Materiały źródłowe

• #1 Mayo Clinic Health Library – Paraganglioma | Swiss Medical Network

  https://www.swissmedical.net/en/healtcare-library/con-20308105

  Paragangliomas often don’t have a clear cause. Some paragangliomas are caused by DNA changes that pass from parents to children. […] But many people with paragangliomas don’t have a family history of these tumors and the cause is not known. […] A paraganglioma starts when chromaffin cells develop changes in their DNA. A cell’s DNA holds the instructions that tell the cell what to do. In healthy cells, the DNA gives instructions to grow and multiply at a set rate. The instructions also tell the cells to die at a set time. In paraganglioma cells, the DNA changes give different instructions. The changes tell the paraganglioma cells to make many more cells quickly. The cells keep living when healthy cells would die. This causes a growth of cells called a tumor. […] The risk of paraganglioma is higher in people who have a family history of this tumor. Some paragangliomas are caused by DNA changes that pass from parents to children. Having a family history of paraganglioma might be a sign that certain DNA changes run in your family. […] Some other health conditions caused by DNA changes that pass from parents to children raise the risk of paragangliomas. These conditions include: Multiple endocrine neoplasia, type 2; Von Hippel-Lindau disease; Neurofibromatosis 1; Hereditary paraganglioma syndromes; Carney-Stratakis dyad.

• #1 Familial paraganglioma syndromes – Genomics Education Programme

  http://www.genomicseducation.hee.nhs.uk/documents/familial-paraganglioma-syndromes/

  Approximately one in three patients presenting with phaeochromocytomas and/or paragangliomas have a gene mutation associated with familial paraganglioma syndromes. […] Features that suggest a familial paraganglioma syndrome include: young age of presentation (50 years), bilateral tumours, a family history of phaeochromocytomas or paragangliomas and presence of metastatic disease. However, even an apparently sporadic presentation may be associated with a familial paraganglioma syndrome. […] Familial paraganglioma syndromes are usually inherited in an autosomal dominant manner. Once the genetic basis of the condition has been established by genetic testing, predictive testing can be offered to the wider family. […] Variants in the following genes are associated with familial paraganglioma syndromes: SDHB (succinate dehydrogenase subunit B): more frequently associated with malignancy. May present with paragangliomas and phaeochromocytomas, as well as renal cell carcinomas. Uncommon association with pituitary adenomas reported. Variable age-related penetrance.

• #1 Hereditary pheochromocytoma-paraganglioma

  https://www.genturis.eu/l=eng/thematic-disease-groups/other-rare-genturis/hereditary-pheochromocytoma-paraganglioma.html

  A significant proportion of pheochromocytomas and paragangliomas (appr. 30-40%) occur as part of a genetic tumour risk syndrome (also termed hereditary cancer predisposition syndrome). […] Hereditary pheochromocytoma-paraganglioma is caused by pathogenic germline variants in one of multiple genes (such as SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127 and MAX). […] The most frequently involved genes encode individual subunits of the succinate dehydrogenase (SDHx) enzyme complex, accounting for at least half of the cases. […] SDHB is one of the major genes predisposing to hereditary pheochromocytoma-paraganglioma, and also the one associated with higher risk of malignant disease. […] Other tumours occurring in families with pathogenic germline variants in the SDHB, SDHC, and SDHD genes are gastrointestinal stromal tumours, pulmonary chondromas and clear cell renal cell carcinoma.

• #1 Hereditary paraganglioma-pheochromocytoma: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hereditary-paraganglioma-pheochromocytoma/

  Hereditary paraganglioma-pheochromocytoma is an inherited condition characterized by the growth of tumors in structures called paraganglia. […] Mutations in at least four genes increase the risk of developing the different types of hereditary paraganglioma-pheochromocytoma. Mutations in the SDHD gene predispose an individual to hereditary paraganglioma-pheochromocytoma type 1; mutations in the SDHAF2 gene predispose to type 2; mutations in the SDHC gene predispose to type 3; and mutations in the SDHB gene predispose to type 4. […] Mutations in the SDHB, SDHC, SDHD, and SDHAF2 genes lead to the loss or reduction of SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. As a result, the hypoxia pathways are triggered in normal oxygen conditions, which lead to abnormal cell growth and tumor formation.

