Multiple paragangliomas or pheochromocytomas and somatostatinomas (in rare cases), both neuroendocrine tumors, and secondary polycythemia linked with elevated erythropoietin levels are all symptoms of the Pacak-Zhuang syndrome in females. Paragangliomas are generally detected in the abdomen in these patients, while somatostatinomas are located in the second section of the duodenum, as evidenced by imaging or biochemistry. This disease is particularly intriguing since it is uncommon to detect more than one type of neuroendocrine tumor in a single person. Patients with hereditary syndromes like multiple endocrine neoplasia (MEN), neurofibromatosis 1 (NF1), or Von Hippel-Lindau (VHL) disease are more likely to have such co-occurrences.
A genetic route
There has never been a tumour associated with mutations in the genes encoding the alpha subunits of hypoxia-inducible factors (HIF-alpha).
Patients with the Pacak–Zhuang syndrome have somatic gain of function mutations in the HIF2A genes, resulting in extended HIF-2 activity and, as a result, an increase in its half-life. While the nucleic acid modifications in each patient varied, all of them contain a point mutation near the prolyl-sensing residue location, which is important for HIF-2 hydroxylation.
Diagnosis
Polycythemia
The majority of patients with this disease develop secondary polycythemia very early in life, frequently at birth. They are diagnosed based on physical symptoms (red cheeks, flushing, and swelling of the limbs), which are subsequently validated by test findings showing unusually high erythropoietin levels.
Tumors
Patients with symptoms such as hypertension, heart palpitations, headaches, and anxiety are first suspected of having paragangliomas; somatostatinomas commonly cause diabetes and cholecystitis. Patients are subjected to biochemical testing of blood and urine samples, as well as functional and anatomical imaging, to confirm the presence of a tumor.
Other discoveries
Ocular abnormalities have been discovered in some individuals with this disease, including bilateral fibrosis of the optic disc and dilated capillaries.
Treatment
Phlebotomies and, for paraganglioma and/or somatostatinoma in this group of patients, surgery combined with antihypertensive medication are the most prevalent treatments for secondary polycythemia. In a patient with Pacak-Zhuang syndrome, the HIF-2 inhibitor belzutifan resulted in a significant improvement in symptoms.
Direction of research
The condition is now being studied in order to better understand it. This disease is currently exclusively known to affect women.