Jamie Robyn

Multilineage involvement of the fusion gene in patients with FIP1L1/PDGFRA-positive hypereosinophilic syndrome

Myeloproliferative hypereosinophilic syndrome (MHES) is a disorder characterised by male predominance, marked eosinophilia, splenomegaly, tissue fibrosis, elevated serum tryptase and the presence of the FIP1L1/PDGFRA fusion gene in peripheral blood mononuclear cells. The characteristic hypercellular bone marrow with dysplastic eosinophils and spindle‐shaped mast cells suggest that multiple lineages may be involved in the clonal process. To determine which haematopoietic lineages are involved in MHES, we purified cells of specific lineages from patients with MHES and used nested reverse transcription polymerase chain reaction (RT‐PCR), quantitative RT‐PCR and fluorescence in situ hybridisation to analyse the purified cell populations for the presence of the fusion gene. The fusion gene was detected in eosinophils, neutrophils, mast cells, T cells, B cells and monocytes. These results suggest that the mutation arises in a pluripotential haematopoietic progenitor cell capable of giving rise to multiple lineages. The basis for the preferential expansion of eosinophils and mast cells remains unclear.

Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis

Cooperating genetic events are likely to contribute to the phenotypic diversity of KIT-D816V systemic mastocytosis. In this study, 44 patients with KIT-D816V systemic mastocytosis were evaluated for coexisting NRAS, KRAS, HRAS or MRAS mutations. Activating NRAS mutations were identified in 2 of 8 patients with advanced disease. NRAS mutations were not found in patients with indolent systemic mastocytosis. To better understand the clonal evolution of mastocytosis, we evaluated the cell compartments impacted by the NRAS and KIT mutations. Clonal mast cells harbored both mutations. KIT-D816V was not detected in bone marrow CD34+ progenitors, whereas the NRAS mutation was present. These findings suggest that NRAS mutations may have the potential to precede KIT-D816V in clonal development. Unlike other mature lineages, mast cell survival is dependent on KIT and the presence of these two activating mutations may have a greater impact on the expansion of this cell compartment and in resultant disease severity. (Clinicaltrials.gov identifier: NCT00044122, NCT00001756)

Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion

Systemic mastocytosis with an associated hematologic non-mast cell lineage disease is a rare subtype of systemic mastocytosis. This study describes a patient with systemic mastocytosis associated with chronic basophilic leukemia and a PRKG2-PDGFRB fusion gene. This patient had a complete response to imatinib mesylate. See related perspective on page 6. Background Translocations involving region 5q31-32 (PDGFRB) have been reported in a variety of myeloproliferative diseases and are often associated with significant peripheral eosinophilia. We report an unusual case of a patient presenting with peripheral basophilia and systemic mastocytosis in whom cytogenetic analysis revealed a t(4;5)(q21.1;q31.3). Design and Methods We used molecular analyses to determine the role of PDGFRB in this case. The patient was treated with imatinib. Results Fluorescence in situ hybridization (FISH) documented a breakpoint in PDGFRB. In agreement with this, the patient responded very well to imatinib with resolution of clinical symptoms, basophilia, and mast cell disease. Molecular analyses revealed that PDGFRB, encoding an imatinib-sensitive tyrosine kinase, was fused to PRKG2. The fusion gene incorporates the first two exons of PRKG2 fused to the truncated exon 12 of PDGFRB, resulting in the disruption of its juxtamembrane domain. Functional studies confirmed that the activity and transforming properties of PRKG2-PDGFRβ were dependent on the disruption of the auto-inhibitory juxtamembrane domain. Conclusions Our results identify a second case of the PRKG2-PDGFRB fusion and confirm the unusual PDGFRB breakpoint associated with this fusion. This work also illustrates the use of imatinib for the treatment of specific cases of systemic mastocytosis.

Imatinib-Responsive Hypereosinophilia in a Patient with B Cell ALL

Hypereosinophilia is a rare presenting sign of acute lymphocytic leukemia. A 29-year-old male was diagnosed with idiopathic hypereosinophilic syndrome with respiratory symptoms. Although his peripheral blood eosinophilia decreased in response to treatment with imatinib mesylate, a follow-up bone marrow showed a diffuse infiltrate of myeloperoxidase-negative blasts. He was subsequently diagnosed with CD10 positive precursor B lymphoblastic leukemia. This case underscores the importance of follow-up bone marrow examination in patients who demonstrate imatinib mesylate-responsive eosinophilia.

Intracranial venous thrombosis and proteinuria during pregnancy and puerperium

To the Editor: We congratulate Drs. Lanska and Kryscio on their recent analysis.1 There were 31 observed cases of peripartum intracranial venous thrombosis (IVT) in the sample of 281,115 sampled deliveries from 1979 to 1991. As the authors point out, there is a wide range of estimates of risk for IVT in the literature, as many studies used data collected before computed tomography, MRI, and MR angiography (MRA) were readily available. MRI and MRA are now the techniques of choice in the diagnosis and follow-up of IVT.2,3 Interestingly, the authors found that hypertension was not a strong and significant predictor of IVT. Only 3 of the 31 observed women with IVT were hypertensive, and reportedly only one woman with hypertension and IVT had eclampsia. Conversely, Carrol et al.4 reviewed 181 women with IVT in pregnancy and puerperium, of whom 10% were reportedly pre-eclamptic/eclamptic.4 We recently proposed that proteinuria in pre-eclampsia/eclampsia with subsequent decreased functional protein S may play …

Can the long-term prognosis of patients with seizures and structural brain lesions be improved by surgical treatment?

Sillanpää et al.1 demonstrated in their prospective study lasting more than 20 years and involving 220 Finnish children with epilepsy that the majority of these patients were seizure-free by the time they became adults. Interestingly, 123 of the originally recruited 245 children had remote symptomatic seizures. Since the study began before neuroimaging techniques such as computed tomography (CT) and magnetic resonance imaging were readily available, it makes sense that the authors reclassified the cause of seizures in numerous patients, thereby reducing the proportion of patients with cryptogenic epilepsy. Gastaut and Gastaut 2 examined 42 children with Lennox–Gastaut syndrome (LGS) by CT with abnormal findings in 25 patients including four cases of porencephalic cysts. It is notable that, in Sillanp ̈ aä’s study, 33 of 39 epileptics who died had remote symptomatic seizures and that, as expected, patients with remote symptomatic seizures were significantly less likely to have a remission. Their proportion in remission was 10% at 15 years after the onset of epilepsy and 25% at 31 years (n = 123). In contrast, 50% of patients with idiopathic seizures(n = 68)were in remission at 15 years after the onset of epilepsy, and 85% at 31 years. We agree with the author’s suggestion that in selected situations, children and adolescents with persistent seizures may be candidates for surgery. However, timely identification of potential candidates for surgery has suffered from the imprecise definition of medically refractory epilepsy 3. Children with intractable generalized seizures such as West syndrome (WS) and LGS were usually not considered candidates for cortical resection, because the seizure onset could not be localized to one cortical area. However, we have recently shown that e rly(not necessarily after 2 years of appropriate but unsuccessful medical therapy) surgical intervention may benefit children with porencephalic cysts and seizures such as WS and LGS4. Of 37 children, 23 (62%) were seizure-free postoperatively and 32 children (86%) had at least a worthwhile reduction according to Engel’s classification. We did not examine the long-term prognosis including social, educational, and employment outcomes in our retrospective report. It certainly would be interesting to prospectively study patients with structural brain lesions and epilepsy 5, comparing the long-term impact of surgical and medical treatment.