• #1 Genetic bases of pheochromocytoma and paraganglioma in: Journal of Molecular Endocrinology Volume 70 Issue 3 (2023)

  https://jme.bioscientifica.com/view/journals/jme/70/3/JME-22-0167.xml

  Approximately 40% of PPGL patients harbor an autosomal dominant germline mutation in 1 of the 20 susceptibility genes described so far. […] Somatic mutations in one of the genes involved in the disease are responsible for tumor development in 30% of patients. Lastly, there are still 30% of PPGLs for which a pathogenic gene mutation has not been identified, including some exhibiting clinical signs indicative of an inherited condition. […] This unexplained heritability represents a major challenge for the proper genetic classification of patients in order to provide the most adequate clinical follow-up. […] The major PPGL susceptibility genes found mutated in the germline include classic driver genes, such as RET, NF1, VHL, SDHD, SDHC, and SDHB, as well as more recently identified genes such as SDHA, SDHAF2, TMEM127, MAX, FH, MDH2, EGLN1, EGLN2, KIF1B, MET, IDH3B, GOT2, SLC25A11, DNMT3A, and DLST.

• #1 Progress in the diagnosis and treatment of paraganglioma – Wang – Translational Cancer Research

  https://tcr.amegroups.org/article/view/32832/html

  Hereditary PGL syndrome is caused by mutations in the four genes encoding subunits of succinate dehydrogenase (SDH). […] The syndrome can also be caused by mutations in the MYC-associated protein X (MAX) and transmembrane protein 127 (TMEM127) genes. […] PPGL can also be caused by mutations in additional susceptibility genes, such as fumarate hydratase and malate dehydrogenase, components of the tricarboxylic acid cycle. […] The different genetic mutations result in PPGL with different clinical features. […] For example, SDHB mutations are associated with increased risk of malignant PPGL, and their early identification is crucial for timely diagnosis and treatment.

• #1 Pheochromocytoma and Paraganglioma Treatment – NCI

  https://www.cancer.gov/types/pheochromocytoma/patient/pheochromocytoma-treatment-pdq

  Pheochromocytoma and paraganglioma are rare tumors that come from the same type of tissue. […] Some inherited disorders and changes in certain genes increase the risk of pheochromocytoma or paraganglioma. […] The following inherited syndromes or gene changes increase the risk of pheochromocytoma or paraganglioma: Multiple endocrine neoplasia 2 syndrome, types A and B (MEN2A and MEN2B), von Hippel-Lindau (VHL) syndrome, Neurofibromatosis type 1 (NF1), Hereditary paraganglioma-pheochromocytoma syndrome, Hereditary leiomyomatosis and renal cell cancer, Carney-Stratakis dyad (paraganglioma and gastrointestinal stromal tumor [GIST]), Carney triad (paraganglioma, GIST, and pulmonary chondroma). […] Anything that increases your chance of getting a disease is called a risk factor. Having a risk factor doesn’t mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk to your doctor if you think you may be at risk.

• #1 Head and Neck: Paraganglioma: an overview

  https://atlasgeneticsoncology.org/solid-tumor/6202/head-and-neck-paraganglioma-an-overview

  Familial inheritance (see below) and chronic hypoxia are the only known risk factors in CBP (Barnes et al., 2005; Hensen and Bayley, 2011). […] The role of chronic hypoxia in the development of head and neck paraganglioma other than CBP (e.g. laryngeal or jugulotympanic paraganglioma) is debated. Chronic hypoxia is known to induce paraganglia hyperplasia (Hensen and Bayley, 2011). […] Since the carotid body plays a central role in oxygen sensing, the latter may be involved in paraganglioma tumorigenesis. Succinate dehydrogenase (SDH) mutations in paraganglial tumors (see below) lead to succinate accumulation resulting in hypoxia-inducible factor 1 (HIF-1) stabilization through inhibition of prolyl hydroxylase-mediated degradation (Hensen and Bayley, 2011, King et al., 2006). This „pseudo-hypoxia” state leads to HIF-induced transcription of genes such as vascular endothelial growth factor (VEGF) and other growth factors.

• #1 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Individuals with variants in the VHL and SDHx genes exhibit a pseudohypoxic response, leading to the stabilization, dysregulation, and overexpression of HIFs. Tumors with pathogenic variants in the VHL gene closely resemble those with variants in the SDHx genes. Shared characteristics of both VHL and SDHx variants include angiogenesis, hypoxia, and a diminished oxidative response, suggesting a common molecular pathway in the development of these tumors. […] The nomenclature of paragangliomas typically reflects their location. In the ear, the collective name is jugulotympanic paraganglioma, after the jugular bulb paraganglia and the tympanic paraganglia. […] Jugulotympanic paragangliomas predominantly affect women in their fifties, with only 10% to 16% being bilateral. While most jugulotympanic paragangliomas are sporadic, around 10% exhibit an autosomal dominant inheritance pattern.

