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This version published online on November 29, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1862
A more recent version of this article appeared on March 1, 2006
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*OMIM
*Substance via MeSH
Medline Plus Health Information
*Pheochromocytoma

Submitted on August 17, 2005
Accepted on November 17, 2005

Clinical presentation and penetrance of Pheochromocytoma/ Paraganglioma syndromes

Diana E. Benn, Anne-Paule Gimenez-Roqueplo, Jennifer R. Reilly, Jérôme Bertherat, John Burgess, Karen Byth, Michael Croxson, Patricia L.M. Dahia, Marianne Elston, Oliver Gimm, David Henley, Philippe Herman, Victoria Murday, Patricia Niccoli-Sire, Janice L. Pasieka, Vincent Rohmer, Kathy Tucker, Xavier Jeunemaitre, Deborah J. Marsh, Pierre-François Plouin, Bruce G. Robinson*, and for the International SDH Consortium

Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney, Australia (DE Benn PhD, JR Reilly BComm, DJ Marsh PhD, BG Robinson MD, MSc, FRACP) and Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia (BG Robinson); Hereditary Cancer Clinic, Prince of Wales Hospital and School of Medicine, University of New South Wales, Sydney, New South Wales, Australia (K Tucker MBBS FRACP); NHMRC Clinical Trials Centre, University of Sydney, Australia (K Byth PhD); Department of Endocrinology, Royal Hobart Hospital, Tasmania, Australia (J Burgess MD FRACP); Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia (D Henley MBBS (Hons); Department of Endocrinology, Greenlane Clinical Centre, Auckland, New Zealand (M Croxson MBChB FRACP); Department of Endocrinology, Waikato Hospital, Hamilton, New Zealand (M Elston MBChB); Department of Genetics (AP Gimenez-Roqueplo MD PhD, X Jeunemaitre MD PhD) and Department of Hypertension (PF Plouin MD PhD), Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, INSERM U36, Collège de France, University Paris 5, France; Department of Otorhinolaryngology and Head and Neck Surgery, Hôpital Lariboisière, Assistance Publique des Hopitaux de Paris, France (P Herman, MD PhD); Department of Endocrinology, INSERM U567, Hôpital Cochin Assistance Publique des Hôpitaux de Paris, University Paris 5, France (J Bertherat MD PhD); Department of Endocrinology, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille, France (P Niccoli-Sire MD); Department of Endocrinology, Hôpital d'Angers, Angers, France (V Rohmer MD); PGL. NET network (AP Gimenez-Roqueplo, J Bertherat, X Jeunemaitre, P Niccoli-Sire, V Rohmer, P Herman, PF Plouin); COMETE network (AP Gimenez-Roqueplo, J Bertherat, X Jeunemaitre, PF Plouin); Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany (O Gimm MD); West of Scotland, Regional Genetics Services, Yorkhill, Scotland (V Murday BSc FRCP); Department of Surgery, Faculty of Medicine, University of Calgary, Calgary, Canada (J Pasieka MD FRCSC FACS); Departments Medicine and Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, Texas, USA (P Dahia MD PhD)

* To whom correspondence should be addressed. E-mail: bgr{at}med.usyd.edu.au.

Context: The identification of succinate dehydrogenase (SDH) gene mutations in Pheochromocytoma/Paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations.

Objective: 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.

Design, Setting and Participants: 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 to September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States of America, Canada and Scotland.

Main Outcome Measures: 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 extra-adrenal 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 yr 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, extra-adrenal (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 extra-adrenal pheochromocytoma.
Key words: pheochromocytoma • paraganglioma • succinate dehydrogenase subunit B (SDHB) • succinate dehydrogenase subunit D (SDHD)




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