Alternative titles; symbols
ORPHA: 29072; DO: 0050773;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p15.33 | Pheochromocytoma/paraganglioma syndrome 5 | 614165 | Autosomal dominant | 3 | SDHA | 600857 |
A number sign (#) is used with this entry because of evidence that pheochromocytoma/paraganglioma syndrome-5 (PPGL5) is caused by heterozygous mutation in the SDHA gene (600857) on chromosome 5p15.
Pheochromocytoma/paraganglioma syndrome-5 (PPGL5) 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).
Burnichon et al. (2010) reported a 32-year-old woman who developed a catecholamine-secreting extraadrenal paraganglioma. Clinical features included hypertension and hyperadrenergic symptoms, such as dizziness, tachycardia, and sweating. She had high concentrations of urinary normetanephrine, norepinephrine, and chromogranin A. The symptoms resolved after surgical resection of the tumor. There was no family history of the disorder.
Korpershoek et al. (2011) reported 6 additional unrelated patients with PGL5. All tumors occurred sporadically and in different locations: abdomen, bladder, thorax, vagal parasympathetic, carotid body parasympathetic, and pheochromocytoma.
In a woman with an extraadrenal paraganglioma, Burnichon et al. (2010) identified a heterozygous germline mutation in the SDHA gene (R589W; 600857.0005). Tumor tissue showed loss of heterozygosity (LOH) at the SDHA locus. In vitro functional expression studies in the yeast homolog showed that the mutation resulted in a loss of SDH activity and rendered the mutant SDHA protein more susceptible to proteolysis. Studies of tumor tissue from the patient showed lack of SDHA and SDHB (185470) expression. Transcriptome analysis of the patient's tumor showed a similar pattern as that of other SDH-subunit mutated paraganglioma tumors, including stabilization of HIF1A (603348), consistent with activation of a pseudohypoxic pathway and angiogenesis. The findings indicated that SDHA, like other SDH subunits, can act as a tumor suppressor gene. Analysis of a large series of paragangliomas and pheochromocytomas found LOH at the SDHA locus in only 9 (4.5%) of 202 tumors, suggesting that it is an infrequent event.
Korpershoek et al. (2011) found that 7 of 316 pheochromocytomas and paragangliomas, including the previously described SDHA-mutated paraganglioma described by Burnichon et al. (2010), were negative for SDHA immunostaining. All patients were found to carry a heterozygous mutation in the SDHA gene (600857.0005; 600857.0008-600857.0009), and all tumor tissue showed loss of heterozygosity for the wildtype SDHA allele. None of the patients had a family history of the disorder. All tumors were also negative for SDHB immunostaining, suggesting that impaired complex II formation results in SDHB degradation. The findings established SDHA as a tumor-suppressor gene.
In a 20-year-old woman with a renal paraganglioma, Welander et al. (2013) identified a heterozygous truncating mutation in the SDHA gene (R75X; 600857.0010).
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]
Burnichon, N,, Briere, J.-J., Libe, R., Vescovo, L., Riviere, J., Tissier, F., Jouanno, E., Jeunemaitre, X., Benit, P., Tzagoloff, A., Rustin, P., Bertherat, J., Favier, J., Gimenez-Roqueplo, A.-P. SDHA is a tumor suppressor gene causing paraganglioma. Hum. Molec. Genet. 19: 3011-3020, 2010. [PubMed: 20484225] [Full Text: https://doi.org/10.1093/hmg/ddq206]
Korpershoek, E., Favier, J., Gaal, J., Burnichon, N., van Gessel, B., Oudijk, L., Badoual, C., Gadessaud, N., Venisse, A., Bayley, J.-P., van Dooren, M. F., de Herder, W. W., Tissier, F., Plouin, P.-F., van Nederveen, F. H., Dinjens, W. N. M., Gimenez-Roqueplo, A.-P., de Krijger, R. R. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J. Clin. Endocr. Metab. 96: E1472-E1476, 2011. Note: Electronic Article. [PubMed: 21752896] [Full Text: https://doi.org/10.1210/jc.2011-1043]
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]
Welander, J., Garvin, S., Bohnmark, R., Isaksson, L., Wiseman, R. W., Soderkvist, P., Gimm, O. Germline SDHA mutation detected by next-generation sequencing in a young index patient with large paraganglioma. J. Clin. Endocr. Metab. 98: E1379-E1380, 2013. Note: Electronic Article. [PubMed: 23750034] [Full Text: https://doi.org/10.1210/jc.2013-1963]