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Paragangliomas 3(PPGL3)

MedGen UID:
340200
Concept ID:
C1854336
Disease or Syndrome
Synonyms: Glomus tumors, familial, 3; PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 3; PPGL3; SDHC-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome; SDHC-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 3)
 
Gene (location): SDHC (1q23.3)
 
Monarch Initiative: MONDO:0011544
OMIM®: 605373

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-3 (PPGL3) 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/605373
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
Carotid body paraganglioma
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.
Paraganglioma
MedGen UID:
10571
Concept ID:
C0030421
Neoplastic Process
A carotid body tumor (also called paraganglionoma or chemodectoma) is a tumor found in the upper neck at the branching of the carotid artery. They arise from the chemoreceptor organ (paraganglion) located in the adventitia of the carotid artery bifurcation.
Extraadrenal pheochromocytoma
MedGen UID:
263453
Concept ID:
C1257877
Neoplastic Process
Pheochromocytoma not originating from the adrenal medulla but from another source such as from chromaffin cells in or about sympathetic ganglia.
Adrenal pheochromocytoma
MedGen UID:
1636437
Concept ID:
C4551683
Neoplastic Process
Pheochromocytoma originating from the adrenal medulla.
Palpitations
MedGen UID:
14579
Concept ID:
C0030252
Finding
A sensation that the heart is pounding or racing, which is a non-specific sign but may be a manifestation of arrhythmia.
Tachycardia
MedGen UID:
21453
Concept ID:
C0039231
Finding
A rapid heartrate that exceeds the range of the normal resting heartrate for age.
Hypertension associated with pheochromocytoma
MedGen UID:
871214
Concept ID:
C4025693
Disease or Syndrome
A type of hypertension associated with pheochromocytoma.
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.
Episodic paroxysmal anxiety
MedGen UID:
923185
Concept ID:
C1387805
Mental or Behavioral Dysfunction
Recurrent attacks of severe anxiety, which occur without restriction to any particular situation or set of circumstances, are therefore unpredictable.
Recurrent paroxysmal headache
MedGen UID:
927617
Concept ID:
C4293708
Sign or Symptom
Repeated episodes of headache with rapid onset, reaching a peak within minutes and of short duration (less than one hour) with pain that is throbbing, pulsating, or bursting in quality.
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.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
Elevated circulating catecholamine level
MedGen UID:
871156
Concept ID:
C4025629
Finding
An abnormal increase in catecholamine concentration in the blood.

Professional guidelines

PubMed

Tikkakoski T, Luotonen J, Leinonen S, Siniluoto T, Heikkilä O, Päivänsälo M, Hyrynkangas K
Laryngoscope 1997 Jun;107(6):821-6. doi: 10.1097/00005537-199706000-00018. PMID: 9185740
Bomanji J, Britton KE, Ur E, Hawkins L, Grossman AB, Besser GM
Nucl Med Commun 1993 Oct;14(10):856-61. doi: 10.1097/00006231-199310000-00004. PMID: 8233228

Curated

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Neuroendocrine and Adrenal Tumors, 2023

Recent clinical studies

Etiology

Ota Y, Liao E, Capizzano AA, Yokota H, Baba A, Kurokawa R, Kurokawa M, Moritani T, Yoshii K, Srinivasan A
J Neuroimaging 2022 May;32(3):502-510. Epub 2021 Dec 22 doi: 10.1111/jon.12959. PMID: 34936708
Rijken JA, de Vos B, Leemans CR, Zwezerijnen GJCB, de Graaf P, Hensen EF, Dreijerink KMA, Dickhoff C, Symersky P
Ann Thorac Surg 2020 Feb;109(2):e87-e90. Epub 2019 Jul 4 doi: 10.1016/j.athoracsur.2019.05.037. PMID: 31279790
Else T, Marvin ML, Everett JN, Gruber SB, Arts HA, Stoffel EM, Auchus RJ, Raymond VM
J Clin Endocrinol Metab 2014 Aug;99(8):E1482-6. Epub 2014 Apr 23 doi: 10.1210/jc.2013-3853. PMID: 24758179Free PMC Article
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
Erdogan BA, Bora F, Altin G, Paksoy M
Prague Med Rep 2012;113(4):262-70. doi: 10.14712/23362936.2015.9. PMID: 23249657

