The rare diagnosis of Von Hippel–Lindau disease in a 29-year-old patient

Von Hippel–Lindau disease (VHL) is a rare multisystem tumor syndrome, associated with a germline mutation in the VHL tumor suppressor gene. It is an autosomal dominant disease with an incidence of approximately 1/40,000 live births, characterized by multiple retinal benign or malignant tumors and cysts, central nervous system, and viscera (kidneys and pancreas).[1,2] Retinal hemangioblastomas (RHs), i.e., benign tumors made of newly formed blood vessels, the most frequent and earliest manifestation, are characteristic and pathognomonic. Characterized by a mean diagnosis age of 25 years, RHs can be found in the peripheral retina, near the macula or optic disc.[1] They may be asymptomatic or cause subretinal fluid accumulation, intraretinal exudation, and vitreoretinal fibrosis, thus leading to exudative and/or tractional retinal detachment (RD) and severe vision loss. Management may include thermal laser, cryotherapy, antivascular endothelial growth factor (VEGF) therapy, photodynamic therapy (PDT), plaque radiotherapy, transpupillary thermotherapy, and tumor resection by pars plana vitrectomy. Despite this plethora of therapeutic options, selecting the appropriate treatment can be challenging and depends on the number of RHs, tumor size, retinal location, and presence of retinal exudation or vitreous hemorrhage.[1] A previously healthy 29-year-old male presented with a 1-month history of painless and progressive visual loss in his right eye (OD). Visual acuity (VA) was 20/100 OD and 20/20 in the left eye (OS). Anterior segment examination was unremarkable, and bilateral intraocular pressure was normal (OU). Fundoscopy, optical coherence tomography (OCT), and fluorescein angiography (FA) were performed (Spectralis Heidelberg Retina Angiograph and OCT; Heidelberg Engineering, Heidelberg, Germany). Fundoscopy revealed multiple circumscribed orange-red retinal tumors (8 OD-7 OS), varying in size, with one being about 2 optic discs in diameter. There was also vessel tortuosity OD and dot hemorrhages peripherally [Figure 1]. OCT depicted serous RD and macular exudates in the right eye while scans in the left eye were unremarkable. FA revealed RHs, particularly in the periphery, with early hyperfluorescence of all tumors and leakage from larger RHs during the late phase [Figure 2].Figure 1: Infrared images; venous tortuosity and segmentation, right, (a) No comparable findings, left, (b) Eye, (c-e) Color photographs; extensive perifoveal exudates and an enlarged parafoveal vascular tumor, right, (c and d) Small tumor, left, (e) Eye, (f) Infrared image; tumor complexFigure 2: Optical coherence tomography showing subretinal fluid accumulation, right fovea, (a) No findings, left, (b) Early-mid, (c) and late, (d) Fluorescein angiography (FA) phases, with central tumor leakage, right eye, (e) Smaller tumors showing hyperfluorescence, late FA phases (left eye, f-h)Potential VHL diagnosis prompted cerebral, abdominal, and spinal imaging. Magnetic resonance imaging of the abdomen revealed multiple, bilateral renal cysts. Genetic analysis confirmed the diagnosis of VHL; the missense mutation c.500G>A; p. Arg167Gln was identified. Regarding family members, a brother was found with the same mutation. Laser photocoagulation (IQ-532, Iridex, CA, USA) was applied on the feeder vessel, around the tumors, and on the actual RH in the small-sized tumor OU. The laser parameters used were energy: 200 mW, spot size: 200 µm, and exposure time: 200 ms. RD resolved completely after three laser sessions with subsequent clinical improvement [Figure 3]. Visceral tumors were removed surgically. At 12 months, the patient was otherwise healthy (VA: 20/25 OD).Figure 3: Following photocoagulation treatment; optical coherence tomography confirming complete subretinal fluid absorption, right eye. (a) Unaltered fovea, left eye, (b) Fluorescein angiography depicting scars from laser applied around RHs, their feeder vessel and the actual tumors, right, (c and d) and left, (e and f) EyeAdditional ruthenium-106 plaque radiotherapy was originally scheduled for RHs OD due to their large size. However, treatment has been deferred, given the positive effect of thermal laser on tumor size and the observed subretinal fluid absorption. This report highlights the complexity of VHL disease. Most patients are unaware of the disease extent, with tumors present in their eyes and other vital organs as well. Long-term tumor surveillance is warranted, while genetic counseling must always be sought. As in our case, family members must also be screened as they may unknowingly be affected by the disease. Since no consensus or guidelines exist, treatment selection depends on the multifocality of tumors, peripheral or juxtapapillary/macular location, and pretherapeutic complications present. RH and feeder vessel laser photocoagulation appears to be preferred, given its ease of application and low complication rate. Laser parameters are dependent on RH size and multiple sessions may be required. Laser photocoagulation has been reported as the safest and most effective treatment, especially for peripheral RHs up to 1.5 mm in diameter.[3] In our case, all lesions responded to laser photocoagulation regardless of size. For lesions refractory to laser photocoagulation, cryotherapy is often effective, if no exudation is present.[3,4] PDT use is supported not only for juxtapapillary RHs, where laser application should be avoided, but for peripheral RHs as well, with satisfactory posttreatment tumor control and visual improvement.[5] Proton beam radiation, despite stabilizing tumor progression, usually results in poor visual outcomes due to radiation-induced maculopathy. Peripheral RHs up to 5 mm in size can also be successfully ablated using ruthenium-106 plaque brachytherapy. No re-exudation was observed at 12 months. In case of relapse, ruthenium-106 plaque brachytherapy may be applied. Chromosome 3p25–26 mutation causes protein dysfunction, leading to the inability to degrade hypoxia-inducible factors (HIF)-1/-2α. HIF-1α/-2α accumulation results in VEGF, platelet-derived growth factor (GF), erythropoietin, and transforming GF-alpha production, all of which contribute to tumor proliferation. Anti-VEGFs and corticosteroids have been reported to reduce retinal edema and exudation, without affecting RH size. Consequently, a combination with either laser photocoagulation, cryotherapy, or PDT could be employed as an effective treatment option. In our case, the response to laser photocoagulation was considered sufficient and no additional treatment was applied. Although specialists agree on the necessity to treat large or exudative RHs causing visual symptoms, management of RHs without active exudation, in eyes with preserved vision, is controversial. A recent publication concluded that 72% of ophthalmologists would rather observe smaller asymptomatic RHs after diagnosis. With RH growth, progression-related complications, such as exudation and vitreoretinal traction, are more likely to develop, leading to RD, neovascular glaucoma, or even phthisis bulbi.[3] Routine RH assessment could facilitate prompt intervention in case of progression or vision deterioration. Regarding treatment decisions and genetic analysis, patients, carriers of missense mutations of the VHL tumor suppressor gene, as in this case, are characterized by RHs with higher progression-related complications compared to truncating mutation carriers; they may also require vitreoretinal surgery more often with inferior outcomes. Thus, genetic analysis in VHL disease may facilitate a more proactive treatment strategy and determine RH prognosis. In conclusion, treatment selection depends on multiple anatomic and genetic factors. A variety of therapeutic modalities may lead to RH regression, either alone or combined. As observed in our case, treatment should always be individualized. As VHL lesions can continue to occur in this case, clinical issues may also arise again in the future. Consequently, the need for long-term follow-up to continue and cautious future prognosis is evident. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.