The Pathogenesis, Diagnosis, And Treatment Of Systemic Mast Cell Disorders

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Systemic mastocytosis, a clonal myeloproliferative disease with variable clinical manifestations is assoicated in most cases with the D816V mutation in the c-kit gene. The identification of the KIT D816V mutation in patients with systemic mastocytosis has gained a major prognostic significance in the last several years, largely because of the availability of tyrosine kinase receptor inhibitors such as imatinib. Imatinib was shown to be ineffective in patients carrying KIT D816V mutation, but effective in cases displaying some other c-kit mutations. Translocations involving region 5q31-32 (PDGFRB) have been reported in a number of myeloproliferative diseases. We have characterized one of two patients with systemic mastocytosis with chronic basophilia where G-banding revealed involvement of the 5q32 region and FISH revealed that the 3 partner gene was PDGFRB. BAC walking revealed a novel 5partner gene, PRKG2. Interestingly, the breakpoint in the PDGFRB gene disrupted the juxtamembrane region. Functional characterization revealed that the PRKG2/PDGFRB fusion gene was capable of transforming Ba/F3 cells to growth factor independence and that it is constitutively phosphorylated. Further, we were able to show that these properties require disruption of the juxtamembrane region of PDGFRB because they were lost when the full juxtamembrane and transmembrane regions were present. Molecular characterization of the second patient with imatinib-responsive systemic mastocytosis with basophilic leukemia is in progress. Heterozygous activating point mutations in NRAS were identified in two patients with aggressive disease while NRAS mutations were absent in patients with indolent disease. Most agents in current clinical trials for mastocytosis target mutated KIT and, despite potent in vitro activity against D816V Kit, have displayed only modest clinical efficacy. Therefore, this finding of two independent acquired activating mutations with the potential to cooperate in disease pathogenesis, has significant therapeutic implications. Patients with mastocytosis are said to be at risk to develop provoked and unprovoked episodes of anaphylaxis associated with anesthesia. To evaluate this risk in the pediatric population, we examined peri-anesthetic records of patients with pediatric mastocytosis who were anesthetized for diagnostic and surgical procedures at NIH from 1993 to 2006. In addition, we conducted a literature review of the clinical features of the disease. Twenty-two patients with pediatric mastocytosis, with a median age of 3.2 years at the time of the procedure, were anesthetized for 29 diagnostic and surgical procedures. All variants of mastocytosis were represented in this series. Most patients had a history of flushing, pruritus, GERD and abdominal pain; one patient had history of spontaneous anaphylaxis. Routine anesthetic techniques were used and despite the complexity of the disease, the peri-operative courses were uncomplicated and without serious adverse events. It was concluded that while many drugs used routinely in anesthesia reportedly cause mast cell degranulation, deviations from routine anesthesia techniques are not necessarily warranted. However, an understanding of the anesthetic implications of the disease and meticulous preparation to treat possible adverse events were advised.