Page 194 - Haematologica May 2022

Letters to the Editor
Table 1. Clinical features and management of ten patients with EGLN1(PHD2)/ EPAS1(HIF2A)/VHL pathogenic variant associated erythrocytosis.
Patient n/ age at diagnosis/ sex
#1 35/F
#2 60/F
#3 67/M
#4 69/M
#5 57/M
#6 56/F
#7 68/M
#8 71/M
#9 61/F
#10 19/M
Gene Family mutation history
EGLN1(PHD2) Sister Heterozygous
c.1111C>T, p.(Arg371Cys)6,7
EGLN1 (PHD2) none Heterozygous
c.1030C>T, p.(Arg344*)4
EGLN1 (PHD2) Brother Heterozygous x2
c.461C>A, p.(Ser154*)4
EPAS1 (HIF2A) none Heterozygous
c.1609G>A, p.(Gly537Arg)19
EPAS1 (HIF2A) none Heterozygous
c.1121T>A, p.(Phe374Tyr)5
EPAS1(HIF2A) none Heterozygous
c.1121T>A, p.(Phe374Tyr)5
EPAS1(HIF2A) none Heterozygous
c.1121T>A, p.(Phe374Tyr)5
EPAS1(HIF2A) none Heterozygous
c.1121T>A, p.(Phe374Tyr)5
EPAS1(HIF2A) none Heterozygous
c.1620C>A, p.(Phe540Leu)20
VHL none Heterozygous
562C>G, p.(Leu188Val) c.598C>T, p.(Arg200Trp)8
Hb/HcT EPO
p50
26
27
27
26
CV Thrombosis risks (Therapy at
event)
Smoking none
HTN none
CAD none
HTN CVA after diagnosis
(phlebotomy)
DM CVA
prior to diagnosis
LV thrombus (none)
HTN MI CVA hyperlipidemia IVC thrombus after diagnosis
Pregnancy
2 live births
2 live births
Phlebotomy
none
HcT< 42
Aspirin
Anticoagulation
17.2/52.6
17/
17.8/50.7
23/58.7
17.9/54.4
19.1/57
19.1/57.2
17.2/52
16.1/47.8
11.2
30
10.3
175
93.4
40.8
20.7
7.7
7.3
81 mg none
81 mg none
19/57 1465
31 none
none
Every 4 weeks HcT <45
81 mg none
hyperlipidemia
none
none 81mg none
Every 3 to 4 months HcT < 50
HcT<45
yes
HcT<50
none
325 mg none
325 mg
Aspirin 81 mg Plavix 75 mg
Enoxaparin apixaban
warfarin
(phlebotomy, aspirin, Plavix) HTN none
none none
81 mg none
27
HTN none
none 81mg none
Hb: hemoglobin; HcT: hematocrit; HTN: hypertension; DM: diabetes mellitus; CVA: cerebrovascular accident; LV: left ventricle; IVC: inferior vena cava; EPO: erythropoietin; p50: oxygen tension at which hemoglobin is 50% saturated.
Canonical exon 8 EPOR c.1316G>A mutations,9 occurred in two patients, 48- and 69-year-old females, with a family history of erythrocytosis, and Hb/Hct/Epo levels of 19.4/56.6/1.1 and 14.6/44.3/<1, respectively, underscoring the suppressed Epo levels with gain of func- tion EPOR mutations (Table 2). Both patients underwent intermittent phlebotomy and had an uncomplicated course in terms of thrombosis and pregnancies.
Two patients harbored BPGM pathogenic variants (Table 2) which included a 25-year-old male with hyper- tension who presented with Hb/Hct/Epo/p50 of 20/58/17.7/31, found to have a heterozygous missense alteration in BPGM at c.184C>T resulting in amino acid substitution p.Arg62Trp (R62W). While this specific
amino acid change is novel, (p.Arg62Gln) has been reported in association with erythrocytosis in patients homozygous for the variant10 and compound heterozy- gous for Arg62Gln and another BPGM pathogenic vari- ant.11 The second case was a 25-year-old male, current smoker with Hb/Hct/Epo of 17/49.1/5.1, who harbored a previously unreported BPGM c.258dup, p.(Leu87Serfs*3) frameshift variant in the first coding exon, predicted to result in a premature stop codon. Similar nonsense muta- tions leading to a predicted premature stop codon have been reported.10,12,13 Both patients had an uneventful clin- ical course, the first patient was receiving phlebotomy and aspirin while the second case was observed.
Among 22 VUS that were reported, PHD2 was most
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