Von Hipple-Lindau disease complicated with central retinal vein occlusion: a case report

Here, we described a case of VHL disease with polycythemia and CRVO caused by VHL c.208G > A. The patient presented phenotypes including RHB, liver tumor, elevated hematocrit and CRVO. To the best of our knowledge, this is the first time that VHL c.208G > A has been reported in Chinese, and the first case report of VHL c.208G > A variant in the etiology of polycythemia and CRVO. And, RHB was found in all affected individuals in this family. In the past, the most of c.208G > A variant patients being reported were in South Korea [69]. Their clinical phenotypes include CHB, RHB, RCC and colorectal adenocarcinoma. The incidence of hemangioblastoma in patients with VHL disease caused by VHL c.208G > A was as high as 88.9%. CHB and RHB account for 50% and 38.9%, respectively (Table 1) [69]. The HIFα binding site is located at residues 65-117of pVHL. The possible pathogenic mechanism is that VHL c.208G > A (p.E70K) mutated the 70E of pVHL, which may affect the ubiquitination of HIFα. The dysregulated HIFα eventually leads to the occurrence of hemangioblastoma [10].

Table 1 Phenotypes of VHL disease caused by VHL c.208 g > A

Cases of polycythemia caused by mutations in the VHL gene are not common. According to the mechanism, these polycythemias are divided into two categories: one is secondary polycythemia caused by the secretion of erythropoietin (EPO) by renal cell carcinoma, cerebellar hemangioblastomas, and hepatocellular carcinoma of VHL disease; the other is the VHL gene mutation which changes the activity of pVHL and affects HIFα pathway increases EPO synthesis, resulting in erythrocytosis type 2 [11]. Patients with erythrocytosis type 2 either are carrying the homozygous state or compound heterozygous with the R200W mutation. In addition, VHL disease-related tumors were not found in patients with erythrocytosis type 2 [12]. EPO is synthesized and secreted by kidney (90%) and liver (10%), and reaches bone marrow through blood circulation to play a role in promoting the proliferation, differentiation and maturation of erythroid progenitor cells [11]. Therefore, when renal cell carcinoma, hepatocellular carcinoma, and the recently discovered cerebellar hemangioblastomas become additional sources of EPO, excessively high levels of EPO cause massive bone marrow erythroid hyperplasia, and eventually lead to polycythemia. Although the proband had no solid kidney lesion, but a huge tumor was found in his liver. His polycythemia is more likely to be caused by abnormal secretion of EPO from liver tumors. Unfortunately, the patient refused to accept pathological examination related to liver tumor and corresponding treatment.

As well known, CRVO is a common retinal vascular disease and a common loss of vision in older patients. The main risk factor for central retinal vein occlusion is age, 90% of patients are over 50 years old [13]. But this 20 s old patient also developed a rare CRVO in his left eye. The patient without small optic disc and juxtapapillary space-occupying lesions, thus excluded optic nerve hypoplasia and RHC as risk factors for CRVO. Further, after excluding other common CRVO risk factors such as hypertension, hyperlipidemia, diabetes, and retinal vascular inflammation, all the clues focused on polycythemia. Polycythemia is an uncommon predisposition for CRVO [13, 14]. It may be that a large number of circulating red blood cells lead to increased erythrocyte aggregation and blood hyper viscosity [14]. In addition, Lu/BCAM on the surface of erythrocytes was phosphorylated when polycythemia. Then erythrocytes and endothelial cells adhered due to the interaction between Lu/BCAM and laminin α5. This process simultaneously activates endothelial cells and stimulates the expression of vascular cell adhesion molecules, which is conducive to leukocyte adhesion [15]. Wautier MP et al. [16] also found a similar molecular mechanism in CRVO patients. The arm-choroid filling time was found to correlate with hematocrit level and platelet counts as the artery-venous transit time was found to correlate to the hematocrit and hemoglobin levels [17]. In a recent report, high blood viscosity and erythrocyte vascular adhesion caused by polycythemia can lead to delay in retinal arteriovenous transit time and retinal artery phase filling time, and finally lead to ischemic retinopathy [18]. In this patient the same phenomenon was observed, therefore ischemic lesions of the eye and brain may have been caused by blood hyper viscosity due to polycythemia. The difference is that the retinal ischemia caused by this factor is relatively mild, which is manifested as small patches of non-perfusion areas with indistinct borders. However, the mechanisms of CRVO caused by VHL disease could be diverse. In the report of AlBloushi AF et al. [19], a 22-year-old woman with VHL disease developed hemiretinal vein occlusion due to the mechanical compression of the juxtapapillary RCH. Our patient refused intravitreal anti-VEGF. CME existed for a long time, which can lead to loss of vision. Singh et al. [20] reported a case of BRVO caused by secondary erythrocytosis. A good visual acuity was restored after regular anti-VEGF and phlebotomy therapy.

In conclusion, we present a rare case of polycythemia complicated by CRVO in patient with VHL disease. It reminds us that the systemic disease factors should be fully considered in the diagnosis of young patients with CRVO, and that treatment requires a coordinated effort of physicians.

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