title: 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.affiliation: Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nielsen
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Rubinstein
authors.forename: Darcy L
authors.initials: DL
authors.lastname: Thull
authors.forename: Michaele J
authors.initials: MJ
authors.lastname: Armstrong
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.forename: Linwah
authors.initials: L
authors.lastname: Yip
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Tisherman
authors.forename: Sally E
authors.initials: SE
authors.lastname: Carty
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics; D017668:Age of Onset; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009386:Neoplastic Syndromes, Hereditary; D010235:Paraganglioma / Q000235:genetics* / Q000401:mortality; D010375:Pedigree; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics* / Q000401:mortality; D025521:Tumor Suppressor Proteins; D014481:United States; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000401:mortality
chemical_list: D025521:Tumor Suppressor Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein