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• W4283698946 abstract "Mutations in the Janus-associated kinase 2 (JAK2) gene are found at varying frequency in myeloproliferative disorders but are almost always present in true cases of polycythaemia vera (PV). In 97% of cases these mutations are the V617F mutation with the majority of the remainder found in exon 12.1 These are activating mutations that lead to proliferation of erythroid precursors independent of stimulation by erythropoietin, resulting in erythrocytosis, defined as a red cell mass 25% above the predicted value for the body mass of the patient. The British Society of Haematology recommend that females with haematocrit ≥0.48, and males with haematocrit ≥0.52 be investigated for the cause of erythrocytosis.2 Often, a secondary cause is evident but cases where there is true erythrocytosis, no JAK2 V617F or exon 12 mutation, and no discernible secondary cause are labelled as idiopathic erythrocytosis. With advances in genetics, germline mutations in a number of genes such as those for α- and β-globin, and those involved in erythropoietin signalling and oxygen sensing, have been discovered as causes of congenital erythrocytosis.3 Additionally, heterozygous germline mutations in JAK2 with and without acquired V617F mutations have been identified as causing various types of myeloproliferation.4-9 In one such report, a 15-year-old boy was found to be a compound heterozygote for two JAK2 germline substitutions, E846D and R1063H, resulting in erythrocytosis and splenomegaly but a normal platelet count.10 Here, we report for the first time three cases of erythrocytosis in adult sisters and their mother both harbouring heterozygous, germline JAK2 E846D substitutions. Two Caucasian sisters were independently referred to our haematology service for assessment and investigation of erythrocytosis within 12 months of one another. Due to these findings, we also reviewed their mother. The youngest sister was referred with a raised haematocrit of 0.57 in 2019 at the age of 43 years. Baseline investigations are shown in Table 1. There was no personal history of thrombosis, and she was a regular blood donor from 2010 to 2018. She had been under the anticoagulation service for warfarin monitoring due to a metallic aortic valve that was inserted in 2018 for treatment of bacterial endocarditis with pneumococcal meningitis. She smoked 5–6 cigarettes a day, did not drink alcohol to excess, and her body mass index (BMI) was 20 kg/m2. Ultrasound of the abdomen showed no splenomegaly. The JAK2 V617F mutation and the BCR-ABL1 translocation were not detected in peripheral blood. Bone-marrow examination was performed, and the aspirate, trephine and cytogenetics were reported as normal. Representative slides are shown in Figure 1. Next-generation sequencing (NGS) to investigate the cause of erythrocytosis was therefore performed. This involved two NGS panels in separate laboratories (hereditary erythrocytosis — Oxford, UK;11 and myeloproliferative neoplasm— Birmingham, UK12). Both panels found, independently, the same JAK2 E846D substitution at 50% variant allelic frequency (VAF) but no other abnormality. The elder sister was referred independently for assessment of erythrocytosis in 2020, when she was aged 48, without knowledge of her sister's history. There was a past medical history of learning disability no personal history of thrombosis. She smoked 10–15 cigarettes a day, did not drink alcohol, and her BMI was 32 kg/m2. Ultrasound of the abdomen was normal and bone marrow was not performed. Again, the JAK2 V617F mutation and the BCR-ABL1 translocation were not detected in peripheral blood and the 36-gene myeloproliferative neoplasm [MPN] NGS panel was requested which confirmed the JAK2 E846D substitution at 50% VAF. The sisters' mother was evaluated at the age of 70 and found to have mild erythrocytosis with a highest haematocrit in the last 4 years of 0.49. She has a past medical history which included radiological evidence of emphysema but she was asymptomatic and was taking no regular medication. She smoked 20 cigarettes per day, did not drink alcohol, and BMI was 22 kg/m2. There was no palpable splenomegaly and bone marrow was not performed. Like her daughters, again the 36-gene MPN NGS panel showed the JAK2 E846D substitution at 50% VAF. Laboratory parameters at diagnosis for all three patients are summarised in Table 1. The only other sibling, a brother, has been evaluated outside of our service and we understand he does not have erythrocytosis but genetic testing has not been performed. The father died of lung cancer at the age of 65. The younger sister has on two occasions been treated with venesection to reduce her haematocrit due to symptoms consistent with erythrocytosis. She continues with therapeutic anticoagulation with warfarin for her metallic heart valve and no further venesection has occurred. The elder sister and mother have not undergone venesection and continue to be observed. To reiterate, none of the three patients have ever had an episode of thrombosis. Haematocrit measurements over time are summarised in Figure 2. This is the first report of isolated heterozygous inheritance of the E846D JAK2 substitution associated with erythrocytosis in kindred. Kapralova et al. previously reported a case of a 15-year-old boy with erythrocytosis who was found to be a compound heterozygote for maternal JAK2 E846D and paternal JAK2 R1063H substitutions.10 The mother with the E846D substitution was reported to have significantly increased sensitivity of burst-forming unit erythrocyte progenitors to erythropoietin in vitro. The father with the R1063H substitution was reported to have slightly increased sensitivity. These results correlated with further in vivo work; cell lines transfected with E846D showed increased proliferation in erythropoietin-limiting conditions compared with transfectants harbouring the R1063H substitution alone. Further subsequent screening of a cohort of 99 individuals by the same authors found the JAK2 E846D substitution in two patients with CALR and JAK2 V617-mutated myeloproliferative disorders respectively. Our findings offer some clinical corroboration to Kapralova et al.’s fascinating study. Extensive NGS for MPNs and hereditary erythrocytosis further strengthens our observations (hereditary erythrocytosis is reviewed in detail by Gangat et al.3). There are however weaknesses to our conclusions. Primarily, all three patients smoke which is a reported cause of erythrocytosis. However, since the vast majority of smokers do not have erythrocytosis,13, 14 those who do likely have additional contributory factors. We postulate that JAK2 variants may be one such factor. Crucially, this report represents 127 patient years with no occurrence of thrombosis indicating that germline heterozygous JAK2 E846D substitutions are unlikely to be a strong independent risk factor for thrombosis. Additionally, the magnitude of erythrocytosis is somewhat lower in the mother, illustrating that many factors are at play. Following consultation with national experts a venesection threshold haematocrit of 0.55 has been set, although appreciably this is not well evidence-based and can be altered according to symptoms. The patients will remain under observation in our clinic and if either develops thrombosis, this will be reported. This report had no external funding source. The authors have no relevant conflicts of interest to disclose. The data that support the findings of this study are available from the corresponding author upon reasonable request. All three patients gave informed, written consent for use of their health data in this report." @default.
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• W4283698946 date "2022-06-28" @default.
• W4283698946 modified "2023-10-14" @default.
• W4283698946 title "Heterozygous, germline <scp><i>JAK2</i> E846D</scp> substitution as the cause of familial erythrocytosis" @default.
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• W4283698946 doi "https://doi.org/10.1111/bjh.18320" @default.
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