Von Hippel-Lindau (VHL) disease: distinct phenotypes suggest more than one mutant allele at the VHL locus

Gm, Glenn; Ln, Daniel; Choyke, Peter L.; Wm, Linehan; Oldfield, Edward H.; Mb, Gorin; Hosoe, Shigeto; Latif, Farida; Weiss, Gary H.; Walther, McClellan M.

doi:10.1007/bf00204184

Cited by 64 publications

(27 citation statements)

References 18 publications

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“…8 9 Our present study which includes comprehensive clinical investigation of 125 eligible subjects with the VHL c.505 T/C germline mutation followed by estimation of the overall penetrance by cumulative incidence functions showed that this mutation had an almost complete penetrance (>95% at 75 years). In contrast, the mortality and survival rate is surprisingly comparable to those of the general population of Germany.…”

Section: Discussionmentioning

confidence: 70%

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

Bender

Eng

Olschewski

et al. 2001

Journal of Medical Genetics

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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 eVect. 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. (J Med Genet 2001;38:508-514)

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Section: Discussionmentioning

confidence: 70%

“…In addition, there are two large families with this mutation in Pennsylvania,5 9 of which at least one originates from the Black Forest. This family was traced to the Schuttertal, a circumscribed area of the Black Forest, and one branch probably migrated from Germany to the USA in the early 1800s 8.…”

mentioning

confidence: 99%

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

Bender

Eng

Olschewski

et al. 2001

Journal of Medical Genetics

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“…Thus, just as Nedd4-1 elevation in a subgroup of hepatocellular carcinomas results in decreased content of Spry2 and a poor outcome (22), it is possible that pVHL elevation in certain hepatocellular carcinomas may result in decreased levels of Spry2 contributing to the growth and progression of these tumors. In von Hippel-Lindau patients, pVHL deficiency leads to development of hemangio- mas and clear cell renal carcinomas (53,54). However, nothing is presently known concerning whether or not pVHL deficiency in these patients alters the levels of Spry isoforms and whether Spry proteins modulate renal clear cell carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cellular Levels of Sprouty2 Protein by Prolyl Hydroxylase Domain and von Hippel-Lindau Proteins

Anderson

Nordquist

Gao

et al. 2011

Journal of Biological Chemistry

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Background: Sprouty2 (Spry2) inhibits the actions of receptor tyrosine kinases (RTK) during development and disease. Results: Stability of Spry2 is regulated by prolyl hydroxylation and binding to von Hippel-Lindau protein-associated E3 ligase. Conclusion: PHD-and pVHL-mediated regulation of cellular levels of Spry2 modulates its ability to inhibit signaling by RTKs. Significance: These findings provide new insights into modulation of levels of Spry2 to regulate RTK actions in disease.

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“…Prior to the cloning of the von Hippel-Lindau disease gene, it was suggested that the disease's phenotypic expression might result from allelic heterogeneity. The cloning efforts have identified a number of different types of mutations including deletions, insertions and point mutations [11]. Whether the variety of mutations explains the variable expression of von Hippel-Lindau disease remains to be seen.…”

Section: Discussionmentioning

confidence: 99%

Von Hippel-Lindau disease presenting as pancreatic neuroendocrine tumour

et al. 1995

Vichows Archiv A Pathol Anat

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A 21-year-old woman with a family history of von Hippel-Lindau disease presented with a mass in the head of the pancreas. Light microscopic features of the tumour suggested neuroendocrine differentiation and although it displayed positive immunostaining for the antigens expected in a neuroendocrine neoplasm, S-100 staining was also present. This unusual feature prompted further evaluation by routine and post-embedding protein-A gold immunoelectron microscopy, which demonstrated the presence of neuroendocrine granules. Tumour cell DNA content was normal by flow cytometry. Although this patient exhibited no other signs of von Hippel-Lindau disease, the presence of a pancreatic tumour with neuroendocrine differentiation demonstrated that she was affected. Future surveillance and genetic counselling will be influenced by this diagnosis.

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Von Hippel-Lindau (VHL) disease: distinct phenotypes suggest more than one mutant allele at the VHL locus

Cited by 64 publications

References 18 publications

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

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

Regulation of Cellular Levels of Sprouty2 Protein by Prolyl Hydroxylase Domain and von Hippel-Lindau Proteins

Von Hippel-Lindau disease presenting as pancreatic neuroendocrine tumour

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