Long-term outcomes, branch-specific expressivity, and disease-related mortality in von Hippel-Lindau type 2A.

Abstract

Although a large kindred with familial pheochromocytoma (Pheo) and paraganglioma (PGL) was discovered in 1962 and later found to represent von Hippel-Lindau (VHL) type 2A (mutation Y112H), the phenotype lacks current characterization. Branch-specific expressivity was suspected based on oral family history. Family pedigree analysis, prospective interviews, and extensive record review were used to extend the pedigree, determine phenotype, examine branch-specific expression, and analyze mortality rates over 5 decades. In its 3 known affected branches the kindred now comprises 107 people with or at-risk for VHL, of whom 49 have been diagnosed and 35/49 (71%) are clinically affected. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. The mean ages for VHL and Pheo/PGL diagnosis were younger in successive generations. Branch II-4 predominately expressed RA, while branch II-5 predominantly expressed Pheo/PGL. Disease-specific mortality occurred early and was less frequent in successive generations. This analysis of Y112H VHL confirms a high cumulative risk for pheochromocytoma/paraganglioma. Over time, both age at diagnosis and disease-specific mortality have decreased. The observed branch-specific expressivity prompts further study of genetic and environmental disease modifiers in this large family.

• Authors: Sarah M Nielsen, Wendy S Rubinstein, Darcy L Thull, Michaele J Armstrong, Eleanor Feingold, Linwah Yip, Samuel A Tisherman, Sally E Carty
• Journal: Familial cancer (Fam Cancer) Vol. 10 Issue 4 Pg. 701-7 (Dec 2011) ISSN: 1573-7292 [Electronic] Netherlands
• PMID: 21713522 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Tumor Suppressor Proteins
• Von Hippel-Lindau Tumor Suppressor Protein

Topics

• Adrenal Gland Neoplasms (genetics)
• Age of Onset
• Female
• Humans
• Longitudinal Studies
• Male
• Neoplastic Syndromes, Hereditary
• Paraganglioma (genetics, mortality)
• Pedigree
• Phenotype
• Pheochromocytoma (genetics, mortality)
• Tumor Suppressor Proteins
• United States
• Von Hippel-Lindau Tumor Suppressor Protein
• von Hippel-Lindau Disease (genetics, mortality)