FaCD Online Syndrome Fact Sheet

Last updated: 30 Jan 2013

Name: Familial Paragangliomas

Synonym: Hereditary Glomus Tumors, Familial Paragangliomas, Hereditary Paragangliomas, type 1-3: PGL1, PGL2, PGL3, incl. Familial Carotid Body Paraganglioma and Sensorineural Hearing Loss

Mode of Inheritance: AD/AD + maternal impr (PGL1 and 2)

Genes

SDHA, mapped to 5p15
SDHAF2/SDH5, mapped to 11q13.1
SDHB, mapped to 1p36.1-p35
SDHC, mapped to 1q21
SDHD, mapped to 11q23

Tumor features

gastrointestinal stromal tumor (GIST)
neuroblastoma, adrenal
neuroblastoma, extra-adrenal
paraganglioma, chromaffin (extra-adrenal pheochromocytoma)
paraganglioma, nonchromaffin (incl.: glomus tumor/chemodectoma)
pheochromocytoma
renal cell cancer of solid histology (not further specified)
renal cell cancer, chromophobe
renal cell cancer, clear-cell (Grawitz tumor)
renal cell cancer, papillary
renal oncocytoma
thyroid cancer, papillary

Tumor features (possible)

breast cancer

Non-tumor features

hearing loss, neurosensory

Comment

This disorder is characterized by the development of nonchromaffin paragangliomas (also known as chemodectomas or glomus tumors, not to be confused with cutaneous glomus tumors) at the site of the carotid body (glomus caroticum), and less often at the site of the glomus jugulare and glomus vagale.[1-7]. In patients/families with non-chromaffin paraganglioma, adrenal and extra-adrenal pheochromocytomas have been observed as well[8;9]. SDHA,B,C, and D germline mutations have also been associated with GIST (see Familial GIST).

Head and neck paragangliomas associated with SDHC (PGL3) mutations are virtually always benign and seldom multifocal.
SDHD(PGL1) mutations are associated with multifocal paragangliomas, infrequent malignancy, and extraadrenal pheochromocytoma.Familial carotid body paragangliomas and sensorineural hearing-loss has been reported as a separate entity[19]. SDHD mutations have been detected in families with this phenotype[20].
SDHB (PGL4) mutations are associated with familial as well as single cases of paraganglioma, later age of onset, extraadrenal tumors, and a higher rate of malignancy. [10-15,25]. Penetrance is probably much lower in SDHB families than in SDHD families[26]. Germline SDHB mutations can cause early-onset renal cell carcinoma (RCC)[16,22]. Henderson et al [22] reviewed SDHB-associated renal cancer. Histological types observed were clear-cell RCC,solid histology (not further specified), papillary type II, eosinophilic chomophobe, oncocytoma and mixed oncocytoma/chromophobe. Ages at diagnos ranged from 16 years to 73 years. Adrenal neuroblastoma and a composite extra-adrenal paraganglioma/neuroblastoma has been reported in a few patients with a germline SDHB deletion[23,24].
Ni et al[21] note that 1% to 5% of SDHB/SDHD mutation carriers have renal cell cancer or papillary thyroid tumors. Therefore, there is an overlap with Cowden syndrome. Ni et al performed SDHB/D mutation analysis in CS/CS-like, PTEN mutation negative and indeed detected mutations/variants in these genes. Compared to PTEN mutation patients, carriers of SDH mutations/variants were enriched for carcinomas of the female breast, thyroid and kidney[21].
A germline SDHA mutation has recently been identified in a woman with a hormonal active extra-adrenal paraganglioma/pheochromocytoma. Evidence to support the pathogenic nature of the mutation was presented; no family data were reported[30].

As a general rule, germline SDHD mutations only cause disease if the mutation is paternally inherited, a classic example of genomic imprinting. However, exceptions to this rule possibly exist[17,18].Absence of SDHB protein staining in the tumour appears to predict germline SDHB, SDHC and SDHD mutations[27]. Germline mutations in SDHAF2, also known as SDH5, are probably very rare. They have recently been identified in a Dutch as well as in a Spanish paraganglioma family (PGL2)[28,29,31].

