Clinical and Molecular Findings in Childhood Polycythemia Vera.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4961-4961
Author(s):  
Holger Cario ◽  
Heike L. Pahl ◽  
Minkov Milen ◽  
Reinhard Harald ◽  
Elisabeth Kohne ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Polycythemia Vera ◽  
Age Of Onset ◽  
Age At Onset ◽  
Treatment Strategies ◽  
Jak2v617f Mutation ◽  
Treatment Modalities ◽  
Unrelated Donor ◽  
Budd Chiari Syndrome ◽  
Chiari Syndrome

Abstract Background: Polycythemia vera (PV) and congenital erythrocytoses constitute extremely rare diseases in pediatric and juvenile patients. Systematic data on clinical and laboratory evaluations as well as on treatment modalities are sparse. Aims/Methods: We developed a protocol (PV-ERY-KA 03) for the systematic collection of clinical, hematological, biological as well as treatment data of children and adolescents with PV or congenital erythrocytoses. The collaborative trial was initiated in March 2004. Results: To date, 5 (2 male / 3 female) pediatric patients with PV have been enrolled. The median age at onset was 14 years (7–18.5 years). 4/5 patients are of German, 1/5 of Turkish origin. Only 3 patients presented with PV-related symptoms (Budd-Chiari syndrome, isolated headache, or headache together with tinnitus, dizziness and weakness). At first presentation, the median hemoglobin content was 18 g/dl (15.5–21.1 g/dl), the median hematocrit 0.60 (0.59–0.73). Thrombocytosis was present in 4/5, leukocytosis in 2/5 patients. All patients presented with mild to marked splenomegaly. Granulocytic PRV-1-mRNA expression and JAK2V617F mutation were assessed in 4/5 patients. PRV-1-mRNA expression was significantly elevated in 3 of them and borderline the 4th patient. 3 patients including the patient with borderline PRV-1-mRNA expression presented with a heterozygous JAK2V617F mutation. Treatment strategies included phlebotomy (4/5), hydroxyurea (1/5), IFN-alpha (1/5), and aspirin (3/5). Stem cell transplantation from a matched unrelated donor was performed in one patient (now in complete remission). Because of progressive liver failure, the patient with Budd-Chiari syndrome underwent orthotopic liver transplantation. Conclusions: The activating JAK2V617F mutation previously reported to be present in up to 90 percent of adult PV patients, is also involved in childhood PV. The age of onset and clinical presentations in the rare cases of childhood PV are varied. Different treatment strategies are applied. A collaborative assessment of children with PV may help to optimise treatment in these patients, but may in addition contribute to a better general understanding of the disease’s pathogenesis.

Polycythemia vera-geïnduceerd syndroom van Budd-Chiari bij een oudere patiënte

2021 ◽  
Author(s):  
S. VAN DESSEL ◽  
W. LALEMAN ◽  
E. GIELEN
Keyword(s):  
Polycythemia Vera ◽  
Myeloproliferative Neoplasms ◽  
Laboratory Data ◽  
Jak2 V617f ◽  
Budd Chiari Syndrome ◽  
Older Patient ◽  
Aged Patients ◽  
Chiari Syndrome ◽  
Hepatic Venous Outflow ◽  
Venous Outflow Obstruction

Polycythemia vera-induced Budd-Chiari syndrome in an older patient The case of a 94-year-old patient with subacute Budd-Chiari syndrome (BCS) caused by a novel diagnosis of polycythemia vera (PV) is reported. BCS is mostly seen in young or middle-aged patients. The presentation in a nonagenarian is rare, making this case exceptional. BCS is defined by a hepatic venous outflow obstruction. Its clinical presentation is variable from fulminant liver failure to an insidious form with symptoms of cirrhosis at the time of the diagnosis. In western countries, primary BCS is mainly seen, which is caused by an endoluminal lesion. A hypercoagulable state provoked by myeloproliferative neoplasms (MPN) is mostly responsible. The patient presented with abdominal distention and anorexia since two months. Physical examination revealed hepatomegaly and ascites. Laboratory data indicated polycythemia and cholestasis. The CT scan of the abdomen was diagnostic for subacute BCS. A JAK2-V617F mutation was found. The therapy consisted of anticoagulation, low-dose acetylsalicylic acid, phlebotomies and supportive care with diuretics and paracentesis.

The JAK2V617F Mutation Is Present in the Liver Endothelial Cells of Patients with Budd-Chiari Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2795-2795
Author(s):  
Selcuk Sozer ◽  
Isabel M. Fiel ◽  
Thomas Schiano ◽  
Faye Feller ◽  
John Mascarenhas ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Liver Biopsy ◽  
Jak2v617f Mutation ◽  
Proliferative Potential ◽  
Wild Type ◽  
Budd Chiari Syndrome ◽  
Jak2 Mutation ◽  
Vein Thrombosis ◽  
Specific Pcr ◽  
Chiari Syndrome

Abstract Post-natal vasculogenesis has been reported to be derived from a hierarchy of circulating endothelial progenitor cells (EPC). Some of these EPC are of myeloid origin while others have a more robust proliferative potential and are solely of endothelial cell (EC) origin. A number of groups have hypothesized that EC dysfunction might contribute to the hypercoagulable state associated with polycythemia vera (PV) by orchestrating the recruitment of blood elements to sites of injury or by regulating vascular tone. The JAK2V617F mutation is present in >95% of patients with PV. In addition, some individuals with normal blood counts who develop splanchnic vein thrombosis, including Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) have been reported to have JAK2V617F positive hematopoiesis (45% and 34%, respectively) indicating that this thrombotic tendency might precede the development of PV. We explored whether this activating mutation is present in EC in the vessels of patients with BCS. We tested this hypothesis by studying EC in venules of liver biopsy specimens of patients with BCS with (n=2) or without PV (n=1) and PVT (n=2) without PV using laser capture microdissection (LCM) followed by nested PCR or RT-PCR in order to determine if EC were JAK2V617F positive and were of hematopoietic or EC origin. EC from the hepatic venules of BCS and PVT patients were captured by LCM from hematoxylin and eosin stained sections of archival formalin-fixed paraffin-embedded liver biopsy tissue specimens. EC were identified by their fusiform nuclei and their location along the lining of the hepatic venules. Hepatocytes were identified by their morphology as having round centrally placed nuclei and abundant cytoplasm with a trabecular arrangement. At least 10 EC and 10 hepatocytes from each biopsy specimen were captured and DNA or RNA was extracted. The JAK2V617F mutation was detected using nested allele-specific PCR. The hepatocytes of each patient contained exclusively wild type JAK2 while the EC of the two BCS patients with PV were homozygous for the JAK2V617F. The EC of the other BCS patient and 2 PVT patients who did not have PV contained exclusively wild type JAK2. The EC identity of these cells in the PV patients was confirmed by the presence of the EC transcripts (VE-Cadherin and VEGF-R2) and the absence of hematopoietic cell transcripts (CD45 and CD14). These findings indicate that hepatic venule EC in BCS patients with PV are JAK2V617F positive. The presence of JAK2V617F in both endothelial cells and hematopoietic cells belonging to such patients suggests that PV originates in an adult hemangioblast like cell in such patients. Further studies are required to understand the consequence of JAK2 mutation in EC as related to their propensity to thrombosis in PV.

Prevalence of 46/1 JAK2 Haplotype in Patients with Budd-Chiari Syndrome with and without JAK2V617F and TET2 Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 434-434
Author(s):  
Nicholas C Lea ◽  
Lara N Roberts ◽  
Raj K Patel ◽  
Rachel Westbrook ◽  
Michael A Heneghan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Skin Biopsy ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Family Members ◽  
Uniparental Disomy ◽  
Cellular Growth ◽  
Jak2v617f Mutation ◽  
Budd Chiari Syndrome ◽  
Chiari Syndrome

