This clinical correspondence is a case study of patients of West Polynesian heritage presenting to a single centre in Auckland, New Zealand with retinal capillary haemangioblastoma (RCH).
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This clinical correspondence is a case study of patients of West Polynesian heritage presenting to a single centre in Auckland, New Zealand with retinal capillary haemangioblastoma (RCH). Case 1 was a 54-year-old Tongan woman with right juxtapapillary RCH (Figure 1a) first diagnosed in 2010. She had a past medical history of bilateral renal cell carcinoma and pancreatic neuroendocrine tumours, diagnosed at ages 41 and 42 respectively, and had been investigated with magnetic resonance imaging of the brain, spine and abdomen (MRI B/S/A). Family history revealed that her mother died of an undiagnosed brain tumour in Tonga in the third to fourth decade of life and her older brother also passed away in similar circumstances. Her late father was not known to be affected. Her 7-year-old son (Case 2) had MRI B/S/A showing brain haemangioblastoma and multiple renal cysts; audiology testing was normal. Her youngest son, aged 3, had a normal ophthalmic examination. Her sister, Case 3, was a 52-year-old with bilateral juxtapapillary RCH (Figure 1b). She had a history of spinal haemangioblastoma, bilateral renal cell carcinoma and multiple pancreatic neuroendocrine tumours—recent MRI B/S/A showed stable tumour size with no new lesions. Her RCH and non-ocular tumours were diagnosed at age 44.
View Figure 1–2.
The family pedigree (Figure 2) is consistent with autosomal dominant inheritance and plausibly a von Hippel-Lindau (vHL)–like syndrome.
All cases had genetic testing for vHL performed at Auckland District Health Board, which was non-confirmatory. The entire coding region of VHL, including intron–exon splice junctions, was sequenced. A copy number analysis of this locus was also performed using an Agilent custom comparative genomic hybridisation array. No pathogenic variants were identified.
RCH is often a key early sign in vHL disease, with a mean age of diagnosis of 18 years.1 This may have significant implications due to multisystem involvement including central nervous system haemangioblastoma, phaeochromocytoma, pancreatic islet carcinoma, increased risk of renal cell carcinoma and cyst formation in the liver, lung, pancreas and kidney.2 RCH may also be observed as an isolated phenomenon and it is estimated that up to half of patients with solitary RCH have vHL disease.1 Approximately 85% of RCH are located in the peripheral retina and 15% are juxtapapillary.3
vHL is an autosomal dominant condition with high penetrance, occurring in one in 36,000 individuals whereby 20% are de novo pathogenic variants.4 As with all phakomotoses, there is no ethnic predisposition.4 In non-familial cases, a retinal or cerebral tumour plus a visceral tumour (or two or more retinal or cerebral tumours) are required for diagnosis.5 However, in those that test negative for gene sequencing and have not met the diagnostic criteria for disease, almost 100% will not develop vHL.6 For those that meet clinical diagnostic criteria, 5% will have no demonstrable pathogenic variant using this diagnostic approach in Case 1.7 Causative VHL variants that would escape detection using the approach utilised here could lie within introns or be epigenetic in nature.
This raises the possibility of a West Polynesian variant of vHL in individuals of Tongan ancestry with manifest angiomata and visceral pathology. During the chart review, two patients of Niuean background were identified: a 38-year-old female with left juxtapapillary RCH and a 35-year-old male with right juxtapapillary RCH, neither of whom had any family history of vHL. Interestingly, there are strong historical and ancestral ties between Tonga and Niue, which have small populations in close geographical proximity. Despite this, there was no familial link between these two patients and systemic screening to-date (MRI B/A) revealed no other associated pathology to fulfil the diagnostic criteria for vHL.7 They therefore represent solitary, non-syndromic RCH, but further follow-up for detection of new retinal lesions and completion of systemic screening is pending.
The location of these tumours next to the optic nerve increases the risk of vision loss due to exudation and oedema, tractional maculopathy, vitreous haemorrhage and neovascular glaucoma.3 This is of particular relevance, as those of Polynesian ancestry have a greater burden of disease (both ocular and systemic) in the New Zealand healthcare setting.8 The familial disorder described here is strongly suggestive of vHL, but access to exhaustive screening, post-mortem analyses and genetic evaluations are restricted in resource-constrained Pacific countries, limiting diagnostic ability. Adoption of a more comprehensive genetic evaluation (exons, introns and methylation) of the VHL locus using “long-read DNA sequencing” (LRDS) is a possible next step to detect an as yet pathogenic variant in these families. The potential of LRDS is that it may offer an affordable, portable and adaptable solution, thereby obviating the need for expensive radiographic screening to make the diagnosis. Another approach could include the characterisation of the transcripts produced from the VHL locus in an affected individual. Both techniques have potential to ameliorate the current 95% detection rate and preclude the need for surveillance in those with monosymptomatic presentations, such as RCH.9 However, optimal analysis would require normative epigenetic data from appropriate tissues as well as an understanding of population-specific genetic variation to make categorical diagnostic conclusions, both of which are yet to be attained at an appropriate scale. Currently, such isolated findings should prompt the screening of other organs for vascular “vHL-like” tumours even when genetic analysis is inconclusive.
Polynesian patients who present with juxtapapillary RCH should be screened for systemic tumours. They should be monitored and treated to prevent vision loss and genetically evaluated using methodologies that can detect the full spectrum of possible causative VHL alleles.
Polynesian peoples have been isolated from other populations for a long period of time and are likely to have genetic diseases that are as yet unrecognised. Paradoxically, in Pacific nations where genetic services are limited, the employment of more comprehensive genetic methodologies used earlier rather than later during diagnostic evaluation would bring economies and efficiencies to clinical practice as well as improve the lives of patients. Such lessons are likely to be replicated across a broad number of genetic disorders and their presentation in Pacific peoples.
Eugene Michael, FRANZCO, MBChB: Ophthalmologist, Department of Ophthalmology, Greenlane Clinical Centre, Auckland, New Zealand.
Peter Hadden, FRANZCO, MBChB: Ophthalmologist, Department of Ophthalmology, Greenlane Clinical Centre, Auckland, New Zealand.
Stephen Robertson: Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, New Zealand.
Dr Peter Hadden: Department of Ophthalmology, Greenlane Clinical Centre, Auckland, New Zealand. +64 21 528252.
None declared.
Statement of ethics:
This was conducted in accordance with the tenets of the Declaration of Helsinki and the National Ethics Advisory Committee guidelines and met the criteria for exemption from formal review by the New Zealand Health and Disability Ethics Committee in accordance with national guidelines.
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