References

[1] Van Baars F, van den Broek P, Cremers C, Veldman J. Familial non-chromaffinic paragangliomas (glomus tumors) : clinical aspects. Laryngoscope 1981; 91(6):988-996.
[2] Mccaffrey TV, Meyer FB, Michels VV, Piepgras DG, Marion MS. Familial paragangliomas of the head and neck. Arch Otolaryngol Head Neck Surg 1994; 120(11):1211-1216.
[3] Kahn LB. Vagal body tumor (nonchromaffin paraganglioma, chemodectoma, and carotid body-like tumor) with cervical node metastasis and familial association: ultrastructural study and review. Cancer 1976; 38(6):2367-2377.
[4] Moore G, Yarington CT, Jr., Mangham CA, Jr. Vagal body tumors: diagnosis and treatment. Laryngoscope 1986; 96(5):533-536.
[5] Sobol SM, Dailey JC. Familial multiple cervical paragangliomas: report of a kindred and review of the literature. Otolaryngol Head Neck Surg 1990; 102(4):382-390.
[6] Lemaire M, Persu A, Hainaut P, De Plaen JF. Hereditary paraganglioma. J Int Med 1999; 246(1):113-116.
[7] Kohn JS, Raftery KB, Jewell ER. Familial carotid body tumors: a closer look. J Vasc Surg 1999; 29(4):649-653.
[8] Parkin JL. Familial multiple glomus tumors and pheochromocytomas. Ann Otol Rhinol Laryngol 1981; 90(1 Pt 1):60-63.
[9] Taschner P, Douwes Dekker PB, Jansen JC, Baysal BE, Bosch A, van Minderhout IH, Rosenberg EH, van der Mey AG, Brocker-Vriends A, van Ommen GJ, Cornelisse CJ, Devilee P. Mutations in the SDHD gene are not only involved in hereditary paragangliomas in the head and neck region, but also in adrenal and extra-adrenal pheochromocytomas. Am J Hum Genet 67[4 (suppl. 2)], 87. 2000. Ref Type: Abstract
[10] Dannenberg H, van Nederveen FH, Abbou M, Verhofstad AA, Komminoth P, de Krijger RR, Dinjens WN. Clinical characteristics of pheochromocytoma patients with germline mutations in SDHD. Journal of clinical oncology 2005; 23(9):1894-901.
[11] Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C, . Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA : the journal of the American Medical Association 2004; 292(8):943-51.
[12] Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW, Pacak K. Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. The Journal of clinical endocrinology and metabolism 2007; 92(3):779-86.
[13] Schiavi F, Boedeker CC, Bausch B, Peçzkowska M, Gomez CF, Strassburg T, Pawlu C, Buchta M, Salzmann M, Hoffmann MM, Berlis A, Brink I, Cybulla M, Muresan M, Walter MA, Forrer F, Välimäki M, Kawecki A, Szutkowski Z, Schipper J, Walz MK, Pigny P, Bauters C, Willet-Brozick JE, Baysal BE, Januszewicz A, Eng C, Opocher G, Neumann HP, . Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA : the journal of the American Medical Association 2005; 294(16):2057-63.
[14] Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M, Gimm O, Henley D, Herman P, Murday V, Niccoli-Sire P, Pasieka JL, Rohmer V, Tucker K, Jeunemaitre X, Marsh DJ, Plouin PF, Robinson BG. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. The Journal of clinical endocrinology and metabolism 2006; 91(3):827-36.
[15] Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peçzkowska M, Szmigielski C, Eng C, . Germ-line mutations in nonsyndromic pheochromocytoma. The New England journal of medicine 2002; 346(19):1459-66.
[16] Vanharanta S, Buchta M, McWhinney SR, Virta SK, Peçzkowska M, Morrison CD, Lehtonen R, Januszewicz A, Järvinen H, Juhola M, Mecklin JP, Pukkala E, Herva R, Kiuru M, Nupponen NN, Aaltonen LA, Neumann HP, Eng C. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. American journal of human genetics 2004; 74(1):153-9.