Abstract Abstract 434 Budd-Chiari Syndrome (BCS) is a group of disorders resulting from obstruction to hepatic venous outflow; myeloproliferative disorder (MPD) accounts for 10-40% of cases. We previously described latent MPD in 58.5% of patients with idiopathic BCS, detected with allele-specific PCR for the JAK2V617F mutation and proposed its use as a screening tool for occult MPD. A predisposing germline JAK2 haplotype (designated 46/1) has since been described as a strong genetic risk factor for MPD and may further characterise latent MPD in BCS. We studied 28 patients with BCS (23 from our original cohort; female n=16, mean age 30.3 years, SD 10) presenting between 1985 and 2008; 14 with the JAK2V617F mutation. Genomic DNA was obtained from archived bone marrow films, fractionated and unfractionated peripheral blood or bone marrow leucocytes. Skin biopsy or CD3+ cells were used as a source of constitutional DNA. DNA was analysed by pyrosequencing for 2 SNPs (rs12340895, rs12343867) which tag the 46/1 JAK2 haplotype. The 46/1 haplotype was detected in 16/28 (57.1%) subjects; 50% of those with the JAK2V617F mutation and 64.3% of those without it. The prevalence in those lacking the JAK2V617F mutation is significantly higher than the frequency in the Wellcome Trust Case Control Consortium cohort of 24% (P=0.0023). 3/28 subjects had previously diagnosed JAK2V617F positive Polycythemia Vera (PV) and all had the 46/1 haplotype, resulting in a prevalence of 36.4% in those with JAK2V617F positive latent MPD. Age at presentation of BCS was significantly lower in those with the 46/1 haplotype (26.4 years compared to 34.8 years, P=0.03). This difference remained significant in those lacking the JAK2V617F mutation (24.0 years compared to 37.6 years, P=0.024) but was not seen in those with the JAK2V617F mutation (P=0.547). There was no difference in presenting clinical features, haematological parameters or treatment between those with and without the 46/1 haplotype. Overall survival in 26/28 patients was 76.9% (median 90 months, range 2 days to 266 months). 17/28 subjects underwent OLT of which 14/17 (11/12 with 46/1 haplotype) are alive at a median of 90 months post transplant (range 9-266 months). 3/17 patients developed post-OLT veno-occlusive disease, all with the JAK2V617F mutation and 2/3 with the 46/1 haplotype. Overt MPD has not developed in any patient without the JAK2V617F mutation; repeat JAK2 mutational analysis was undertaken in 3/14 (2/3 with 46/1 haplotype) and none have acquired the mutation at a mean of 54 months. 19/28 cases were genotyped using SNP markers (Affymetrix SNP6); 3/19 have acquired uniparental disomy (aUPD) on 9p overlapping the JAK2 gene. As TET2 has been postulated as a ‘pre-JAK2' aberration, we sequenced the complete TET2 gene using massively parallel high throughput sequencing (Roche 454); 2/15 patients samples were positive for TET2 mutations. One of our cases had a familial history of PV; the patient, his father and uncle all have JAK2V617F positive PV and were heterozygous for the 46/1 haplotype in DNA extracted from a skin biopsy. 2/3 were homozygous for both the 46/1 haplotype and JAK2V617F mutation in bone marrow granulocytes with SNP6 array data confirming aUPD on 9p. JAK2V617F was detected in cultured in vitro colonies from all 3 family members. All 3 affected family members had normal cytogenetics and normal TET2 gene. 3 unaffected siblings were heterozygous for the 46/1 haplotype both in peripheral blood, CD3+ cells and granulocytes but negative for JAK2V617F mutation and lacked aUPD on 9p. We have found a highly significant prevalence of the 46/1 haplotype in our cohort of BCS, as well as in family members of a patient with JAK2V617F positive BCS and PV. The 46/1 haplotype was detected in patients with idiopathic BCS with and without the JAK2V617F mutation, suggesting a predisposition to idiopathic BCS independent of JAK2V617F mutation acquisition and latent MPD. The prevalence and lower age of presentation in those with the 46/1 haplotype lacking the JAK2V617F mutation supports an alternate, as yet unknown, mechanism predisposing to BCS. The presence of the 46/1 haplotype in unaffected relatives of our JAK2V617F BCS patient suggests that additional germline variation may predispose to or protect from acquisition of JAK2V617F positive disease. Alternatively the 46/1 haplotype may directly confer a cellular growth advantage via increased responsiveness of JAK2 to cytokine stimulation. Disclosures: No relevant conflicts of interest to declare.

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