• #1 Hereditary Paraganglioma-Pheochromocytoma Syndrome | Children’s Hospital of Philadelphia

  https://www.chop.edu/conditions-diseases/hereditary-paraganglioma-pheochromocytoma-syndrome

  Hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC) is a group of familial cancer syndromes characterized by the presence of: […] PGL/PCC is caused by alterations (mutations) at specific areas within an individuals genetic information. Hereditary PGL/PCC most often develops as the result of alterations in one of several specific genes, including SDHA, SDHAF2, SDHB, SDHC and SDHD. […] These tumors are believed to develop because, over time, the second copy of the SDH gene becomes altered within one or more cells. Cells in which both SDH gene copies are impaired can divide excessively and ultimately become cancerous.

• #1 Paraganglioma – MD Searchlight

  https://mdsearchlight.com/health/paraganglioma/

  Paragangliomas mainly occur spontaneously, but in 30% to 50% of cases, they can be inherited. Some inherited forms are related to certain genetic conditions and variations in specific genes. […] Tumors that grow from these paraganglia are called paragangliomas. Sometimes, these tumors can be related to specific family genes. Kids are more prone to these tumors if there’s a family history. Genes such as those responsible for different parts of the SDH enzyme complex are often involved. […] Certain genetic syndromes also put people at a higher risk of developing these tumors. These syndromes include Multiple Endocrine Neoplasia type 2 (MEN2), Neurofibromatosis type 1 (NF1), Von Hippel-Lindau disease (VHL), and Carney-Stratakis dyad. […] Factors like living in high altitudes or illnesses that result in low oxygen levels, like cyanotic congenital heart disease and chronic obstructive lung disease, can boost the risk of these tumors, specifically those found in the carotid body.

• #1 Paraganglioma: Symptoms, Causes and Treatments

  https://www.cancercenter.com/cancer-types/neuroendocrine-tumors/types/paraganglioma

  Paragangliomas are a rare tumor type they occur in about two out of every 1 million people, according to the National Cancer Institute (NCI). […] Some cases of paragangliomas are linked to genetics. These types of tumors are associated with some hereditary syndromes, including: Multiple endocrine neoplasia type 2A (MEN2A) and type 2B (MEN2B), von Hippel-Lindau syndrome (VHL), Neurofibromatosis type 1 (NF1). […] Mutations in more than 20 genes have been identified that may lead to an increased risk for developing pheochromocytomas and paragangliomas, according to the NCI. […] If the patient’s paraganglioma isn’t associated with a hereditary syndrome, it’s considered nonsyndromic. Nonsyndromic paragangliomas are more common in women than in men.

• #1 Paraganglioma Symptoms, Treatment, Diagnosis & More

  https://pheopara.org/education/paraganglioma

  Paraganglioma (pr-gnggl-m) is a rare, slow-growing tumor that is closely related to pheochromocytoma. They originate in the parasympathetic or sympathetic nervous system. […] 30-40% of pheochromocytomas and paragangliomas are hereditary. If you are diagnosed with paraganglioma talk to your doctor about genetic testing. […] All paraganglioma have the potential to become metastatic, or spread to other parts of the body. This happens in approximately 15-25% of cases. […] It is highly recommended for metastatic patients to receive treatment from an experienced, multi-disciplinary pheo para team. In addition, everyone who has metastatic para should have genetic testing. Knowing your genetic status will help your medical team determine an appropriate course of treatment. […] Some genetic mutations are more likely to develop metastatic para. You can read more about each genetic mutation and its prognosis on the genetics page.

• #1 Malignant Paraganglioma (Multiple, Multicentric, and Metastatic) in a Female Patient With Family History of Paraganglioma | Cirugía Española (English Edition)

  https://www.elsevier.es/en-revista-cirugia-espanola-english-edition–436-articulo-malignant-paraganglioma-multiple-multicentric-metastatic–S2173507715002641

  Malignant paragangliomas are rare, but may occur especially in patients with familial forms of the disease. […] The main known risk factor in patients with these tumours is that they live in areas higher than 2000m above sea level. […] In 10%30% of cases there is a family history of the disease, with dominant autosomal transmission linked to the male sex. […] A malignant presentation is reported in 6% of cases, and is strongly associated with cases in the same family. […] Genetic study is recommended in these patients, given that they are associated with the presence of mutations in the von HippelLindau (VHL) genes, the RET (MEN II) gene, the succinate dehydrogenase (SDH) gene and type I neurofibromatosis in 10%50% of cases. […] King et al. showed that SDHB mutation is the main risk factor for the development of metastatic disease at an early age, so it is recommended that early tests be made for SDHD gene mutation in PG of the head or neck.

