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Pacak–Zhuang syndrome

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Pacak–Zhuang syndrome
SpecialtyEndocrinology, Medical genetics
SymptomsParagangliomas, polycythemia, somatostatinomas, vascular malformations, ocular anomalies
ComplicationsHypertension, metastasis, diabetes mellitus (secondary to somatostatinoma), vision impairment
Usual onsetChildhood or early adulthood
DurationLifelong
CausesSomatic mosaicism of gain-of-function mutations in EPAS1 (HIF-2α)
Risk factorsCurrently unknown; the syndrome arises sporadically due to postzygotic somatic mutations in the EPAS1 gene
Diagnostic methodBiochemical testing (elevated erythropoietin, plasma metanephrines, 3-methoxytyramine), imaging (PET with 18F-fluorodopa, 18F-fluorodopamine or 68Ga-DOTATATE), genetic testing (somatic EPAS1 variants)
Differential diagnosisVon Hippel–Lindau disease, Multiple endocrine neoplasia type 2, Polycythemia vera (to exclude primary polycythemia), chronic hypoxia, Chuvash polycythemia
TreatmentSurgical resection (for tumors), alpha/beta blockade (for pheochromocytoma/paraganglioma), belzutifan (HIF-2α inhibitor), phlebotomy (for polycythemia), somatostatin analogs (optional, for somatostatinomas)
PrognosisVariable; depends on tumor burden, metastasis, and management of polycythemia
FrequencyExtremely rare; only a limited number of cases reported since its first description in 2013

Overview

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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.[1] 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.[2][3][4]

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.[5] 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.[6][7][8]

Pathophysiology

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Pacak-Zhuang syndrome is caused by variants in HIF-2α centered within the oxygen degradation domain (ODD).[9] 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.[10][11]

Clinical Features

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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.[12][13]

  • 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.[14] 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.[15] 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

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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.[16]

Diagnosis

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Diagnosis involves a combination of clinical, biochemical, and genetic evaluations.

  • 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

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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. [17]
  • 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

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Prognosis varies depending on tumor burden, metastatic potential, and timely intervention.[18] 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

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Ongoing research seeks to unravel the molecular mechanisms of Pacak-Zhuang syndrome, particularly the interplay between hypoxia signaling and tumorigenesis.[19][20][21] 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.

