Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.
BACKGROUND
The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations.


OBJECTIVE
Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations.


METHODS
The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland.


METHODS
Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined.


RESULTS
SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008).


CONCLUSIONS
For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.
Benn
Diana E
DE
Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia.
Gimenez-Roqueplo
Anne-Paule
AP
Reilly
Jennifer R
JR
Bertherat
Jérôme
J
Burgess
John
J
Byth
Karen
K
Croxson
Michael
M
Dahia
Patricia L M
PL
Elston
Marianne
M
Gimm
Oliver
O
Henley
David
D
Herman
Philippe
P
Murday
Victoria
V
Niccoli-Sire
Patricia
P
Pasieka
Janice L
JL
Rohmer
Vincent
V
Tucker
Kathy
K
Jeunemaitre
Xavier
X
Marsh
Deborah J
DJ
Plouin
Pierre-François
PF
Robinson
Bruce G
BG
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D002648:Child; D015331:Cohort Studies; D005838:Genotype; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010235:Paraganglioma / Q000235:genetics*; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics
D007506:Iron-Sulfur Proteins; D021122:Protein Subunits; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase