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Paragangliomas 2(PPGL2)

MedGen UID:
357076
Concept ID:
C1866552
Disease or Syndrome
Synonyms: Glomus tumors, familial, 2; PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 2; PPGL2; SDHAF2-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome; SDHAF2-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 2)
 
Gene (location): SDHAF2 (11q12.2)
 
Monarch Initiative: MONDO:0011121
OMIM®: 601650

Disease characteristics

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck paragangliomas [HNPGLs]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, extra-adrenal sympathetic paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCCs result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas. Additional tumors reported in individuals with hereditary PGL/PCC syndromes include gastrointestinal stromal tumors (GISTs), pulmonary chondromas, and clear cell renal cell carcinoma. [from GeneReviews]
Authors:
Tobias Else  |  Samantha Greenberg  |  Lauren Fishbein   view full author information

Additional descriptions

From OMIM
Pheochromocytoma/paraganglioma syndrome-2 (PPGL2) is an autosomal dominant disorder characterized by the development of neuroendocrine tumors, usually in adulthood. Paragangliomas are tumors derived from paraganglia located throughout the body. Nonchromaffin types primarily serve as chemoreceptors and are located in the head and neck region (i.e., carotid body, jugular, vagal, and tympanic regions), whereas chromaffin types have endocrine activity, conventionally referred to as 'pheochromocytomas,' and are usually located below the head and neck (i.e., adrenal medulla and pre- and paravertebral thoracoabdominal regions). PPGL can manifest as nonchromaffin head and neck tumors only, adrenal and/or extraadrenal pheochromocytomas only, or a combination of the 2 types of tumors (Baysal, 2002; Neumann et al., 2004). For a discussion of genetic heterogeneity of pheochromocytoma/paraganglioma syndrome, see PPGL1 (168000).  http://www.omim.org/entry/601650
From MedlinePlus Genetics
Hereditary paraganglioma-pheochromocytoma is an inherited condition characterized by the growth of tumors in structures called paraganglia. Paraganglia are groups of cells that are found near nerve cell bunches called ganglia. A tumor involving the paraganglia is known as a paraganglioma. A type of paraganglioma known as a pheochromocytoma develops in the adrenal glands, which are located on top of each kidney and produce hormones in response to stress. Other types of paraganglioma are usually found in the head, neck, or trunk. People with hereditary paraganglioma-pheochromocytoma develop one or more paragangliomas, which may include pheochromocytomas.

Pheochromocytomas and some other paragangliomas are associated with ganglia of the sympathetic nervous system. The sympathetic nervous system controls the "fight-or-flight" response, a series of changes in the body due to hormones released in response to stress. Sympathetic paragangliomas found outside the adrenal glands, usually in the abdomen, are called extra-adrenal paragangliomas. Most sympathetic paragangliomas, including pheochromocytomas, produce hormones called catecholamines, such as epinephrine (adrenaline) or norepinephrine. These excess catecholamines can cause signs and symptoms such as high blood pressure (hypertension), episodes of rapid heartbeat (palpitations), headaches, or sweating.

Most paragangliomas are associated with ganglia of the parasympathetic nervous system, which controls involuntary body functions such as digestion and saliva formation. Parasympathetic paragangliomas, typically found in the head and neck, usually do not produce hormones. However, large tumors may cause signs and symptoms such as coughing, hearing loss in one ear, or difficulty swallowing.

Paragangliomas and pheochromocytomas are typically considered an undetermined tumor type, meaning they can be noncancerous (benign) or become cancerous (malignant) and spread to other parts of the body (metastasize). Extra-adrenal paragangliomas become malignant more often than other types of paraganglioma or pheochromocytoma.

Researchers have identified several types of hereditary paraganglioma-pheochromocytoma. Each type is distinguished by its genetic cause. People with types 1, 2, and 3 typically develop paragangliomas in the head or neck region. People with type 4 usually develop extra-adrenal paragangliomas in the abdomen and are at higher risk for malignant tumors that metastasize. The other types are very rare. Hereditary paraganglioma-pheochromocytoma is typically diagnosed in a person's 30s.

