somatostatinomas usually induce diabetes and cholecystitis. From these symptoms, patients undergo

biochemical Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology an ...

testing from blood and urine samples as well as

functional Functional may refer to: * Movements in architecture: ** Functionalism (architecture) ** Form follows function * Functional group, combination of atoms within molecules * Medical conditions without currently visible organic basis: ** Functional sy ...

and

anatomical Anatomy () is the branch of biology concerned with the study of the structure of organisms and their parts. Anatomy is a branch of natural science that deals with the structural organization of living things. It is an old science, having it ...

imaging to confirm tumor presence.

Other findings

Some patients with this syndrome have also been found to have ocular abnormalities, including bilateral fibrosis upon the

optic disc The optic disc or optic nerve head is the point of exit for ganglion cell axons leaving the eye. Because there are no rods or cones overlying the optic disc, it corresponds to a small blind spot in each eye. The ganglion cell axons form the ...

and dilated capillaries.

Treatment

The most common therapies for secondary polycythemia are

phlebotomies Phlebotomy is the process of making a puncture in a vein, usually in the arm, with a cannula for the purpose of drawing blood. The procedure itself is known as a venipuncture, which is also used for intravenous therapy. A person who performs a ph ...

and, for paraganglioma and/or somatostatinoma in this cohort of patients, surgery accompanied by

antihypertensive Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests tha ...

medication. HIF-2α inhibitor belzutifan led to substantial improvement of symptoms in a patient with Pacak–Zhuang syndrome.

Research direction

Researchers are presently seeking to better characterize the syndrome. Currently, this syndrome is known to only manifest in females.

References

* {{DEFAULTSORT:Pacak-Zhuang syndrome Syndromes