Von Hippel-Lindau disease (VHL) is a rare, multisystem, oncogenic disorder. Morphologically, it is characterised by multiple lesions of varying histological types [1-4], including benign cysts, benign vascular tumours and malignant tumours. There are six organ systems which are mainly affected, the CNS (Central Nervous System), retina, pancreas, kidney, adrenal gland and epididymis, and there are varying manifestations in each [1, 5]. Variable intra- and inter-familial expressivity is typical of VHL disease [6], but correlations have been demonstrated between mutational genotype and phenotype. For instance, deletions are associated with a low risk of pheochromocytoma, in contrast to missense mutations [1, 7-9]; a higher frequency of renal involvement has also been reported in truncating mutations compared to missense mutations [10]. Similarly, the risk of retinal capillary haemangioma (RCH) is also affected by the genotype, occurring in 38% of patients with missense mutations and 40% of those with truncating mutations, but only 14% of those with deletions [11]. It has also been reported that truncating mutations lead to an earlier age of onset of RCH compared to missense mutations and deletions [12].

However, the ocular manifestations of VHL which occur in patients with visceral cysts are much less well characterised and have not previously been reported. The aim of this study was to determine the ocular phenotype of patients identified as having visceral cysts and to assess any relationship with the underlying genotype.

In this study, we report a prospective case series of proven VHL disease gene carriers under the care of the VHL clinic at the Hammersmith Hospital, London, UK. Patients were eligible for inclusion in this study if they were undergoing follow-up in the VHL clinic and had proven VHL mutations on genotyping. Eligible participants were invited for ophthalmic screening in addition to their routine systemic screening. At the initial clinic visit, a retrospective review of the case notes was undertaken. Data relating to ocular and systemic disease manifestations were then collected prospectively for two years. The type of VHL mutation was documented in each case, VHL mutations being categorised as missense mutations, truncating mutations, or deletions.

VHL disease features were noted and categorised into one of four groups: cystic visceral lesions, other visceral lesions, CNS manifestations and ocular features. All patients had a good fundal view and a complete ophthalmic examination was carried out at the first and all subsequent clinic visits, including indirect peripheral retinal examination. All fundal lesions were documented by colour fundus photography and fundus fluorescein angiography was performed when the diagnosis of a retinal capillary haemangioma was uncertain.

Twenty-one patients were identified from the VHL clinic as carrying VHL disease genes and were thus eligible for inclusion in the study. All twenty-one agreed to participate in the study and to attend for ophthalmological screening. Of the 21 patients, eleven (52%) were male and ten (48%) were female. Twelve patients (57%) were Asian and nine (43%) were Caucasian; there were no patients of African or Afro-Caribbean descent. The mean age at the time of VHL diagnosis was 25 years (range, 6 to 59 years), but patients with RCH were diagnosed at a younger age (mean 17 years vs 29 years for patients without RCH).

Six of the twenty-one patients (29%) either presented with visceral cysts or developed them during the follow-up period of two years. Disease manifestations and associated mutational genotypes are summarised in Table 1. One patient presented with an epididymal cystadenoma and one presented with a renal cyst. Three patients developed pancreatic cysts during follow-up and three patients developed renal cysts. All of these patients who developed pancreatic cysts had VHL gene deletions and all developed CNS HGB at some stage. Only one of the six patients developed ocular manifestations of VHL, namely retinal capillary haemangiomas; none of the other patients developed any ocular manifestations.

We performed a study of patients with an atypical manifestation of VHL, namely visceral cysts, followed in a Genetics Clinic. Owing to their relatively benign nature, cystic visceral lesions have received comparatively less attention in relation to both their correlation with other phenotypic manifestations of VHL disease and genotypic associations. Cystic visceral lesions were detected in six of the 21 patients in the clinic (29%). These included renal cysts in four patients, pancreatic cysts in three patients, and an epididymal cystadenoma in one patient.

There are two case reports in the literature of epididymal cysts forming the first clinical manifestation of VHL [13, 14], one of which occurred in association with early-onset renal cell carcinoma. Epididymal cystadenomas have no established genotypic association [15], and we had only one patient with this manifestation in our cohort. Renal cysts are usually asymptomatic and found on screening in approximately 15% of patients with VHL disease [4, 16]. They are considered precursors to malignancy, but transformation appears uncommon [15]. In this study group, renal cysts were not associated with any specific genotype. Pancreatic cysts are also usually asymptomatic and detected on systemic screening; their reported prevalence varies from 15% to 74% of patients with VHL disease, with one recent systematic review finding an overall prevalence of 60% [17-20]. In our study, 3 patients (14%) had pancreatic cysts. All of these patients had VHL gene deletions and all developed CNS HGB at some stage. This association has been previously reported, but only one study contains genotypic data [17, 21].

The small numbers of patients included in our study and limited follow-up make it impossible to make any definitive conclusions about the genotypes and phenotypes of visceral cystic lesions. Nevertheless, our study does provide some supporting evidence for the previously observed phenotype comprising pancreatic cysts and CNS HGB linked to VHL deletions. In addition, one of our principal aims in performing this study was to see whether there was any association between visceral cystic lesions and ocular involvement. Although our small numbers again require us to be guarded in our conclusions, our failure to find any association suggests that further ocular study of a larger population of patients with visceral cystic lesions would be unlikely to prove rewarding.

In conclusion, we present the findings of clinical and molecular examination of a small group of patients with visceral cystic lesions in VHL disease. Pancreatic cysts appeared to be associated with VHL deletions, but ocular involvement was uncommon in this group of patients.

This paper describes the phenotype of a cohort of patients with von Hippel-Lindau disease who developed visceral cystic lesions. Genotyping results suggested that VHL gene deletions may be associated with pancreatic cysts and the development of central nervous system haemangioblastomas. Ocular manifestations proved uncommon in this group of patients.