A Hitherto Undescribed Von Hippel Lindau Polymorphism Induced/Related Polycythemia Entity, Clinical Features, Cancer Association and Familiar Characteristics, Preliminary Data
Authors: Miklos Udvardy , Egyed Miklos , Bodó Imre , Remenyi Gyula , Bereczky Zsuzsanna , Ujfalusi Aniko , Illes Arpad 
Published: October 2019

Introduction

Von Hippel Lindau disease (VHL) is a complex disorder, in which increased oxygen demand of tissues results in a complex setting of neoplastic disorders: i.e. clear cell renal carcinoma, pheochromocytoma, hemangiomas, Lindau tumor, etc., usually appearing well before the age of forty, and usually without polyglobulia. The background of this disease are a series of mutation in VHL gene.This is positioned on the short arm of chromosome 3 (3p25-26). There are over 1500 germline mutations and somatic mutations found or identified in VHL disease. Some rare cases of mutated VHL gene might induce isolated polycythemia, interestingly these cases the other tumors are missing: so it is recommended to check VHL gene in polycythemia if aetiology otherwise not explained. Much less is known about non classical VHL mutations, but just simple VHL polymorphism issues (usually considered innocent, no clinical significance).

Wen-Chu Wang et al. BMC Res Notes, 7:628, 2014, VHL polymorphism: Not at all are innocents, at least two single nucleotide polymorphisms of them are not insignificant on clinical grounds. For example Rs779805 polymorphism associates clear renal cell cancer in Taiwan and Mainland China more frequently, but, much less in caucasian population. Somewhat more prostatic and large bowel cancer have been found in this polymorphism, as well. VHL polymorphism Rs1642742: similar disorder association and geographic distribution. However, no blood count abnormalities mentioned in these Chinese reports.

Patients and Methods

We referred some patient samples gained from eastern Hungary (roughly 2 Million population) with polycythemia like syndrome without Jak2 V617F or exon 12 mutations, no mpl W515 mutation, with low or normal erythropoietin and O2 saturation values (during the past 4 years). We eagerly screened VHL gene in the patients especially if they were young (under 30) or there was evidence of familiar polyglobulia pattern or more cancer. VHL sequenations were performed: VHL gene coding regions: We performed the PCR amplification of intron (IVS1-195-nt) before 1st exon sequences PCR amplification, followed by direct fluorescent sequenation. This work had been performed by Zsuzsanna Bereczky, University Laboratory Medicine institute, her work is kindly acknowledged and highly appreciated

Results

1. We have found, even to our surprise,13 patients or probands with the same VHL homo or heterozygous VHL polymorphism, namely the intron (IVS1-195-nt) before the 1st exon: i.e. rs779805 G>A, similar to what had been described in chinese population without blood count abnormalities (but associations with solid tumours)

2. None of the samples so far sequenced revealed true, classical VHL gene mutation.

3. We have found additional cancers in five families: clear renal cell cancer (1), large bowel cancer (2) , melanoma (1) in the same family. more sporadic large bowel cancers, a single Hodgkin lymphoma, bony tumour, gynecological cancers (might or might not be coincidental). There were some patients (during family exploration) who had hemoglobin level over 190 g/L under the age of twenty.

4. Clinical features: Most patients were unusually young. High hemoglobin/red cell count was isolated in most instances, normal white blood cell or platelet counts. Aquagenic pruritus was usually absent, two cases had very mild, atypical itching. Spleen sizes were normal in all cases. In respect of transformation the two-four years observational period is irrelevantly short. Bone marrow examinations were performed in some cases, with normal description and analysis results. We used cautious phlebotomies, targeting 0,52 hematocrit levels. All of them were advised smoking cessation. We performed ultrasound and simple cancer screening on a yearly basis, which we do recommend further on.

5. by chance we identified one young polycythemia patients with same polymorphism and in addition Jak2 V617F mutated status.

Conclusions: we do recommend VHL gene sequenation in young patients with otherwise unxplained polyglobulia, especially if there is any sign of familiarity, or unusual precipitation of cancer in the family. We are extending our family screening more deeply, and try to gain data on this polymorphism in 100 young healthy volunteers, analysing their bloofd counts and complex family history. We plan careful hematologic and oncologic followup of our patients and first degree relatives.

Disclosures

Miklos: Novo nordisk: Honoraria; AOP Orphan: Honoraria.