Paragangliomas and pheochromocytomas can occur in individuals with other inherited disorders, such as von Hippel-Lindau syndrome, Carney-Stratakis syndrome, and certain types of multiple endocrine neoplasia. These other disorders feature additional tumor types and have different genetic causes. Some paragangliomas and pheochromocytomas occur in people with no history of the tumors in their families and appear not to be inherited. These cases are designated as sporadic.  https://medlineplus.gov/genetics/condition/hereditary-paraganglioma-pheochromocytoma

Clinical features

From HPO
Chemodectoma
MedGen UID:
2853
Concept ID:
C0007279
Neoplastic Process
Pheochromocytoma/paraganglioma syndrome-1 (PPGL1) is an autosomal dominant disorder characterized by the development of neuroendocrine tumors, usually in adulthood. Pheochromocytomas arise from chromaffin cells in the adrenal medulla, whereas paragangliomas arise in extra-adrenal sympathetic ganglia in the thorax, abdomen, and pelvis or from parasympathetic paraganglia in the head and neck area (summary by Cascon et al., 2023). Paragangliomas, also referred to as 'glomus body tumors,' are tumors derived from paraganglia located throughout the body. Nonchromaffin types primarily serve as chemoreceptors (hence, the tumor name 'chemodectomas') and are located in the head and neck region (i.e., carotid body, jugular, vagal, and tympanic regions), whereas chromaffin types have endocrine activity, conventionally referred to as 'pheochromocytomas,' and are usually located below the head and neck (i.e., adrenal medulla and pre- and paravertebral thoracoabdominal regions). PPGL can manifest as nonchromaffin head and neck tumors only, adrenal and/or extraadrenal pheochromocytomas only, or a combination of the 2 types of tumors (Baysal, 2002; Neumann et al., 2004). The triad of gastric leiomyosarcoma, pulmonary chondroma, and extraadrenal paraganglioma constitutes a syndrome that occurs mainly in young women and is known as the Carney triad (604287). This triad is not to be confused with the other Carney syndrome of myxoma, spotty pigmentation, and endocrinopathy (160980). Baysal (2008) provided a review of the molecular pathogenesis of hereditary paraganglioma. Genetic Heterogeneity of Pheochromocytoma/Paraganglioma Syndrome See also PPGL2 (601650), caused by mutation in the SDHAF2 gene (613019) on chromosome 11q13; PPGL3 (605373), caused by mutation in the SDHC gene (602413) on chromosome 1q21; PPGL4 (115310), caused by mutation in the SDHB gene (185470) on chromosome 1p36; PPGL5 (614165), caused by mutation in the SDHA gene (600857) on chromosome 5p15; PPGL6 (618464), caused by mutation in the SLC25A11 gene (604165) on chromosome 17p13; and PPGL7 (618475), caused by mutation in the DLST gene (126063) on chromosome 14q24.
Glomus jugular tumor
MedGen UID:
4905
Concept ID:
C0017671
Neoplastic Process
An extra-adrenal parasympathetic paraganglioma arising from paraganglia in the base of the skull and middle ear.
Neoplasm
MedGen UID:
10294
Concept ID:
C0027651
Neoplastic Process
An organ or organ-system abnormality that consists of uncontrolled autonomous cell-proliferation which can occur in any part of the body as a benign or malignant neoplasm (tumor).
Vagal paraganglioma
MedGen UID:
141635
Concept ID:
C0474819
Neoplastic Process
A tumor that develops in the retrostyloid compartment of the parapharyngeal space, arising from an island of paraganglion tissue derived from the neural crest that is located on the vagus nerve.
Glomus tympanicum paraganglioma
MedGen UID:
105375
Concept ID:
C0474820
Neoplastic Process
A middle ear paraganglioma arising from paraganglia around the tympanum. Signs and symptoms include a mass behind the tympanum, tinnitus, and conductive hearing loss.
Pulsatile tinnitus
MedGen UID:
148340
Concept ID:
C0751559
Sign or Symptom
Pulsatile tinnitus is generally classified a kind of objective tinnitus, meaning that it is not only audible to the patient but also to the examiner on auscultation of the auditory canal and/or of surrounding structures with use of an auscultation tube or stethoscope. Usually, pulsatile tinnitus is heard as a lower pitched thumping or booming, a rougher blowing sound which is coincidental with respiration, or as a clicking, higher pitched rhythmic sensation.
Cranial nerve paralysis
MedGen UID:
57717
Concept ID:
C0151311
Disease or Syndrome
Injury to any of the cranial nerves or their nuclei in the brain resulting in muscle weakness.
Loss of voice
MedGen UID:
2006
Concept ID:
C0003564
Sign or Symptom
A term referring to the inability to speak. It may result from injuries to the vocal cords or may be functional (psychogenic).
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.
Vocal cord paralysis
MedGen UID:
53047
Concept ID:
C0042928
Disease or Syndrome
A loss of the ability to move the vocal folds.

