Longitudinal Analysis of Retinal Hemangioblastomatosis and Visual Function in Ocular von Hippel-Lindau Disease

Abstract

Objective Characterization of the structural and functional progression of ocular von Hippel-Lindau (VHL) disease and analysis of patient factors influencing disease progression. Design Retrospective analysis of a case series from a longitudinal observational study. Participants Two hundred and forty-nine participants with clinically-defined systemic VHL disease and greater than two years of ophthalmic follow-up. Methods Standardized scoring of ocular phenotype and systemic characteristics was performed at each study visit and analyzed longitudinally to determine progression of ocular VHL disease. Main Outcome Measures Measures evaluated include: visual acuity, features of ocular VHL disease (presence, location, number, and extent of retinal capillary hemangioblastomas [RCHs]), germline mutation in the VHL gene, demographics (age, sex, age of onset of ocular disease), and patient characteristics (smoking status, body mass index). Results A majority of participants demonstrated relative anatomical and functional stability in ocular VHL disease status over a mean follow-up period of 8.2±4.0 years. About three-quarters (73%) of participants without ocular VHL disease at baseline remained disease-free at the end of follow-up. Among eyes with ocular VHL disease at baseline, 88% did not develop RCH in a new retinal location, 70% remained stable in RCH number, and 79% remained stable in the extent of RCH involvement. Mean visual acuity for all study eyes (n = 498) decreased by 5.1±0.6 letters across follow-up, with 16.1% decreasing by more than 10 letters. Among eyes affected at baseline, greater vision loss was associated with the presence of juxtapapillary RCHs, development of RCH in a new location, and increase in peripheral RCH number and extent. Younger baseline age, younger age at onset of ocular VHL disease, involvement of fellow eye with ocular VHL disease, and missense or protein-truncating germline mutations were significantly associated with increased anatomical involvement and functional deterioration. Conclusions Patients with ocular VHL disease maintain relative anatomical and functional stability, with only a minority demonstrating marked anatomical progression and marked vision loss. Systemic and ocular risk factors for anatomical progression and vision loss can help practitioners identify patients with a higher risk profile for counseling, closer follow-up, and proactive treatment.

Von Hippel-Lindau Disease: A Genetic and Clinical Review

“…They worked on genotype-phenotype correlations and found that the genotype category of the germline VHL mutation was associated with ocular VHL disease progression using Kaplan-Meier time-to-event analyses on the basis of individual participants, even if not significantly associated with disease progression in univariate or multivariate analyses. 56 For example, complete deletion mutation of the VHL gene was protective and development of retinal hemangioblastomas in these patients was significantly lower relative to patients with a missense or protein-truncating mutation. Moreover, those with complete deletions have better visual acuity and decreased incidence of retinal hemangioblastomas.…”

“…Toy et al 56 reported the following factors to be significantly linked to anatomic progression of retinal hemangioblastomas: younger age at onset of ocular VHL disease, younger age at baseline visit, and involvement of the fellow eye with ocular VHL disease. They did not find a correlation between the presence of extraocular VHL disease and anatomic progression of ocular VHL disease.…”

“…11 Furthermore, through the HIF pathway, there is an increase in the secretion of cytokines and growth factors such as TGF, FGF, PDGF, and EGF. 56 In addition, Chan et al detected expression of CXCR4 in VHL-associated retinal hemangioblastomas. CXCR4 is a chemokine receptor.…”

Von Hippel–Lindau disease

“…Between 49% and 62% of VHL patients will develop retinal hemangioblastomas (Poulsen et al, 2010; Toy et al, 2012; Wittström et al, 2014). Retinal hemangioblastomas are often the first manifestation of VHL, with the lowest median age of onset (21 years) among the various manifestations of VHL (Kreusel et al, 2006; Poulsen et al, 2010).…”

Imaging of Pediatric Orbital Diseases

“…15B), 26 and retinal hemangioblastomas are a feature of von Hippel-Lindau disease. [27][28][29][30] Joubert syndrome is characterized by abnormal eye movements and optic nerve and/or chorioretinal coloboma, less commonly retinal abnormalities. 31 Several ocular abnormalities occur in congenital muscular dystrophies such as WalkerWarburg syndrome, including cataracts, microphthalmos, buphthalmos, retinal pigmentary changes, PHPV, retinal detachment, vitreous hemorrhage, coloboma, Peter anomaly, and ONH.…”