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

系统性肥大细胞增多症是一种临床表现多样的克隆性骨髓增生性疾病，大多数病例与c-kit基因D816 V突变有关。在过去的几年中，系统性肥大细胞增多症患者中KIT D816 V突变的鉴定具有重要的预后意义，这主要是因为酪氨酸激酶受体抑制剂如伊马替尼的可用性。伊马替尼对携带KIT D816 V突变的患者无效，但对显示其他一些c-kit突变的病例有效。 涉及区域5 q31 -32（PDGFRB）的易位已在许多骨髓增生性疾病中报道。我们的特点之一，2例系统性肥大细胞增多症与慢性嗜碱性粒细胞增多症的G显带显示参与5 q32区域和FISH显示，3伙伴基因是PDGFRB。BAC步移揭示了一个新的5-partner基因PRKG 2。有趣的是，PDGFRB基因中的断裂点破坏了质膜区域。功能表征显示PRKG 2/PDGFRB融合基因能够将Ba/F3细胞转化为生长因子非依赖性，并且它是组成性磷酸化的。此外，我们能够证明这些特性需要破坏PDGFRB的跨膜区域，因为当存在完整的跨膜和跨膜区域时，它们会丢失。第二例伊马替尼反应性系统性肥大细胞增多症伴嗜碱性白血病患者的分子特征正在进行中。 在2例侵袭性疾病患者中发现了NRAS的杂合激活点突变，而在惰性疾病患者中不存在NRAS突变。目前用于肥大细胞增多症的临床试验中的大多数药物靶向突变的KIT，尽管对D816 V Kit具有有效的体外活性，但仅显示出适度的临床疗效。因此，这两个独立的获得性激活突变的发现具有在疾病发病机制中合作的潜力，具有重要的治疗意义。 肥大细胞增多症患者有发生与麻醉相关的激发和非激发过敏反应的风险。 为了评估儿童人群中的这种风险，我们检查了1993年至2006年在NIH接受诊断和外科手术麻醉的儿童肥大细胞增多症患者的围麻醉期记录。 此外，我们对该病的临床特征进行了文献综述。22例儿童肥大细胞增多症患者，手术时中位年龄为3.2岁，麻醉后接受29次诊断和外科手术。肥大细胞增多症的所有变体均在本系列中呈现。大多数患者有潮红、瘙痒、GERD和腹痛病史; 1例患者有自发性过敏反应病史。 使用常规麻醉技术，尽管疾病复杂，围手术期过程并不复杂，没有严重的不良事件。得出的结论是，虽然许多药物常规使用的麻醉报告引起肥大细胞脱粒，偏离常规麻醉技术不一定是必要的。 然而，建议了解疾病的麻醉影响，并精心准备治疗可能的不良事件。

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.