Professional guidelines

PubMed

Sato Y, Hashimoto S, Mizuno K, Takeuchi M, Terai S
World J Gastroenterol 2016 Aug 14;22(30):6817-28. doi: 10.3748/wjg.v22.i30.6817. PMID: 27570419Free PMC Article
Torrealba JI, Valdés F, Krämer AH, Mertens R, Bergoeing M, Mariné L
Ann Vasc Surg 2016 Jul;34:200-5. Epub 2016 May 12 doi: 10.1016/j.avsg.2015.12.029. PMID: 27179981
Yip L, Lee JE, Shapiro SE, Waguespack SG, Sherman SI, Hoff AO, Gagel RF, Arens JF, Evans DB
J Am Coll Surg 2004 Apr;198(4):525-34; discussion 534-5. doi: 10.1016/j.jamcollsurg.2003.12.001. PMID: 15051000

Recent clinical studies

Etiology

Castelhano L, Correia F, Donato S, Ferreira L, Montalvão P, Magalhães M
Acta Med Port 2022 Nov 2;35(11):789-797. Epub 2022 Mar 15 doi: 10.20344/amp.17185. PMID: 35290759
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Ann Vasc Surg 2016 Jul;34:200-5. Epub 2016 May 12 doi: 10.1016/j.avsg.2015.12.029. PMID: 27179981
Boedeker CC, Hensen EF, Neumann HP, Maier W, van Nederveen FH, Suárez C, Kunst HP, Rodrigo JP, Takes RP, Pellitteri PK, Rinaldo A, Ferlito A
Head Neck 2014 Jun;36(6):907-16. Epub 2013 Nov 30 doi: 10.1002/hed.23436. PMID: 23913591
Işik AC, Imamoğlu M, Erem C, Sari A
Med Princ Pract 2007;16(3):209-14. doi: 10.1159/000100392. PMID: 17409756
Nakano PH, Bloom RR, Brown BC, Gray SW, Skandalakis JE, Kibbe JM
Am Surg 1987 Sep;53(9):505-9. PMID: 2820286

Diagnosis

Castelhano L, Correia F, Donato S, Ferreira L, Montalvão P, Magalhães M
Acta Med Port 2022 Nov 2;35(11):789-797. Epub 2022 Mar 15 doi: 10.20344/amp.17185. PMID: 35290759
Sato Y, Hashimoto S, Mizuno K, Takeuchi M, Terai S
World J Gastroenterol 2016 Aug 14;22(30):6817-28. doi: 10.3748/wjg.v22.i30.6817. PMID: 27570419Free PMC Article
Torrealba JI, Valdés F, Krämer AH, Mertens R, Bergoeing M, Mariné L
Ann Vasc Surg 2016 Jul;34:200-5. Epub 2016 May 12 doi: 10.1016/j.avsg.2015.12.029. PMID: 27179981
Boedeker CC, Hensen EF, Neumann HP, Maier W, van Nederveen FH, Suárez C, Kunst HP, Rodrigo JP, Takes RP, Pellitteri PK, Rinaldo A, Ferlito A
Head Neck 2014 Jun;36(6):907-16. Epub 2013 Nov 30 doi: 10.1002/hed.23436. PMID: 23913591
Işik AC, Imamoğlu M, Erem C, Sari A
Med Princ Pract 2007;16(3):209-14. doi: 10.1159/000100392. PMID: 17409756

Therapy

Torrealba JI, Valdés F, Krämer AH, Mertens R, Bergoeing M, Mariné L
Ann Vasc Surg 2016 Jul;34:200-5. Epub 2016 May 12 doi: 10.1016/j.avsg.2015.12.029. PMID: 27179981
Zagar I, Han R, Mitrovic S
Q J Nucl Med 1995 Dec;39(4 Suppl 1):13-6. PMID: 9002742

Prognosis

Işik AC, Imamoğlu M, Erem C, Sari A
Med Princ Pract 2007;16(3):209-14. doi: 10.1159/000100392. PMID: 17409756
Zagar I, Han R, Mitrovic S
Q J Nucl Med 1995 Dec;39(4 Suppl 1):13-6. PMID: 9002742
Karamitopoulou E, Perentes E, Diamantis I, Maraziotis T
Acta Neuropathol 1994;87(1):47-54. doi: 10.1007/BF00386253. PMID: 7511316
Karamitopoulou E, Perentes E, Melachrinou M, Maraziotis T
Acta Neuropathol 1993;85(3):316-22. doi: 10.1007/BF00227728. PMID: 7681617

Clinical prediction guides

Goldsmith SJ
Semin Nucl Med 2020 Jan;50(1):87-97. Epub 2019 Nov 6 doi: 10.1053/j.semnuclmed.2019.07.006. PMID: 31843064
Poletti AM, Dubey SP, Colombo G, Cugini G
Ear Nose Throat J 2016 Dec;95(12):E1-E6. PMID: 27929599
Torrealba JI, Valdés F, Krämer AH, Mertens R, Bergoeing M, Mariné L
Ann Vasc Surg 2016 Jul;34:200-5. Epub 2016 May 12 doi: 10.1016/j.avsg.2015.12.029. PMID: 27179981
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Karamitopoulou E, Perentes E, Diamantis I, Maraziotis T
Acta Neuropathol 1994;87(1):47-54. doi: 10.1007/BF00386253. PMID: 7511316

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