• #1 Malignant Paraganglioma (Multiple, Multicentric, and Metastatic) in a Female Patient With Family History of Paraganglioma | Cirugía Española (English Edition)

  https://www.elsevier.es/en-revista-cirugia-espanola-english-edition–436-articulo-malignant-paraganglioma-multiple-multicentric-metastatic–S2173507715002641

  The definitive criterion of malignancy is metastasis to regional lymphatic ganglia or distant organs. […] In cases involving several locations and metastasis, such as ours, it may prove hard to select the best treatment due to the risk involved in resecting the primary tumour and the unknown prognosis of the metastasis. […] It is important to follow-up these patients, given their high risk of developing metachronic or synchronic tumours after initial treatment, especially those with family forms of the disease. […] To conclude, it is only possible to define PG as malignant in cases of metastasis at a distance or regional lymphatic ganglia involvement, especially in cases with a family history of PG.

• #1 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Paragangliomas are related to pheochromocytomas and are often grouped together, contributing to some uncertainty regarding their precise incidence. […] Most patients with sporadic paraganglioma present between their 30s and 50s, with the mean age of diagnosis being 47. […] The incidence of malignant paragangliomas is around 90 to 95 cases per 400 million person-years. […] The primary pathophysiology underlying a paraganglioma involves either the excessive secretion of catecholamines or bony erosion due to mass effect. […] The sympathetic nervous system receptors, collectively referred to as adrenergic receptors because they bind and release norepinephrine, include 1, 2, 1, and 2. […] Parasympathetic paragangliomas located in the skull base are usually non-secretory, with less than 5% secreting catecholamines and becoming symptomatic.

• #1

  https://journals.lww.com/cardiologyinreview/fulltext/2009/08000/paragangliomas__etiology,_presentation,_and.2.aspx

  Paragangliomas are catecholamine-secreting tumors arising from the chromaffin cells of the sympathetic ganglia, and are known as extra-adrenal pheochromocytomas. […] Although the majority of paragangliomas are sporadic, a growing percentage of cases are found to be part of a familial genetic syndrome. […] Genetic testing should be offered to patients diagnosed with paraganglioma, particularly in patients who are young, have multiple tumors, or have a family history of malignancy. […] Ongoing research into the genetic underpinnings of this tumor may allow for more targeted molecular therapies in the future.

• #1 Genetic bases of pheochromocytoma and paraganglioma in: Journal of Molecular Endocrinology Volume 70 Issue 3 (2023)

  https://jme.bioscientifica.com/view/journals/jme/70/3/JME-22-0167.xml

  The genetics of pheochromocytoma and paraganglioma (PPGL) has become increasingly complex over the last two decades. The list of genes involved in the development of these tumors has grown steadily, and there are currently more than 20 driver genes implicated in either the hereditary or the sporadic nature of the disease. […] Although genetic diagnosis is achieved in about 7580% of patients, genetic etiology remains unexplained in a significant percentage of cases. Patients lacking a genetic diagnosis include not only those with apparently sporadic PPGL but also patients with a family history of the disease or with multiple tumors, that meet the criteria to be considered as candidates for carrying germline mutations in yet undiscovered genes. […] Mutations in known PPGL genes deregulate three main signaling pathways (hypoxia, kinase signaling, and Wnt-signaling pathways), which could be the starting point for the development of personalized treatment for PPGL patients.

• #2 Paraganglioma: Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/22394-paraganglioma

  A paraganglioma (also known as an extra-adrenal pheochromocytoma) is a rare neuroendocrine tumor (NET) that forms near your carotid artery (the major blood vessels in your neck), along nerve pathways in your head and neck and in other parts of your body. […] In most cases of paraganglioma, the exact cause is unknown, and it occurs randomly. Approximately 25% to 35% of people who have paraganglioma have a hereditary condition (passed through the family) thats linked to paraganglioma, including: […] While most paraganglioma cases have an unknown cause, theres a significant link to certain inherited conditions.

• #2 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Paragangliomas are primarily sporadic, although 30% to 50% of cases are familial. Some familial forms may be associated with genetic syndromes, such as variations in the genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme, Carney-Stratakis dyad, neurofibromatosis type 1 (NF1), von Hippel-Lindau (VHL), and multiple endocrine neoplasia types 2A and 2B (MEN2). […] Pathogenic mutations in SDHx lead to 5 autosomal dominant hereditary paraganglioma syndromes. […] The most common mutation occurs in SDHD.