[17] Pigny P, Vincent A, Bauters CC, Bertrand M, de Montpreville VT, Crepin M, Porchet N, Caron P. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab 2008 May;93(5):1609-15
[18] Neumann HP, Erlic Z. Maternal transmission of symptomatic disease with SDHD mutation: fact or fiction?. The Journal of clinical endocrinology and metabolism 2008; 93(5):1573-5.
[19] Lord RS, Chambers AJ. Familial carotid body paragangliomas and sensorineural hearing-loss: a new syndrome. Cardiovascular surgery (London, England) 1999; 7(1):134-8.
[20] Badenhop RF, Cherian S, Lord RS, Baysal BE, Taschner PE, Schofield PR. Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. Genes, chromosomes & cancer 2001; 31(3):255-63.
[21] Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C. Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes. American journal of human genetics 2008; 83(2):261-268.
[22] Henderson A, Douglas F, Perros P, Morgan C, Maher ER. SDHB-associated renal oncocytoma suggests a broadening of the renal phenotype in hereditary paragangliomatosis. Fam Cancer. 2009 Jan 29. [Epub ahead of print]
[23] A Cascón, Í Landa, E López-Jiménez, A Díez-Hernández, M Buchta, C Montero-Conde, S Leskelä, L J Leandro-García1, R Letón, C Rodríguez-Antona, C Eng, H P H Neumann and M Robledo. Molecular characterisation of a common SDHB deletion in paraganglioma patients. J Med Genet. 2008 Apr;45(4):233-8
[24] R Armstrong, K L Greenhalgh, E Rattenberry, B Judd, R Shukla, P D Losty and E R Maher. Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma. Journal of Medical Genetics 2009;46:215-216.
[25] Cascón A, Pita G, Burnichon N, Landa I, López-Jiménez E, Montero-Conde C, Leskelä S, Leandro-García LJ, Letón R, Rodríguez-Antona C, Díaz JA, López-Vidriero E, González-Neira A, Velasco A, Matias-Guiu X, Gimenez-Roqueplo AP, Robledo M. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab. 2009 May;94(5):1701-5.
[26] Bayley JP, Grimbergen AE, van Bunderen PA, van der Wielen M, Kunst HP, Lenders JW, Jansen JC, Dullaart RP, Devilee P, Corssmit EP, Vriends AH, Losekoot M, Weiss MMThe first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients. BMC Med Genet. 2009 Apr 15;10:34.
[27] van Nederveen FH et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009 Jul 1. [Epub ahead of print]
[28] Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, Devilee P, Cremers CW, Schiffman JD, Bentz BG, Gygi SP, Winge DR, Kremer H, Rutter J. SDH5, a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma.Science. 2009 Jul 23. [Epub ahead of print]
[29] Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E, Hinojar-Gutierrez A, Timmers HJ, Hoefsloot LH, Hermsen MA, Suárez C, Hussain AK, Vriends AH, Hes FJ, Jansen JC, Tops CM, Corssmit EP, de Knijff P, Lenders JW, Cremers CW, Devilee P, Dinjens WN, de Krijger RR, Robledo M. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol. 2010 Jan 11. [Epub ahead of print]
[30] Burnichon N, Brière JJ, Libé R, Vescovo L, Rivière J, Tissier F, Jouanno E, Jeunemaitre X, Bénit P, Tzagoloff A, Rustin P, Bertherat J, Favier J, Gimenez-Roqueplo AP. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010 Aug 1;19(15):3011-20.
[31] Kunst HP, Rutten MH, de Mönnink JP, Hoefsloot LH, Timmers HJ, Marres HA, Jansen JC, Kremer H, Bayley JP, Cremers CW. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011 Jan 15;17(2):247-54.