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Paragangliomas 3(PGL3)

MedGen UID:
340200
Concept ID:
C1854336
Disease or Syndrome
Synonyms: Glomus tumors, familial, 3; PGL3; SDHC-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome; SDHC-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 3)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): SDHC (1q23.3)
OMIM®: 605373

Disease characteristics

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas hypersecrete catecholamines; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base, neck, and upper medistinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically hypersecrete catecholamines. Symptoms of PGL/PCC result either from 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 malignant transformation is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas or skull base and neck paragangliomas. [from GeneReviews]
Authors:
Salman Kirmani  |  William F Young   view full author information

Additional description

From GHR
Hereditary paraganglioma-pheochromocytoma is an inherited condition characterized by the growth of noncancerous (benign) 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.Although most paragangliomas and pheochromocytomas are noncancerous, some can 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://ghr.nlm.nih.gov/condition/hereditary-paraganglioma-pheochromocytoma

Clinical features

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).
Chemodectoma
MedGen UID:
2853
Concept ID:
C0007279
Neoplastic Process
A benign or malignant extra-adrenal parasympathetic paraganglioma arising from paraganglia adjacent to or in the bifurcation of the common carotid artery. Most patients present with a slow growing, painless mass in the neck.
Glomus jugular tumor
MedGen UID:
4905
Concept ID:
C0017671
Neoplastic Process
A benign or malignant extra-adrenal parasympathetic paraganglioma arising from paraganglia in the base of the skull and middle ear.
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
An unnaturally deep or rough quality of voice.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
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.
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues symmetrically distributed along the paravertebral axis from the base of the skull to the pelvis) and by pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas hypersecrete catecholamines; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base, neck, and upper medistinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically hypersecrete catecholamines. Symptoms of PGL/PCC result either from 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 malignant transformation is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas or skull base and neck paragangliomas.
Tachycardia
MedGen UID:
21453
Concept ID:
C0039231
Finding
A rapid heartrate that exceeds the range of the normal resting heartrate for age.
Vocal cord paralysis
MedGen UID:
53047
Concept ID:
C0042928
Disease or Syndrome
A loss of the ability to move the vocal folds.
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.
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. Pulsatile tinnitus may be associated with vascular abnormalities such as arterioevenous shunts or glomus tumors or the jugular vein, arterial bruits related to a high-riding carotid artery (close to the auditory areas) or carotid stenosis, or venous abnormalities such as a dehiscent jugular bulb or to hypertension. Finally, in some patients, mechanical abnormalities such a spatulous eustachian tubes, palatomyoclonus (small spasms of muscles in the soft palate area), or idiopathic stapedial muscle spasm may represent the underlying cause of pulsatile tinnitus.
Extraadrenal pheochromocytoma
MedGen UID:
263453
Concept ID:
C1257877
Neoplastic Process
A benign or malignant sympathetic paraganglioma arising from paraganglia outside the adrenal gland. Clinical symptoms are related to secretion of catecholamines. Representative examples include the superior and inferior paraaortic and bladder paragangliomas.
Episodic paroxysmal anxiety
MedGen UID:
340203
Concept ID:
C1854339
Finding
Recurrent attacks of severe anxiety, whose occurence is not restricted to any particular situation or set of circumstances and is therefore unpredictable.
Elevated circulating catecholamine level
MedGen UID:
871156
Concept ID:
C4025629
Finding
An abnormal increase in catecholamine concentration in the blood.
Hypertension associated with pheochromocytoma
MedGen UID:
871214
Concept ID:
C4025693
Disease or Syndrome
A type of hypertension associated with pheochromocytoma.
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.

Professional guidelines

PubMed

Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee.
Genet Med 2015 Jan;17(1):70-87. Epub 2014 Nov 13 doi: 10.1038/gim.2014.147. PMID: 25394175
ACMG Board of Directors.
Genet Med 2015 Jan;17(1):68-9. Epub 2014 Nov 13 doi: 10.1038/gim.2014.151. PMID: 25356965
Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr; Endocrine Society.
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Can Urol Assoc J 2013 Sep-Oct;7(9-10):319-23. doi: 10.5489/cuaj.1496. PMID: 24319509Free PMC Article
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics.
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. PMID: 23788249Free PMC Article
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External

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

Recent clinical studies

Etiology

Knie B, Plotkin M, Zschieschang P, Prasad V, Moskopp D
Nuklearmedizin 2016;55(1):34-40. Epub 2016 Jan 7 doi: 10.3413/Nukmed-0755-15-07. PMID: 26740102
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
Mohyuddin N, Ferrer K, Patel U
Ear Nose Throat J 2013 Feb;92(2):E20-3. PMID: 23460222
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

Knie B, Plotkin M, Zschieschang P, Prasad V, Moskopp D
Nuklearmedizin 2016;55(1):34-40. Epub 2016 Jan 7 doi: 10.3413/Nukmed-0755-15-07. PMID: 26740102
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
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
Maeda M, Funahashi Y, Katoh M, Fujita T, Tsuruta K, Gotoh M
Aktuelle Urol 2013 Sep;44(5):381-2. Epub 2013 Jun 27 doi: 10.1055/s-0033-1345147. PMID: 23807799
Mohyuddin N, Ferrer K, Patel U
Ear Nose Throat J 2013 Feb;92(2):E20-3. PMID: 23460222

Therapy

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Bomanji J, Britton KE, Ur E, Hawkins L, Grossman AB, Besser GM
Nucl Med Commun 1993 Oct;14(10):856-61. 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. PMID: 8233228

Clinical prediction guides

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
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