The clinical phenotype of SDHC-associated hereditary paraganglioma syndrome (PGL3).
BACKGROUND
Mutations in the genes encoding subunits of the succinate dehydrogenase complex cause hereditary paraganglioma syndromes. Although the phenotypes associated with the more commonly mutated genes, SDHB and SDHD, are well described, less is known about SDHC-associated paragangliomas.


OBJECTIVE
To describe functionality, penetrance, number of primary tumors, biological behavior, and location of paragangliomas associated with SDHC mutations.


METHODS
Families with an SDHC mutation were identified through a large cancer genetics registry. A retrospective chart review was conducted with a focus on patient and tumor characteristics. In addition, clinical reports on SDHC-related paragangliomas were identified in the medical literature to further define the phenotype and compare findings.


METHODS
A cancer genetics clinic and registry at a tertiary referral center.


METHODS
Eight index patients with SDHC-related paraganglioma were identified.


RESULTS
Three of the eight index patients had mediastinal paraganglioma and four of the eight patients had more than one paraganglioma. Interestingly, the index patients were the only affected individuals in all families. When combining these index cases with reported cases in the medical literature, the mediastinum is the second most common location for SDHC-related paraganglioma (10% of all tumors), occurring in up to 13% of patients.


CONCLUSIONS
Our findings suggest that thoracic paragangliomas are common in patients with SDHC mutations, and imaging of this area should be included in surveillance of mutation carriers. In addition, the absence of paragangliomas among at-risk relatives of SDHC mutation carriers suggests a less penetrant phenotype as compared to SDHB and SDHD mutations.
Department of Internal Medicine, Divisions of Metabolism Endocrinology and Diabetes (T.E., R.J.A.), Molecular Medicine and Genetics (J.N.E., V.M.R.), and Gastroenterology (E.M.S.), Department of Human Genetics (M.L.M.), and Department of Otolaryngology-Head and Neck Surgery (H.A.A.) at the University of Michigan Hospital and Health Systems, Ann Arbor, Michigan 48109; and Norris Cancer Center (S.B.G.), University of Southern California, Los Angeles, California 90033.
Tobias
T
Else
Monica L
ML
Marvin
Jessica N
JN
Everett
Stephen B
SB
Gruber
H Alexander
HA
Arts
Elena M
EM
Stoffel
Richard J
RJ
Auchus
Victoria M
VM
Raymond
D000293:Adolescent; D000328:Adult; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006258:Head and Neck Neoplasms / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D008479:Mediastinal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000453:epidemiology / Q000235:genetics*; D010235:Paraganglioma / Q000453:epidemiology / Q000235:genetics*; D019683:Penetrance; D010641:Phenotype; D012042:Registries / Q000706:statistics & numerical data; D012189:Retrospective Studies; D013577:Syndrome; D055815:Young Adult
D008565:Membrane Proteins; C108096:SDHC protein, human