See also

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References

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  1. ^ Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, Tirosh A, Wei MH, Popovic V, Stratakis CA, Simonds WF, Brucker-Davis F, Vantyghem MC, Walther MM, Linehan WM, Pacak K (September 2012). "Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia". N Engl J Med. 367 (10): 922–30. doi:10.1056/NEJMoa1205119. PMID 22931260.
  2. ^ Toledo RA, Qin Y, Siqueira DR, et al. (August 2013). "Involvement of hypoxia pathway genes in paragangliomas/pheochromocytomas". Clin Cancer Res. 19 (15): 3851–9. doi:10.1158/1078-0432.CCR-12-3819. PMID 23509317.
  3. ^ Pacak K (February 2024). "New biomarkers for pheochromocytoma and paraganglioma". J Clin Endocrinol Metab. 109 (2): 321–9. doi:10.1210/clinem/dgad713. PMID 38767322.
  4. ^ Yang C, Zhuang Z, Fliedner SM, et al. (March 2013). "Somatic HIF2A mutations in paraganglioma and somatostatinoma associated with polycythemia". Hum Mol Genet. 22 (5): 958–68. doi:10.1093/hmg/dds491. PMID 23190243.
  5. ^ Jochmanova I, Zhuang Z, Pacak K (September 2013). "Hypoxia-inducible factor signaling in pheochromocytoma: turning the rudder in the right direction". J Natl Cancer Inst. 105 (17): 1270–3. doi:10.1093/jnci/djt242. PMID 23940289.
  6. ^ Yang C, Yuan W, Pakbaz Z, et al. (October 2020). "Somatic HIF2A mutations in multiple paragangliomas and pheochromocytomas". Endocr Relat Cancer. 27 (10): 533–43. doi:10.1530/ERC-20-0381. PMID 33497361.
  7. ^ Kamihara J, Pacak K, Ball E, et al. (March 2019). "Morning glory anomaly and EPAS1 mutations". Ophthalmic Genet. 40 (1): 83–6. doi:10.1080/13816810.2019.1702224. PMID 31876943.
  8. ^ Yang C, Yuan W, Pakbaz Z, et al. (August 2022). "Clinical manifestations and genetic analysis of Pacak-Zhuang syndrome". J Med Genet. 59 (8): 808–815. doi:10.1136/jmg-2021-108048. PMID 37450881.
  9. ^ Yang C, Zhuang Z, Fliedner SM, et al. (March 2013). "Somatic HIF2A mutations in paraganglioma and somatostatinoma associated with polycythemia". Hum Mol Genet. 22 (5): 958–68. doi:10.1093/hmg/dds491. PMID 23190243.
  10. ^ Zhuang Z, Yang C, Lorenzo F, et al. (September 2012). "Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia". N Engl J Med. 367 (10): 922–30. doi:10.1056/NEJMoa1205119. PMID 22931260.
  11. ^ Yang C, Yuan W, Pakbaz Z, et al. (October 2020). "Somatic HIF2A mutations in multiple paragangliomas and pheochromocytomas". Endocr Relat Cancer. 27 (10): 533–43. doi:10.1530/ERC-20-0381. PMID 33497361.
  12. ^ Ghander C, Darr R, Peitzsch M, et al. (December 2016). "Plasma methoxytyramine and the risk for metastatic pheochromocytoma and paraganglioma". J Clin Endocrinol Metab. 101 (12): 4461–70. doi:10.1210/jc.2016-2515. PMID 27679736.
  13. ^ Yang C, Yuan W, Pakbaz Z, et al. (August 2022). "Clinical manifestations and genetic analysis of Pacak-Zhuang syndrome". J Med Genet. 59 (8): 808–815. doi:10.1136/jmg-2021-108048. PMID 37450881.
  14. ^ Yang C, Yuan W, Pakbaz Z, et al. (August 2022). "Clinical manifestations and genetic analysis of Pacak-Zhuang syndrome". J Med Genet. 59 (8): 808–815. doi:10.1136/jmg-2021-108048. PMID 37450881.
  15. ^ Kamihara J, Pacak K, Ball E, et al. (March 2019). "Morning glory anomaly and EPAS1 mutations". Ophthalmic Genet. 40 (1): 83–6. doi:10.1080/13816810.2019.1702224. PMID 31876943.
  16. ^ Yang C, Yuan W, Pakbaz Z, et al. (October 2020). "Somatic HIF2A mutations in multiple paragangliomas and pheochromocytomas". Endocr Relat Cancer. 27 (10): 533–43. doi:10.1530/ERC-20-0381. PMID 33497361.
  17. ^ Jochmanova I, Wolf KI, King KS, et al. (January 2024). "Clinical and functional outcomes of patients with Pacak-Zhuang syndrome treated with HIF2α inhibitor belzutifan". J Clin Endocrinol Metab. 109 (1): 89–99. doi:10.1210/clinem/dgad740. PMID 39442048.
  18. ^ Yang C, Yuan W, Pakbaz Z, et al. (August 2022). "Clinical manifestations and genetic analysis of Pacak-Zhuang syndrome". J Med Genet. 59 (8): 808–815. doi:10.1136/jmg-2021-108048. PMID 37450881.
  19. ^ Lu W, Yang C, Yuan W, et al. (February 2024). "Targeting HIF-2α in Pacak-Zhuang syndrome". Nat Rev Endocrinol. 20 (2): 75–90. doi:10.1038/s41574-023-00921-2. PMID 38418569.
  20. ^ Pacak K, Wolf KI, King KS, et al. (June 2020). "The evolving landscape of paraganglioma genetics and therapeutic implications". Endocr Rev. 41 (3): 457–75. doi:10.1210/endrev/bnz012. PMID 31091718.
  21. ^ Jochmanova I, Wolf KI, King KS, et al. (January 2024). "Clinical and functional outcomes of patients with Pacak-Zhuang syndrome treated with HIF2α inhibitor belzutifan". J Clin Endocrinol Metab. 109 (1): 89–99. doi:10.1210/clinem/dgad740. PMID 39442048.
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