VHL C.505 T>C Mutation Confers A High Age Related Penetrance But ...

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• VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality

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PDF Original article VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality

1. Bernhard U Bendera,
2. Charis Engb,
3. Manfred Olschewskic,
4. Dietmar P Bergerd,
5. Jörg Laubenbergere,
6. Carsten Altehöfere,
7. Günter Kirstef,
8. Miro Orszaghg,
9. Vera van Velthoven,
10. Henning Miosczkag,
11. Dieter Schmidt,
12. Hartmut P H Neumanna

1. aDepartment of Nephrology and Hypertension, Albert-Ludwigs-University, Freiburg, Germany, bClinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA, and CRC Human Cancer Genetics Research Group, University of Cambridge, Cambridge, UK, cInstitute of Medical Biometry and Informatics, Albert-Ludwigs-University, Freiburg, Germany, dDepartment of Oncology, Albert-Ludwigs-University, Freiburg, Germany, eDepartment of Radiology, Albert-Ludwigs-University, Freiburg, Germany, fDepartment of Surgery, Albert-Ludwigs-University, Freiburg, Germany, gDepartment of Neuroradiology, Albert-Ludwigs-University, Freiburg, Germany

1. Dr Bender, Medizinische Universitätsklinik, Hugstetterstrasse 55, 79106 Freiburg, Germany, bender{at}med1.ukl.uni-freiburg.de

Abstract

BACKGROUND Germline mutations of the VHL gene cause von Hippel-Lindau syndrome (VHL). In southern Germany, a specific mutation in this gene, c.505 T>C, is one of the most frequent alterations owing to a founder effect.

METHODS This study was conducted to evaluate morbidity, specific clinical risk profile, and mortality among a series of VHL c.505 T/C mutation carriers. A total of 125 eligible subjects carryingVHL c.505 T/C underwent ophthalmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, the spinal cord, and the abdomen. Age related penetrance, morbidity, and mortality were assessed.

RESULTS Frequently observed lesions were phaeochromocytoma (47%), retinal angiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was symptomatic in 47% of subjects; 30% were asymptomatic despite the presence of at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estimated at 48% by 35 years and 88% by 70 years. In contrast to the only existing published report based on patients with presumably unselected VHLgermline mutations, the mortality rate for c.505 T/C mutation carriers is comparable to that of the general population of Germany.

CONCLUSIONS Our results are an important example that a specific genotype, at least in the case ofVHL c.505 T/C, can favourably impact on mortality despite a high age related penetrance. Our study also indirectly provides objective data which might be useful to the life and health insurance industry; it would appear that c.505 T>C mutation positive subjects have similar disease specific mortality to that of the general population owing to a combination of phenotype and timely detection of mutation carrier status followed by aggressive clinical screening and, if necessary, treatment.

• VHL gene
• c.505 T/C germline mutation
• VHL morbidity
• VHL mortality

https://doi.org/10.1136/jmg.38.8.508

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• VHL gene
• c.505 T/C germline mutation
• VHL morbidity
• VHL mortality

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