1. The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family
- Author
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Annette H. J. T. Vriends, Jean-Pierre Bayley, Maaike Siemers, Eleonora P M Corssmit, Erik F. Hensen, Jan C. Oosterwijk, Jeroen C. Jansen, Peter Devilee, Andel G. L. van der Mey, Cees J. Cornelisse, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Targeted Gynaecologic Oncology (TARGON)
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pediatrics ,PHEOCHROMOCYTOMA ,SDHB CAUSE SUSCEPTIBILITY ,Adolescent ,Genetic counseling ,NETHERLANDS ,phaeochromocytoma ,Biology ,HEREDITARY GLOMUS TUMORS ,Article ,Pheochromocytoma ,Young Adult ,paraganglioma ,Germline mutation ,Paraganglioma ,Internal medicine ,Genetics ,medicine ,CAROTID-BODY ,Malignant Paraganglioma ,Humans ,inheritance ,HEAD ,Age of Onset ,penetrance ,Genetics (clinical) ,IMPRINTED GENE ,Family Characteristics ,COMPLEX-II ,Middle Aged ,medicine.disease ,NECK PARAGANGLIOMAS ,Penetrance ,paraganglioma phaeochromocytoma inheritance SDHD penetrance hereditary glomus tumors sdhb cause susceptibility neck paragangliomas complex-ii nonchromaffin paragangliomas imprinted gene carotid-body head pheochromocytoma netherlands ,Founder Effect ,SDHD ,Pedigree ,Succinate Dehydrogenase ,Endocrinology ,Amino Acid Substitution ,NONCHROMAFFIN PARAGANGLIOMAS ,Female ,Age of onset - Abstract
Germline mutations in SDHD predispose to the development of head and neck paragangliomas, and phaeochromocytomas. The risk of developing a tumor depends on the sex of the parent who transmits the mutation: paragangliomas only arise upon paternal transmission. In this study, both the risk of paraganglioma and phaeochromocytoma formation, and the risk of developing associated symptoms were investigated in 243 family members with the SDHD. D92Y founder mutation. By using the Kaplan-Meier method, age-specific penetrance was calculated separately for paraganglioma formation as defined by magnetic resonance imaging (MRI) and for paraganglioma-related signs and symptoms. Evaluating clinical signs and symptoms alone, the penetrance reached a maximum of 57% by the age of 47 years. When MRI detection of occult paragangliomas was included, penetrance was estimated to be 54% by the age of 40 years, 68% by the age of 60 years and 87% by the age of 70 years. Multiple tumors were found in 65% and phaeochromocytomas were diagnosed in 8% of paraganglioma patients. Malignant paraganglioma was diagnosed in one patient (3%). Although the majority of carriers of a paternally inherited SDHD mutation will eventually develop head and neck paragangliomas, we find a lower penetrance than previous estimates from studies based on predominantly index cases. The family-based study described here emphasizes the importance of the identification and inclusion of clinically unaffected mutation carriers in all estimates of penetrance. This finding will allow a more accurate genetic counseling and warrants a 'wait and scan' policy for asymptomatic paragangliomas, combined with biochemical screening for catecholamine excess in SDHD-linked patients. European Journal of Human Genetics (2010) 18, 62-66; doi:10.1038/ejhg.2009.112; published online 8 July 2009
- Published
- 2010