• #2 Familial paraganglioma syndromes – Genomics Education Programme

  http://www.genomicseducation.hee.nhs.uk/documents/familial-paraganglioma-syndromes/

  SDHD (succinate dehydrogenase subunit D): associated frequently with head and neck paragangliomas. Uncommon association with pituitary adenomas reported. Tumours less frequently associated with malignancy. Exhibits maternal imprinting (in other words, if a patient inherits a causative variant in SDHD from their father, they are more likely to develop tumours than if they inherit the causative variant from their mother). […] VHL (von Hippel-Lindau disease): associated with other features of VHL such as renal cysts, renal cell carcinoma, pancreatic cysts and neuroendocrine tumours. […] NF1 (neurofibromatosis type 1): associated with other features of the syndrome, including neurofibromas and caf-au-lait spots. […] MEN2/RET (multiple endocrine neoplasia type 2): associated with other features of the syndrome, including medullary thyroid carcinoma and hyperparathyroidism. […] SDHA (succinate dehydrogenase subunit A), SDHC (succinate dehydrogenase subunit C), SDHAF2 (SDH assembly factor 2), FH (fumarate hydratase), TMEM127 and MAX: rarer causes of familial paraganglioma syndrome.

• #2 Head and Neck: Paraganglioma: an overview

  https://atlasgeneticsoncology.org/solid-tumor/6202/head-and-neck-paraganglioma-an-overview

  The classic „rule of 10” for paraganglial tumors (i.e. 10% are malignant, 10% are hereditary and 10% are extra-adrenal) has become inaccurate (Fishbein et al., 2013). […] The identification of novel causative or susceptibility genes in pheochromocytomas and paragangliomas led to an increase in the rate of familial forms. About one third of all patients with (even apparently sporadic) HNPG are carriers of germline mutations. The rate varies between 24% and 32% (Fishbein et al., 2013) with one study reporting a rate as high as 41% (Burnichon et al., 2009). […] But the true incidence of familial paragangliomas may be even higher (i.e. 50%). The mode of inheritance is autosomal dominant with, for some syndromes, genomic imprinting (see below) (Boedeker et al., 2013). […] Hereditary paragangliomas of the head and neck (HNPG) have been described in association with mutations of at least 10 different genes (Boedeker et al., 2013; Dahia, 2014). Mutations of the genes succinate dehydrogenase subunit D (SDHD), succinate dehydrogenase complex assembly factor 2 (SDHAF2, formerly known as SDH5), SDHC, and SDHB are the cause of paraganglioma syndromes (PGL) 1, 2, 3, and 4, respectively.

• #2 Genetic bases of pheochromocytoma and paraganglioma in: Journal of Molecular Endocrinology Volume 70 Issue 3 (2023)

  https://jme.bioscientifica.com/view/journals/jme/70/3/JME-22-0167.xml

  Somatic mutations in some of these driver genes (mainly RET, VHL, NF1, and MAX) and in others (EPAS1, HRAS, IDH1, IDH2, CSDE1, FGFR1, and BRAF) are found in 30% of PPGLs without a known germline variant. […] In almost all cases, tumor development is associated with the presence of a single mutation in one of the driver genes, regardless of whether it is germline or somatic. […] However, anecdotal reports of PPGLs carrying mutations in two driver genes have been reported (NF1 along with RET, VHL, or FGFR1; RET with SDHA or MAX with HRAS mutations). […] Considering all these data, it is advised that all patients with PPGL undergo genetic screening since the patient’s management and genetic counseling are significantly impacted by the identification of the underlying mutation.

• #2 Nonsyndromic paraganglioma: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/nonsyndromic-paraganglioma/

  Mutations in the RET gene have been found in nonsyndromic pheochromocytoma in addition to a pheochromocytoma-predisposing syndrome. […] Mutations in the TMEM127 gene have been identified most commonly in people with nonsyndromic pheochromocytoma and are rarely seen in people with other paraganglioma. […] Mutations in the KIF1B gene have been reported in nonsyndromic pheochromocytoma. […] Many people with nonsyndromic paraganglioma or pheochromocytoma do not have a mutation in any of the genes associated with the conditions. It is likely that other, unidentified genes also predispose to development of paraganglioma or pheochromocytoma.

• #2 Paragangliomas: Causes, Symptoms, and Treatment

  https://www.tgh.org/institutes-and-services/conditions/paragangliomas

  The majority of paragangliomas have no known cause. A small percentage of tumors are linked to an inherited gene mutation or an underlying neuroendocrine condition, such as: […] Neurofibromatosis type 1 (NF1) […] Multiple endocrine neoplasia 2 syndrome, types A and B (MEN2A and MEN2B) […] von Hippel-Lindau disease.

