Del Fabbro Sebastiano, Cicinelli Maria Vittoria, Lattanzio Rosangela, Bousyf Soufiane, Bruno Lorenza, Antropoli Alessio, Bianco Lorenzo, Bruschi Elena, Arrigo Alessandro, Pipitone Giovanni, Cei Francesco, Salerno Lucia, Larcher Alessandro, Salonia Andrea, Bandello Francesco, Battaglia Parodi Maurizio
School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.
Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Ophthalmol Sci. 2025 Jun 9;5(6):100846. doi: 10.1016/j.xops.2025.100846. eCollection 2025 Nov-Dec.
To investigate the longitudinal progression, risk factors, and complications associated with retinal hemangioblastomas (RHs) in nonadvanced stages of von Hippel-Lindau (VHL) syndrome using ultra-widefield (UWF) imaging.
Single-center longitudinal cohort study.
Caucasian patients with genetically confirmed VHL syndrome.
Annual evaluations included dilated fundus examinations, UWF pseudocolor fundus retinal images, UWF fluorescein angiography, and OCT. Genetic analysis classified VHL mutations. Baseline RH counts and anatomical distributions were recorded as central (juxtapapillary, macular), peripheral, or both. Longitudinal follow-up tracked new RH formation and visual acuity (VA) values.
Cumulative incidence, incidence rate ratios (IRRs), and risk factors of new RHs assessed using mixed-effects negative binomial regression models. Hazard of recurrent RHs evaluated through Cox frailty models and longitudinal changes in VA.
Among 78 eyes of 43 patients (mean age: 47.8 ± 13.6 years), 110 RHs were documented at baseline, with 3 (3%) centrally located, 35 (32%) peripherally, and 72 (65%) spanning both zones. von Hippel-Lindau variants were investigated in 37 patients: 19 had missense variants (51%), and 18 had presumed null alleles (49%), including nonsense (10 of 37; 27%), frameshift (1 of 37; 3%), splice site (1 of 37; 3%), and exon deletion mutations (6 of 37; 16%). Over a median follow-up of 31 months (interquartile range: 27-109), 35 (43%) eyes developed new RHs, with an incidence rate of 0.22 RHs per eye-year (95% confidence interval: 0.17-0.27). By the last available examination, 26 eyes (34%) remained disease-free, whereas17 (23%) showed no progression of existing RHs. Age reduced the IRR of new RHs by 4.2% annually ( = 0.003), whereas higher baseline tumor burden and vascular leakage increased the IRR significantly ( < 0.001 and = 0.03, respectively). Peripheral RHs were the strongest predictor of recurrence (hazard ratio = 16.4, < 0.001), whereas older age remained protective (hazard ratio = 0.96, = 0.04). Visual acuity (logarithm of the minimum angle of resolution) worsened from 0.05 ± 0.2 (Snellen equivalent: 20/22) at baseline to 0.11 ± 0.3 (Snellen equivalent: 20/25) at the final visit.
Peripheral RHs and vascular leakage are significant risk factors for RH progression and recurrence in VHL syndrome. Although older age provides a protective effect, close monitoring of high-risk eyes is essential to enable timely intervention and preserve vision.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
使用超广角（UWF）成像技术，研究冯·希佩尔-林道（VHL）综合征非晚期阶段视网膜血管瘤（RH）的纵向进展、危险因素及并发症。
单中心纵向队列研究。
基因确诊为VHL综合征的白种人患者。
每年的评估包括散瞳眼底检查、UWF伪彩色眼底视网膜图像、UWF荧光素血管造影及光学相干断层扫描（OCT）。基因分析对VHL突变进行分类。记录基线时RH的数量及解剖分布，分为中心型（乳头旁、黄斑）、周边型或混合型。纵向随访追踪新RH的形成及视力（VA）值。
使用混合效应负二项回归模型评估新RH的累积发病率、发病率比（IRR）及危险因素。通过Cox脆弱模型及VA的纵向变化评估RH复发的风险。
43例患者的78只眼中（平均年龄：47.8±13.6岁），基线时记录到110个RH，其中3个（3%）位于中心，35个（32%）位于周边，72个（65%）跨越两个区域。对37例患者进行了VHL变异研究：19例有错义变异（51%），18例有假定的无效等位基因（49%），包括无义突变（37例中的10例；27%）、移码突变（37例中的1例；3%）、剪接位点突变（37例中的1例；3%）及外显子缺失突变（37例中的6例；16%）。中位随访31个月（四分位间距：27 - 109个月），35只眼（43%）出现新的RH，发病率为每眼每年0.22个RH（95%置信区间：0.17 - 0.27）。到最后一次可获得的检查时，26只眼（34%）仍无疾病进展，而17只眼（23%）现有RH无进展。年龄使新RH的IRR每年降低4.2%（P = 0.003），而较高的基线肿瘤负荷及血管渗漏显著增加IRR（分别为P < 0.001及P = 0.03）。周边型RH是复发的最强预测因素（风险比 = 16.4，P < 0.001），而年龄较大仍具有保护作用（风险比 = 0.96，P = 0.04）。视力（最小分辨角对数）从基线时的0.05±0.2（Snellen等效值：20/22）恶化至最后一次就诊时的0.11±0.3（Snellen等效值：20/25）。
周边型RH及血管渗漏是VHL综合征中RH进展及复发的重要危险因素。尽管年龄较大具有保护作用，但密切监测高危眼对于及时干预及保留视力至关重要。
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