Alternative titles; symbols
ORPHA: 29072; DO: 0050773;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q23.3 | Pheochromocytoma/paraganglioma syndrome 3 | 605373 | Autosomal dominant | 3 | SDHC | 602413 |
A number sign (#) is used with this entry because of evidence that pheochromocytoma/paraganglioma syndrome-3 (PPGL3) is caused by heterozygous mutation in the SDHC gene (602413), which encodes subunit C of the succinate dehydrogenase complex, on chromosome 1q23.
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).
In a large German family with autosomal dominant hereditary paraganglioma, Niemann et al. (1999) excluded linkage to PGL1 and PGL2 (601650), suggesting the existence of a third locus. There was no evidence of maternal imprinting.
Niemann et al. (2001) described a family with maternally transmitted paraganglioma. The diagnosis had been histologically proven in 5 patients, and 1 patient had imaging findings consistent with a paraganglioma. Linkage studies indicated mapping to chromosome 1q21-q23.
In affected members of a family with PGL3, Niemann and Muller (2000) identified a heterozygous mutation in the SDHC gene (602413.0001).
Baysal et al. (2004) described a family with PGL3 in which an 8,372-bp deletion in the SDHC gene (602413.0003) was transmitted both maternally and paternally, without evidence of genomic imprinting. They also identified the deletion in an unrelated sporadic case. They concluded that hereditary paraganglioma with imprinted transmission is restricted to SDHD (602690) among complex II genes.
Schiavi et al. (2005) identified mutations in the SDHC gene in 5 (4%) of 121 index patients with head and neck paragangliomas from a European registry. Clinically, 4 patients had jugular paragangliomas, and 1 had a carotid body tumor. All were benign, and none were multifocal. None of the mutation carriers or their carrier family members had signs of pheochromocytoma. Of 371 patients with sporadic pheochromocytomas, there were none with SDHC mutations, 21 with SDHB (185470) mutations, and 21 with SDHD (602690) mutations. Schiavi et al. (2005) concluded that SDHC-associated tumors are not likely to be pheochromocytomas and are less likely to be malignant or multifocal compared to SDHB- or SDHD-associated tumors.
Hensen et al. (2012) determined the mutation frequency of 4 succinate dehydrogenase genes in a total of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma. Mutations were identified in 690 cases from 239 families. The most commonly affected gene in mutation carriers was SDHD (87.1%), followed by SDHAF2 (613019) (6.7%), SDHB (5.9%), and SDHC (0.3%). Almost 70% of all carriers had the founder mutation D92Y (602690.0004) in SDHD; approximately 89% of all SDH mutation carriers had 1 of 6 Dutch founder mutations. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere.
Baysal, B. E., Willett-Brozick, J. E., Filho, P. A. A., Lawrence, E. C., Myers, E. N., Ferrell, R. E. An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. J. Med. Genet. 41: 703-709, 2004. Note: Erratum: J. Med. Genet. 42: 582 only, 2005. [PubMed: 15342702] [Full Text: https://doi.org/10.1136/jmg.2004.019224]
Baysal, B. E. Hereditary paraganglioma targets diverse paraganglia. J. Med. Genet. 39: 617-622, 2002. [PubMed: 12205103] [Full Text: https://doi.org/10.1136/jmg.39.9.617]
Hensen, E. F., van Duinen, N., Jansen, J. C., Corssmit, E. P. M., Tops, C. M. J., Romijn, J. A., Vriends, A. H. J. T., van der Mey, A. G. L., Cornelisse, C. J., Devilee, P., Bayley, J. P. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin. Genet. 81: 284-288, 2012. [PubMed: 21348866] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01653.x]
Neumann, H. P. H., Pawlu, C., Peczkowska, M., Bausch, B., McWhinney, S. R., Muresan, M., Buchta, M., Franke, G., Klisch, J., Bley, T. A., Hoegerle, S., Boedeker, C. C., Opocher, G., Schipper, J., Januszewicz, A., Eng. C. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292: 943-951, 2004. Note: Erratum: JAMA 292: 1686 only, 2004. [PubMed: 15328326] [Full Text: https://doi.org/10.1001/jama.292.8.943]
Niemann, S., Becker-Follmann, J., Nurnberg, G., Ruschendorf, F., Sieweke, N., Hugens-Penzel, M., Traupe, H., Wienker, T. F., Reis, A., Muller, U. Assignment of PGL3 to chromosome 1 (q21-q23) in a family with autosomal dominant non-chromaffin paraganglioma. Am. J. Med. Genet. 98: 32-36, 2001. [PubMed: 11426453]
Niemann, S., Muller, U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genet. 26: 268-270, 2000. [PubMed: 11062460] [Full Text: https://doi.org/10.1038/81551]
Niemann, S., Steinberger, D., Muller, U. PGL3, a third, not maternally imprinted locus in autosomal dominant paraganglioma. Neurogenetics 2: 167-170, 1999. [PubMed: 10541590] [Full Text: https://doi.org/10.1007/s100480050078]
Schiavi, F., Boedeker, C. C., Bausch, B., Peczkowska, M., Gomez, C. F., Strassburg, T., Pawlu, C., Buchta, M., Salzmann, M., Hoffmann, M. M., Berlis, A., Brink, I., and 17 others. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA 294: 2057-2063, 2005. Note: Erratum: JAMA 295: 628 only, 2006. [PubMed: 16249420] [Full Text: https://doi.org/10.1001/jama.294.16.2057]