ABSTRACT
Von Hippel-Lindau (VHL) disease is a familial cancer syndrome characterized by benign or malignant tumors which may involve more than one system. Retinal hemangioblastomas are usually the initial manifestation of VHL disease and can cause vision loss. A 32-year-old man presented to our clinic with vision loss in the left eye for 2 months. He had a history of cerebral hemangioblastoma operation. Family history showed that his mother had unilateral vision loss and died because of renal cell carcinoma. Ophthalmologic examination revealed multiple retinal hemangioblastomas in both eyes. VHL gene sequencing was performed and heterozygous p.R161X mutation was detected. His sister and daughter were also found to have the same variant. A treatment and follow-up plan was initiated for the patient and affected family members. Considering VHL disease in the differential diagnosis of retinal hemangioblastomas has a very important role in the early detection of life-threatening tumors in these patients.
Introduction
Von Hippel-Lindau (VHL) disease a familial cancer syndrome characterized by benign or malignant tumors and cystic lesions affecting multiple systems. It may present with hemangioblastomas in the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and ligamentum latum cysts. Retinal hemangioblastomas are usually the initial sign of VHL disease and can cause vision loss. Up to 70% of affected individuals are diagnosed at an average age of 25 years old by detection of retinal hemangioblastomas.1,2,3 Renal cell carcinoma is seen in about 70% of VHL patients and constitutes the greatest cause of mortality.4 Identifying patients with retinal hemangioblastoma and evaluating them for VHL is of vital importance to both the patients and their relatives. Herein, we present a case diagnosed with VHL based on retinal hemangioblastomas after presenting to our clinic with reduced vision, and the treatment and follow-up of the patient and his relatives.
Discussion
VHL disease is a rare, autosomal dominant, monogenic disease arising from heterozygous mutations of the VHL gene, located on chromosome 3p25.3. The incidence of VHL has been determined as approximately 1 in 36,000 live births.5 Seventy-two percent of patients can be diagnosed with VHL gene sequence analysis; large exonic or whole gene deletions or duplications are responsible for the remaining 28%.6 The p.R161X mutation identified in the family in the present study is a nonsense mutation described previously in the literature.7 According to the phenotypic characteristics, VHL disease can be divided into 4 phenotypic groups based on the presence of pheochromocytoma or renal cell carcinoma (type 1, type 2A, type 2B, and type 2C). Pheochromocytoma is not present in type 1, but occurs with all other types. Considering his clinical findings and family/medical history, our patient was consistent with type 1. Although further evidence is needed in the literature to establish the genotype/phenotype relationship, it has been reported that missense and nonsense mutations lead to the type 1 VHL phenotype.8
Retinal hemangioblastomas are generally located in the peripheral temporal retina, but may rarely occur in the posterior pole and on the optic disc. Lesions are usually bilateral and multiple.9 The differential diagnosis should include Coat’s disease, retinal cavernous hemangioma, retinal macroaneurysm, and vasoproliferative tumor.10
In the retina, hemangioblastomas are slow-growing, benign tumors. Without treatment, however, they can cause complications such as macular edema, exudative and tractional retinal detachment, intravitreal hemorrhage, and neovascular glaucoma.11 There is no standard treatment approach to retinal hemangioblastomas. The treatment method varies depending on the hemangioblastoma’s location, size, and related complications. Treatment options include laser photocoagulation, cryotherapy, photodynamic therapy, transpupillary thermotherapy, plaque radiotherapy, external beam radiotherapy, and vitreoretinal surgical ablation.12,13,14 Intravitreal anti-vascular endothelial growth factor inhibitors have recently come into use for reducing exudation resulting from hemangioblastoma.15 Active surveillance is recommended for juxtapapillary hemangioblastomas and peripheral hemangioblastomas smaller than 500 microns that do not cause exudation or subretinal fluid. Laser photocoagulation is more common to treat small tumors, while cryotherapy is more often preferred for very peripheral tumors larger than 3 mm.12 We chose cryotherapy for our patient because the hemangioblastoma causing perifoveal intraretinal cystic fluid collection in the left eye was larger than 4.5 mm in size and was situated peripherally. Cryotherapy resulted in regression of the perifoveal intraretinal cystic fluid and improved visual acuity. Early diagnosis and appropriate treatment reduces the risk of vision loss, especially with tumors located in the periphery. The likelihood of favorable outcome is lower with tumors located on or around the optic disc.9
In this case, VHL disease was suspected based on findings of multiple retinal hemangioblastomas and was confirmed with genetic testing. Although the patient had previously undergone surgery for cerebral hemangioblastoma, it was apparent that the possible role of VHL in its etiology had not been investigated through a comprehensive differential diagnosis. We also informed the patient’s relatives about this genetic condition and performed the necessary examination and tests. Because hemorrhages associated with renal cancer and cerebral hemangioblastomas are the leading causes of mortality in these patients at young ages, systemic evaluation and monitoring is crucial. Our patient and his sister were diagnosed with renal cysts and routine follow-up was scheduled. The patients were advised to avoid tobacco products, as well as chemical and industrial toxins. They were also recommended to avoid contact sports due to their renal and pancreatic lesions.
As an ophthalmologist, identifying retinal hemangioblastomas and determining whether they are related to VHL is extremely important for the early diagnosis and treatment of life-threatening tumors and complications that may develop in these patients and their families.