• #2 Paraganglioma – MD Searchlight

  https://mdsearchlight.com/health/paraganglioma/

  Paragangliomas mainly occur spontaneously, but in 30% to 50% of cases, they can be inherited. Some inherited forms are related to certain genetic conditions and variations in specific genes. […] Tumors that grow from these paraganglia are called paragangliomas. Sometimes, these tumors can be related to specific family genes. Kids are more prone to these tumors if there’s a family history. Genes such as those responsible for different parts of the SDH enzyme complex are often involved. […] Certain genetic syndromes also put people at a higher risk of developing these tumors. These syndromes include Multiple Endocrine Neoplasia type 2 (MEN2), Neurofibromatosis type 1 (NF1), Von Hippel-Lindau disease (VHL), and Carney-Stratakis dyad. […] Factors like living in high altitudes or illnesses that result in low oxygen levels, like cyanotic congenital heart disease and chronic obstructive lung disease, can boost the risk of these tumors, specifically those found in the carotid body.

• #2 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Paragangliomas are tumors originating from the paraganglia. Researchers and clinicians refer to parasympathetic paragangliomas as nonchromaffin paragangliomas, contrasting them with chromaffin paragangliomas arising from chromaffin cells within the sympathetic paraganglia and the adrenal medulla. […] While usually sporadic, they may also present as part of familial syndromes. Children are more likely to have paraganglioma in the presence of a familial syndrome. Most hereditary variants, especially involving the skull base and neck, are due to variations in the genes encoding different subunits of the SDH enzyme complex. Patients with MEN2, NF1, VHL, and Carney-Stratakis dyad are also at increased risk of developing intra- and extra-adrenal paragangliomas. […] In addition to genetic predispositions, factors such as hypoxia from residing at high altitudes or having cyanotic congenital heart disease and chronic obstructive lung disease elevate the risk of carotid body paragangliomas. Recent data indicates that hypoxia-inducible factors (HIFs) may play a role in the genesis of paragangliomas in specific cases.

• #2 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Individuals with variants in the VHL and SDHx genes exhibit a pseudohypoxic response, leading to the stabilization, dysregulation, and overexpression of HIFs. Tumors with pathogenic variants in the VHL gene closely resemble those with variants in the SDHx genes. Shared characteristics of both VHL and SDHx variants include angiogenesis, hypoxia, and a diminished oxidative response, suggesting a common molecular pathway in the development of these tumors. […] The nomenclature of paragangliomas typically reflects their location. In the ear, the collective name is jugulotympanic paraganglioma, after the jugular bulb paraganglia and the tympanic paraganglia. […] Jugulotympanic paragangliomas predominantly affect women in their fifties, with only 10% to 16% being bilateral. While most jugulotympanic paragangliomas are sporadic, around 10% exhibit an autosomal dominant inheritance pattern.

• #2 Paraganglioma | UM Health-Sparrow

  https://www.uofmhealthsparrow.org/departments-conditions/conditions/paraganglioma

  Paragangliomas often don’t have a clear cause. Some paragangliomas are caused by DNA changes that pass from parents to children. […] A paraganglioma starts when chromaffin cells develop changes in their DNA. A cell’s DNA holds the instructions that tell the cell what to do. In healthy cells, the DNA gives instructions to grow and multiply at a set rate. The instructions also tell the cells to die at a set time. In paraganglioma cells, the DNA changes give different instructions. The changes tell the paraganglioma cells to make many more cells quickly. The cells keep living when healthy cells would die. This causes a growth of cells called a tumor. […] Most paragangliomas stay where they started. They don’t spread to other parts of the body. But sometimes cells can break away from a paraganglioma and spread. When this happens, it’s called metastatic paraganglioma. When a paraganglioma spreads, it most often spreads to nearby lymph nodes. It also can spread to the lungs, liver and bones.

• #2 Jugulotympanic Paraganglioma: Symptoms, Causes And Treatment

  https://www.medicoverhospitals.in/diseases/jugulotympanic-paraganglioma/

  Jugulotympanic paraganglioma is a rare type of tumor that develops in the head and neck region. […] While the exact cause of jugulotympanic paraganglioma is not fully understood, it is believed to be linked to genetic mutations that lead to abnormal growth of these cells. […] The exact cause of this condition is not fully understood; however, it is often associated with genetic mutations in genes like SDHD, SDHC, and SDHB. These mutations disrupt the normal regulation of cell growth, leading to the formation of tumors in the head and neck region. […] Genetic predisposition, such as mutations in the SDHB, SDHD, SDHC, or SDHA genes, can contribute to the development of Jugulotympanic Paraganglioma. […] Exposure to high levels of environmental toxins or radiation may increase the risk of developing Jugulotympanic Paraganglioma.

