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Congenital erythrocytosis due to Chuvash polycythemia

Author:  Nabhajit Mallik; Prashant Sharma; Jasbir Kaur; Pankaj Malhotra1; Neelam Varma; Reena Das, 09/20/2019
Category: Red Cell: Other Disorders > Congenital erythrocytosis
Published Date: 10/02/2019
     
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A 30 years old north Indian male presented with intermittent claudication in both feet and calves for six months, and in both the hands for one month. The patient was a non-smoker with no organomegaly. Investigations revealed persistently high hemoglobin levels, and the clinical impression was of a myeloproliferative neoplasm, likely polycythemia vera. There was no family history of a similar illness.

The hematological investigations at presentation were as follows:

Index case

Hb (g/l): 240

PCV (%): 74.8

Reticulocyte (%): 1.66

RBC (x109/l): 7.86

MCV (fl): 95.2

MCH (pg): 30.2

MCHC (g/l): 32.1

RDW (%): 16.3

Platelet count (x109/l): 74

WBC (x109/l): 6.6

DLC: P68, L21, M09, E02

Erythropoietin level was 16.9 mU/mL (reference range 4.5–30 mU/mL). The oxygen saturation was normal, and the hemoglobin HPLC using BioRad Variant II showed a normal pattern. Sanger sequencing and PCR-RFLP revealed homozygous VHL:c.598C>T (p.Arg200Trp) (rs28940298) substitution, diagnostic of Chuvash polycythemia.

Learning points

1.     Chuvash polycythemia is known to be endemic in the Chuvash Republic in Russia but has been found in people belonging to other ethnicities as well.

2.     It is caused by the homozygous VHL:c.598C>T (p.Arg200Trp) substitution and is inherited in an autosomal recessive manner. Hence a positive family history may not be present.

3.     Other genes frequently mutated in congenital erythrocytosis include EGLN1, EPAS1, EPOR, and the alpha or beta-globin genes. These usually display autosomal dominant inheritance.

Figure 1

A. The peripheral smear examination shows increased RBC density, confirming erythrocytosis with mild thrombocytopenia; B. A bone marrow aspirate is normocellular for age; C. Adequate erythroid cells are present; D. The trephine biopsy is normocellular and shows adequate megakaryocytes with normal morphology. This is in contrast to polycythemia vera where panmyelosis leads to a hypercellular marrow, and the megakaryocytes are pleomorphic.

Figure-1
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Figure 2

Sanger sequencing of VHL exon 3 reveals a homozygous VHL:c.598C>T (p.Arg200Trp) (rs28940298) substitution, which is characteristic of Chuvash polycythemia. The top panel shows the wild type, while the bottom panel shows the homozygous variant.

Figure-2
#00062787
 
Figure 3

Polyacrylamide gel electrophoresis of PCR-RFLP for Chuvash polycythemia. The wild type VHL allele produces a 268 bp PCR product, which is digested by the restriction enzyme Fnu4HI into 187 bp and 81 bp bands (lanes 1, 2, 3, 5, 6, 7). However, the VHL:c.598C>T substitution in Chuvash polycythemia patients results in an undigested 268 bp band (lane 4). Heterozygotes will show all the 3 bands (268bp, 187bp, and 81bp).

Figure-3
#00062788