Details of Disease

General Information of Disease (ID: DISP9K7L)

• Disease Name: Hereditary pheochromocytoma-paraganglioma
• Synonyms: hereditary paraganglioma-pheochromocytoma; SDHx-related paraganglioma-pheochromocytoma; familial pheochromocytoma-paraganglioma; hereditary pheochromocytoma-paraganglioma
• Definition: Hereditary paraganglioma-pheochromocytomas (PGL/PCC) are rare neuroendocrine tumors represented by paragangliomas (occurring in any paraganglia from the skull base to the pelvic floor) and pheochromocytomas (adrenal medullary paragangliomas).
• Disease Hierarchy:
  DISFS818: Adrenal gland disorder
  DISP9K7L: Hereditary pheochromocytoma-paraganglioma
• Disease Identifiers:
  MONDO ID: MONDO_0017366
  UMLS CUI: C1708353
  MedGen ID: 313270
  Orphanet ID: 29072

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 17 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
VHL	OT2C3JRN	Supportive	Autosomal dominant	[1]
KMT2D	OTTVHCLY	Limited	Biomarker	[10]
MITF	OT6XJCZH	Limited	Biomarker	[11]
DLST	OTBDF9HJ	Supportive	Autosomal dominant	[12]
FH	OTEQWU6Q	Supportive	Autosomal dominant	[13]
KIF1B	OTI1XQTO	Supportive	Autosomal dominant	[14]
MDH2	OT7364GY	Supportive	Autosomal dominant	[15]
NF1	OTC29NHH	Supportive	Autosomal dominant	[16]
SLC25A11	OT7EVFBK	Supportive	Autosomal dominant	[9]
MEN1	OTN6U6V0	moderate	Biomarker	[17]
MAX	OTKZ0YKM	Definitive	Autosomal dominant	[6]
SDHA	OTOJ8QFF	Definitive	Autosomal dominant	[6]
SDHAF2	OT0UG9H5	Definitive	Autosomal dominant	[6]
SDHB	OTRE1M1T	Definitive	Autosomal dominant	[6]
SDHC	OTC8G2MX	Definitive	Autosomal dominant	[6]
SDHD	OTYZ8XRH	Definitive	Autosomal dominant	[6]
TMEM127	OTYHUXC1	Definitive	Autosomal dominant	[6]

This Disease Is Related to 11 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
EGLN2	TTMHFRY	Limited	Biomarker	[2]
GDNF	TTF23ML	Limited	Biomarker	[1]
MERTK	TTO7LKR	Limited	Biomarker	[3]
MET	TTNDSF4	Limited	Biomarker	[3]
EPAS1	TTWPA54	Disputed	Biomarker	[4]
VHL	TTEMWSD	Supportive	Autosomal dominant	[1]
EGLN1	TT9ISBX	moderate	Biomarker	[2]
RET	TT4DXQT	Definitive	Biomarker	[5]
SDHD	TTVH9W8	Definitive	Autosomal dominant	[6]
SDHD	TTVH9W8	Definitive	CausalMutation	[7]
VHL	TTEMWSD	Definitive	Biomarker	[8]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC25A11	DT0YAUQ	Supportive	Autosomal dominant	[9]

References

• [1] Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Hum Mol Genet. 1997 Jul;6(7):1051-6. doi: 10.1093/hmg/6.7.1051.
• [2] Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia.J Mol Med (Berl). 2015 Jan;93(1):93-104. doi: 10.1007/s00109-014-1205-7. Epub 2014 Sep 30.
• [3] Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas.Clin Cancer Res. 2016 May 1;22(9):2301-10. doi: 10.1158/1078-0432.CCR-15-1841. Epub 2015 Dec 23.
• [4] Analysis of protein-coding genetic variation in 60,706 humans.Nature. 2016 Aug 18;536(7616):285-91. doi: 10.1038/nature19057.
• [5] Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma.Cancer Cell. 2017 Feb 13;31(2):181-193. doi: 10.1016/j.ccell.2017.01.001. Epub 2017 Feb 2.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice.J Clin Endocrinol Metab. 2015 May;100(5):E710-9. doi: 10.1210/jc.2014-4297. Epub 2015 Feb 19.
• [8] Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma.Hum Mol Genet. 2011 Oct 15;20(20):3974-85. doi: 10.1093/hmg/ddr324. Epub 2011 Jul 22.
• [9] Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas. Cancer Res. 2018 Apr 15;78(8):1914-1922. doi: 10.1158/0008-5472.CAN-17-2463. Epub 2018 Feb 5.
• [10] Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene.Genes Chromosomes Cancer. 2015 Sep;54(9):542-54. doi: 10.1002/gcc.22267. Epub 2015 May 29.
• [11] The MITF, p.E318K Variant, as a Risk Factor for Pheochromocytoma and Paraganglioma.J Clin Endocrinol Metab. 2016 Dec;101(12):4764-4768. doi: 10.1210/jc.2016-2103. Epub 2016 Sep 28.
• [12] Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas. Am J Hum Genet. 2019 May 2;104(5):1008-1010. doi: 10.1016/j.ajhg.2019.04.010.
• [13] Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014 May 1;23(9):2440-6. doi: 10.1093/hmg/ddt639. Epub 2013 Dec 13.
• [14] The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 2008 Apr 1;22(7):884-93. doi: 10.1101/gad.1648608. Epub 2008 Mar 11.
• [15] Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. J Natl Cancer Inst. 2015 Mar 11;107(5):djv053. doi: 10.1093/jnci/djv053.
• [16] Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma. J Intern Med. 2019 Feb;285(2):187-204. doi: 10.1111/joim.12869. Epub 2019 Jan 15.
• [17] Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.J Clin Endocrinol Metab. 2015 Mar;100(3):E531-41. doi: 10.1210/jc.2014-3399. Epub 2014 Dec 12.