• #2 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Paragangliomas are related to pheochromocytomas and are often grouped together, contributing to some uncertainty regarding their precise incidence. […] Most patients with sporadic paraganglioma present between their 30s and 50s, with the mean age of diagnosis being 47. […] The incidence of malignant paragangliomas is around 90 to 95 cases per 400 million person-years. […] The primary pathophysiology underlying a paraganglioma involves either the excessive secretion of catecholamines or bony erosion due to mass effect. […] The sympathetic nervous system receptors, collectively referred to as adrenergic receptors because they bind and release norepinephrine, include 1, 2, 1, and 2. […] Parasympathetic paragangliomas located in the skull base are usually non-secretory, with less than 5% secreting catecholamines and becoming symptomatic.

• #2 Hereditary pheochromocytoma-paraganglioma

  https://www.genturis.eu/l=eng/thematic-disease-groups/other-rare-genturis/hereditary-pheochromocytoma-paraganglioma.html

  A significant proportion of pheochromocytomas and paragangliomas (appr. 30-40%) occur as part of a genetic tumour risk syndrome (also termed hereditary cancer predisposition syndrome). […] Hereditary pheochromocytoma-paraganglioma is caused by pathogenic germline variants in one of multiple genes (such as SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127 and MAX). […] The most frequently involved genes encode individual subunits of the succinate dehydrogenase (SDHx) enzyme complex, accounting for at least half of the cases. […] SDHB is one of the major genes predisposing to hereditary pheochromocytoma-paraganglioma, and also the one associated with higher risk of malignant disease. […] Other tumours occurring in families with pathogenic germline variants in the SDHB, SDHC, and SDHD genes are gastrointestinal stromal tumours, pulmonary chondromas and clear cell renal cell carcinoma.

• #2 Urinary bladder paraganglioma | Applied Radiology

  https://appliedradiology.com/articles/urinary-bladder-paraganglioma

  Malignant paragangliomas of the bladder constitutes 10-15% of these tumors. Malignant pheochromocytomas cannot be differentiated from benign lesions based on the gross anatomy or histology. The malignant nature of the paraganglioma is determined based on its deep invasion, lymph-node involvement, and metastasis to local or distant organs. […] Paragangliomas are rare neuroendocrine tumors that arise from the neural crest cells. They are extra-adrenal pheochromocytomas. The most common location of paragangliomas is the retroperitoneal space and its location is rare in the pelvis.

• #2 Paraganglioma | Columbia Surgery

  https://columbiasurgery.org/conditions-and-treatments/paraganglioma

  Paragangliomas are rare tumors that make too much adrenaline. Paraganglioma are found in 2 out of every million people each year and is the cause of high blood pressure in less than 0.2% of people with high blood pressure. […] Paragangliomas can occur at any age and there are no known risk factors except for certain genetic syndromes. Up to 25% of paragangliomas are inherited. […] Most paragangliomas are not genetic in origin, but the only known risk factor is a family history of them; the rest of these tumors do not have a known cause (i.e. are spontaneous). About 25% of paraganglioma are inherited or familial. […] Familial paraganglioma syndrome is caused by mutations in the succinate dehydrogenase gene (SDH). There are a number of different mutations including the B, C, and D mutations, each of which causes different forms of the disease.

• #2 Paraganglioma – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/paraganglioma/diagnosis-treatment/drc-20575710

  Some DNA changes passed from parents to children make paragangliomas more likely to form. […] If you have a paraganglioma, your healthcare professional may recommend genetic testing to look for these DNA changes in your body. Results of genetic testing can help predict the chances of your tumor coming back after treatment. […] Your parents, children or siblings also can be checked for DNA changes that raise the risk of paragangliomas.

• #2 Genetic bases of pheochromocytoma and paraganglioma in: Journal of Molecular Endocrinology Volume 70 Issue 3 (2023)

  https://jme.bioscientifica.com/view/journals/jme/70/3/JME-22-0167.xml

  Approximately 40% of PPGL patients harbor an autosomal dominant germline mutation in 1 of the 20 susceptibility genes described so far. […] Somatic mutations in one of the genes involved in the disease are responsible for tumor development in 30% of patients. Lastly, there are still 30% of PPGLs for which a pathogenic gene mutation has not been identified, including some exhibiting clinical signs indicative of an inherited condition. […] This unexplained heritability represents a major challenge for the proper genetic classification of patients in order to provide the most adequate clinical follow-up. […] The major PPGL susceptibility genes found mutated in the germline include classic driver genes, such as RET, NF1, VHL, SDHD, SDHC, and SDHB, as well as more recently identified genes such as SDHA, SDHAF2, TMEM127, MAX, FH, MDH2, EGLN1, EGLN2, KIF1B, MET, IDH3B, GOT2, SLC25A11, DNMT3A, and DLST.

