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.
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 VHLc.505 T/C mutation carriers. A total of 125 eligible subjects carrying VHLc.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 VHLc.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: G M Glenn; L N Daniel; P Choyke; W M Linehan; E Oldfield; M B Gorin; S Hosoe; F Latif; G Weiss; M Walther Journal: Hum Genet Date: 1991-06 Impact factor: 4.132
Authors: Marie Louise Mølgaard Binderup; Michael Galanakis; Esben Budtz-Jørgensen; Michael Kosteljanetz; Marie Luise Bisgaard Journal: Eur J Hum Genet Date: 2016-12-14 Impact factor: 4.246
Authors: Yves Pastore; Katerina Jedlickova; Yongli Guan; Enli Liu; James Fahner; Henrik Hasle; Jaroslav F Prchal; Josef T Prchal Journal: Am J Hum Genet Date: 2003-07-03 Impact factor: 11.025
Authors: Elisa Majounie; Alan E Renton; Kin Mok; Elise G P Dopper; Adrian Waite; Sara Rollinson; Adriano Chiò; Gabriella Restagno; Nayia Nicolaou; Javier Simon-Sanchez; John C van Swieten; Yevgeniya Abramzon; Janel O Johnson; Michael Sendtner; Roger Pamphlett; Richard W Orrell; Simon Mead; Katie C Sidle; Henry Houlden; Jonathan D Rohrer; Karen E Morrison; Hardev Pall; Kevin Talbot; Olaf Ansorge; Dena G Hernandez; Sampath Arepalli; Mario Sabatelli; Gabriele Mora; Massimo Corbo; Fabio Giannini; Andrea Calvo; Elisabet Englund; Giuseppe Borghero; Gian Luca Floris; Anne M Remes; Hannu Laaksovirta; Leo McCluskey; John Q Trojanowski; Vivianna M Van Deerlin; Gerard D Schellenberg; Michael A Nalls; Vivian E Drory; Chin-Song Lu; Tu-Hsueh Yeh; Hiroyuki Ishiura; Yuji Takahashi; Shoji Tsuji; Isabelle Le Ber; Alexis Brice; Carsten Drepper; Nigel Williams; Janine Kirby; Pamela Shaw; John Hardy; Pentti J Tienari; Peter Heutink; Huw R Morris; Stuart Pickering-Brown; Bryan J Traynor Journal: Lancet Neurol Date: 2012-03-09 Impact factor: 44.182