Diagnosis

Ota Y, Liao E, Capizzano AA, Yokota H, Baba A, Kurokawa R, Kurokawa M, Moritani T, Yoshii K, Srinivasan A
J Neuroimaging 2022 May;32(3):502-510. Epub 2021 Dec 22 doi: 10.1111/jon.12959. PMID: 34936708
Rijken JA, de Vos B, Leemans CR, Zwezerijnen GJCB, de Graaf P, Hensen EF, Dreijerink KMA, Dickhoff C, Symersky P
Ann Thorac Surg 2020 Feb;109(2):e87-e90. Epub 2019 Jul 4 doi: 10.1016/j.athoracsur.2019.05.037. PMID: 31279790
Vanoli A, Albarello L, Uncini S, Fassan M, Grillo F, Di Sabatino A, Martino M, Pasquali C, Milanetto AC, Falconi M, Partelli S, Doglioni C, Schiavo-Lena M, Brambilla T, Pietrabissa A, Sessa F, Capella C, Rindi G, La Rosa S, Solcia E, Paulli M
Am J Surg Pathol 2019 Jun;43(6):725-736. doi: 10.1097/PAS.0000000000001234. PMID: 30913089
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
Rindi G, Paolotti D, Fiocca R, Wiedenmann B, Henry JP, Solcia E
Virchows Arch 2000 Mar;436(3):217-23. doi: 10.1007/s004280050033. PMID: 10782879

Therapy

Palavani LB, Camerotte R, Pari Mitre L, Batista S, Banderali I, Vilardo M, Vieira Nogueira B, Pereira V, Macedo L, Bertani R, Rassi MS, de Oliveira JG
World Neurosurg 2024 Oct;190:487-503.e4. Epub 2024 Aug 13 doi: 10.1016/j.wneu.2024.08.058. PMID: 39147025
Tikkakoski T, Luotonen J, Leinonen S, Siniluoto T, Heikkilä O, Päivänsälo M, Hyrynkangas K
Laryngoscope 1997 Jun;107(6):821-6. doi: 10.1097/00005537-199706000-00018. PMID: 9185740
Bomanji J, Britton KE, Ur E, Hawkins L, Grossman AB, Besser GM
Nucl Med Commun 1993 Oct;14(10):856-61. doi: 10.1097/00006231-199310000-00004. PMID: 8233228

Prognosis

Luiz HV, da Silva TN, Pereira BD, Santos JG, Gonçalves D, Manita I, Portugal J
Pediatrics 2013 Dec;132(6):e1709-14. Epub 2013 Nov 25 doi: 10.1542/peds.2013-0492. PMID: 24276837
Mohyuddin N, Ferrer K, Patel U
Ear Nose Throat J 2013 Feb;92(2):E20-3. PMID: 23460222
Rekhi B, Ingle A, Agarwal M, Puri A, Laskar S, Jambhekar NA
Pathology 2012 Jan;44(1):11-7. doi: 10.1097/PAT.0b013e32834d7ba4. PMID: 22173238
Bomanji J, Britton KE, Ur E, Hawkins L, Grossman AB, Besser GM
Nucl Med Commun 1993 Oct;14(10):856-61. doi: 10.1097/00006231-199310000-00004. PMID: 8233228

Clinical prediction guides

Palavani LB, Camerotte R, Pari Mitre L, Batista S, Banderali I, Vilardo M, Vieira Nogueira B, Pereira V, Macedo L, Bertani R, Rassi MS, de Oliveira JG
World Neurosurg 2024 Oct;190:487-503.e4. Epub 2024 Aug 13 doi: 10.1016/j.wneu.2024.08.058. PMID: 39147025
Vanoli A, Albarello L, Uncini S, Fassan M, Grillo F, Di Sabatino A, Martino M, Pasquali C, Milanetto AC, Falconi M, Partelli S, Doglioni C, Schiavo-Lena M, Brambilla T, Pietrabissa A, Sessa F, Capella C, Rindi G, La Rosa S, Solcia E, Paulli M
Am J Surg Pathol 2019 Jun;43(6):725-736. doi: 10.1097/PAS.0000000000001234. PMID: 30913089
Tsuji K, Ishikawa Y, Imamura T
Hum Pathol 2012 Mar;43(3):356-63. Epub 2011 Aug 10 doi: 10.1016/j.humpath.2011.05.004. PMID: 21835426
Rindi G, Paolotti D, Fiocca R, Wiedenmann B, Henry JP, Solcia E
Virchows Arch 2000 Mar;436(3):217-23. doi: 10.1007/s004280050033. PMID: 10782879

Recent systematic reviews

Palavani LB, Camerotte R, Pari Mitre L, Batista S, Banderali I, Vilardo M, Vieira Nogueira B, Pereira V, Macedo L, Bertani R, Rassi MS, de Oliveira JG
World Neurosurg 2024 Oct;190:487-503.e4. Epub 2024 Aug 13 doi: 10.1016/j.wneu.2024.08.058. PMID: 39147025

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    • NCCN, 2023
      NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Neuroendocrine and Adrenal Tumors, 2023

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