Impact of screening kindreds for SDHD p.Cys11X as a common mutation associated with paraganglioma syndrome type 1.
OBJECTIVE
Germline mutations of the genes SDHB, SDHC, and SDHD predispose to paraganglioma syndromes. Mutation-specific counseling, risk assessment, and management recommendations ideally should be performed. Here, we provide data for a single common mutation of the SDHD gene.


METHODS
The European-American Pheochromocytoma-Paraganglioma Registry served as the source for unrelated index cases affected by pheochromocytoma or paraganglioma. Patients with the SDHD c.33 C-->A (p.Cys11X) germline mutations were reinvestigated by whole-body magnetic resonance imaging and 24-h urinary catecholamine assay. First-degree relatives underwent genetic testing and those testing positive had same clinical investigations. Microsatellite analyses were used to test the hypothesis that all index cases were related and the mutation is a founding one.


RESULTS
Sixteen index cases with the mutation SDHD p.Cys11X are registered. After testing their relatives, there were a total of 25 mutation carriers. We excluded seven subjects who inherited the mutation from the mother because of maternal imprinting. Thus, 18 mutation carriers were clinically affected. Among these 16 (89%) had head and neck paragangliomas, six (33%) thoracic tumors, six (33%) extraadrenal retroperitoneal, and five (28%) intraadrenal. Of note, 16 (89%) had multiple tumors at first diagnosis, and one (5%) had signs of malignancy during follow-up. Overall penetrance was 100% at age 54. Haplotype analyses revealed evidence for a founder effect.


CONCLUSIONS
The SDHD p.Cys11X mutation is a founding mutation associated with a high penetrance for paraganglial tumors of the skull base, neck, thorax, and retroperitoneum in the first four decades of life and, rarely, with malignancy.
Peczkowska
Mariola
M
Department of Hypertension, Institute of Cardiology, 04-628 Warsaw, Poland.
Erlic
Zoran
Z
Hoffmann
Michael M
MM
Furmanek
Mariusz
M
Cwikla
Jaroslaw
J
Kubaszek
Agata
A
Prejbisz
Aleksander
A
Szutkowski
Zbigniew
Z
Kawecki
Andrzej
A
Chojnowski
Krzysztof
K
Lewczuk
Anna
A
Litwin
Mieczyslaw
M
Szyfter
Witold
W
Walter
Martin A
MA
Sullivan
Maren
M
Eng
Charis
C
Januszewicz
Andrzej
A
Neumann
Hartmut P H
HP
D000328:Adult; D017668:Age of Onset; D002395:Catecholamines / Q000652:urine; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D005820:Genetic Testing; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D048631:Micronucleus, Germline; D018895:Microsatellite Repeats; D009154:Mutation / Q000502:physiology; D010235:Paraganglioma / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery; D019683:Penetrance; D010673:Pheochromocytoma / Q000235:genetics; D012042:Registries; D018570:Risk Assessment; D013385:Succinate Dehydrogenase / Q000235:genetics*; D055815:Young Adult
D002395:Catecholamines; C491545:SDHD protein, human; D013385:Succinate Dehydrogenase