• #2 Genetic bases of pheochromocytoma and paraganglioma in: Journal of Molecular Endocrinology Volume 70 Issue 3 (2023)

  https://jme.bioscientifica.com/view/journals/jme/70/3/JME-22-0167.xml

  The genetics of pheochromocytoma and paraganglioma (PPGL) has become increasingly complex over the last two decades. The list of genes involved in the development of these tumors has grown steadily, and there are currently more than 20 driver genes implicated in either the hereditary or the sporadic nature of the disease. […] Although genetic diagnosis is achieved in about 7580% of patients, genetic etiology remains unexplained in a significant percentage of cases. Patients lacking a genetic diagnosis include not only those with apparently sporadic PPGL but also patients with a family history of the disease or with multiple tumors, that meet the criteria to be considered as candidates for carrying germline mutations in yet undiscovered genes. […] Mutations in known PPGL genes deregulate three main signaling pathways (hypoxia, kinase signaling, and Wnt-signaling pathways), which could be the starting point for the development of personalized treatment for PPGL patients.

• #3 Genetic bases of pheochromocytoma and paraganglioma in: Journal of Molecular Endocrinology Volume 70 Issue 3 (2023)

  https://jme.bioscientifica.com/view/journals/jme/70/3/JME-22-0167.xml

  Approximately 40% of PPGL patients harbor an autosomal dominant germline mutation in 1 of the 20 susceptibility genes described so far. […] Somatic mutations in one of the genes involved in the disease are responsible for tumor development in 30% of patients. Lastly, there are still 30% of PPGLs for which a pathogenic gene mutation has not been identified, including some exhibiting clinical signs indicative of an inherited condition. […] This unexplained heritability represents a major challenge for the proper genetic classification of patients in order to provide the most adequate clinical follow-up. […] The major PPGL susceptibility genes found mutated in the germline include classic driver genes, such as RET, NF1, VHL, SDHD, SDHC, and SDHB, as well as more recently identified genes such as SDHA, SDHAF2, TMEM127, MAX, FH, MDH2, EGLN1, EGLN2, KIF1B, MET, IDH3B, GOT2, SLC25A11, DNMT3A, and DLST.

• #3 Pheochromocytoma and Paraganglioma – Missouri Cancer Associates

  https://missouricancer.com/cancer_type/pheochromocytoma-and-paraganglioma/

  Pheochromocytoma and paraganglioma are rare tumors that come from the same type of tissue. […] Certain inherited disorders and changes in certain genes increase the risk of pheochromocytoma or paraganglioma. […] The following inherited syndromes or gene changes increase the risk of pheochromocytoma or paraganglioma: Multiple endocrine neoplasia 2 syndrome, types A and B (MEN2A and MEN2B), von Hippel-Lindau (VHL) syndrome, Neurofibromatosis type 1 (NF1), Hereditary paraganglioma syndrome, Carney-Stratakis dyad (paraganglioma and gastrointestinal stromal tumor [GIST]), Carney triad (paraganglioma, GIST, and pulmonary chondroma).

• #3 Paraganglioma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK549834/

  Paragangliomas are related to pheochromocytomas and are often grouped together, contributing to some uncertainty regarding their precise incidence. […] Most patients with sporadic paraganglioma present between their 30s and 50s, with the mean age of diagnosis being 47. […] The incidence of malignant paragangliomas is around 90 to 95 cases per 400 million person-years. […] The primary pathophysiology underlying a paraganglioma involves either the excessive secretion of catecholamines or bony erosion due to mass effect. […] The sympathetic nervous system receptors, collectively referred to as adrenergic receptors because they bind and release norepinephrine, include 1, 2, 1, and 2. […] Parasympathetic paragangliomas located in the skull base are usually non-secretory, with less than 5% secreting catecholamines and becoming symptomatic.

• #3 Genetic bases of pheochromocytoma and paraganglioma in: Journal of Molecular Endocrinology Volume 70 Issue 3 (2023)

  https://jme.bioscientifica.com/view/journals/jme/70/3/JME-22-0167.xml

  Somatic mutations in some of these driver genes (mainly RET, VHL, NF1, and MAX) and in others (EPAS1, HRAS, IDH1, IDH2, CSDE1, FGFR1, and BRAF) are found in 30% of PPGLs without a known germline variant. […] In almost all cases, tumor development is associated with the presence of a single mutation in one of the driver genes, regardless of whether it is germline or somatic. […] However, anecdotal reports of PPGLs carrying mutations in two driver genes have been reported (NF1 along with RET, VHL, or FGFR1; RET with SDHA or MAX with HRAS mutations). […] Considering all these data, it is advised that all patients with PPGL undergo genetic screening since the patient’s management and genetic counseling are significantly impacted by the identification of the underlying mutation.

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