title: VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality.
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 carrying VHL 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 VHL germline 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 of VHL 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.
authors.affiliation: Department of Nephrology and Hypertension, Albert-Ludwigs-University, Freiburg, Germany. bender@med1.ukl.uni-freiburg.de
authors.forename: B U
authors.initials: BU
authors.lastname: Bender
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: M
authors.initials: M
authors.lastname: Olschewski
authors.forename: D P
authors.initials: DP
authors.lastname: Berger
authors.forename: J
authors.initials: J
authors.lastname: Laubenberger
authors.forename: C
authors.initials: C
authors.lastname: Altehöfer
authors.forename: G
authors.initials: G
authors.lastname: Kirste
authors.forename: M
authors.initials: M
authors.lastname: Orszagh
authors.forename: V
authors.initials: V
authors.lastname: van Velthoven
authors.forename: H
authors.initials: H
authors.lastname: Miosczka
authors.forename: D
authors.initials: D
authors.lastname: Schmidt
authors.forename: H P
authors.initials: HP
authors.lastname: Neumann
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000798:Angiomatosis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D018325:Hemangioblastoma / Q000235:genetics; D006801:Humans; D008025:Ligases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019683:Penetrance; D010673:Pheochromocytoma / Q000235:genetics; D017354:Point Mutation; D016019:Survival Analysis; D015996:Survival Rate; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000401:mortality
chemical_list: D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human