The Pacak-Zhuang

syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...

is a recently described disease manifestation in females that includes multiple paragangliomas or

pheochromocytoma Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. These neuroendocrine tumors can be sympathetic, where they relea ...

s and

somatostatinoma Somatostatinomas are a tumor of the delta cells of the endocrine pancreas that produces somatostatin. Increased levels of somatostatin inhibit pancreatic hormones and gastrointestinal hormones. Thus, somatostatinomas are associated with mild d ...

s (in some), both

neuroendocrine Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules ( hormones) into the blood. In this way they b ...

tumors, and secondary

polycythemia Polycythemia (also known as polycythaemia) is a laboratory finding in which the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythr ...

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 th ...

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 vertebrates, including mammals, reptiles, and birds. In mammals, it may be the principal site for iron absorption. The duodenum precedes the jejunum and ileum and is the shortest p ...

, 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 Multiple endocrine neoplasia (abbreviated MEN) is a condition which encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benig ...

(MEN),

neurofibromatosis 1 Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system neurocutaneous disorder caused by a subset of genetic mutations at the neurofibromin 1 (''NF1'') locus. Other conditions associated with mutation of the ...

(NF1), or von Hippel-Lindau (VHL) disease.

Genetic pathway

Mutations in the genes encoding alpha subunits of

hypoxia-inducible factor Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They also respond to instances of pseudohypoxia, such as thiamine deficiency. Both hypoxia an ...

s (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 A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...

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, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

, heart

palpitations Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...

, headaches, and

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

; somatostatinomas usually induce

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

and

cholecystitis Cholecystitis is inflammation of the gallbladder. Symptoms include Right upper quadrant (abdomen), right upper abdominal pain, pain in the right shoulder, nausea, vomiting, and occasionally fever. Often gallbladder attacks (biliary colic) precede ...

. 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, ...

testing from blood and urine samples as well as functional and

anatomical Anatomy () is the branch of morphology concerned with the study of the internal 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 scien ...

imaging to confirm tumor presence.

Other findings

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

fibrosis Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...

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 t ...

and dilated capillaries.

Treatment

The most common therapies for secondary polycythemia are phlebotomies 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, heart failure, kidney failure and myocardial infa ...

medication. HIF-2α inhibitor

belzutifan Belzutifan, sold under the brand name Welireg, is an anti-cancer medication used for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma. It is taken by mouth. Belzutifan is an hypoxia-inducible factor-2 alpha (HIF-2α ...

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