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，在大多数情况下与KIT中的D816 V突变相关。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。 JAK 2（JAK 2 V617 F）和RAS基因家族中的激活突变与骨髓增生性疾病相关。 我们将继续对成人肥大细胞增多症患者进行这些基因突变的筛查。 在2例侵袭性系统性肥大细胞增多症患者（2/10，20%）中发现了NRAS中获得性杂合激活点突变。 惰性疾病患者中不存在NRAS突变。 1例血小板增多症惰性患者（1/14; 7%）携带杂合JAK 2 V617 F点突变。 临床试验中用于侵袭性肥大细胞增多症的大多数药物靶向KIT，尽管体外活性强，但临床疗效中等。因此，发现具有在疾病发病机制中合作的潜力的激活突变具有重要的治疗意义。 儿童肥大细胞增多症通常表现为色素性荨麻疹，较少表现为弥漫性皮肤肥大细胞增多症。虽然文献表明，疾病往往解决，有一个移动到更积极的治疗肥大细胞增多症在生命的早期。我们探讨了儿童发病的疾病的长期预后，通过检查17名儿童肥大细胞增多症，我们在1989年报告。 我们成功联系了其中15名患者，并收集了有关其临床状态的数据。原始骨髓标本重新染色，重新检查，并与疾病的结果使用共识标准。5例持续性疾病患者中有3例接受了重复骨髓活检。15例患者中有10例（67%）的皮肤发现和症状（临床疾病严重程度）定义为疾病完全消退。3例患者有重大（20%）和2个部分消退的疾病（13%）。对3例持续性疾病患者进行重复骨髓检查，根据1例疾病部分消退患者的骨髓检查结果记录了全身性肥大细胞增多症，该患者是唯一具有全身性疾病初始形态学证据的患者。在其余2例患者中，1例表现出部分消退，另1例表现出疾病的主要消退;两例均无全身性肥大细胞增多症的证据。这项研究表明，最初的骨髓活检是预后的，因为那些没有全身性疾病的证据经历了疾病的消退;并且肥大细胞增多症患儿的长期预后非常令人鼓舞。 我们将继续评估系统性肥大细胞增多症的新临床标志物。由于5-羟色胺与某些慢性疾病相关的临床症状的发生有关，我们测定了29例诊断为肥大细胞增多症的患者的全血5-羟色胺水平，并将这些水平与多种临床和实验室参数相关联。 血清素值较低的患者出现疲劳、偏头痛、精神症状、腹泻、潮红、腹痛和骨痛的几率明显较高。 人糜蛋白酶是一种由肥大细胞表达的高效血管紧张素II生成丝氨酸肽酶。 一种新的和敏感的检测方法被用来确定肥大细胞增多症患者血清糜酶水平。在大多数系统性肥大细胞增多症患者的血清中检测到天然糜酶活性。 肥大细胞增多症的这些临床标志物的鉴定可能有助于疾病分类，确定预后和改善治疗方案。

Systemic mastocytosis, a clonal myeloproliferative disease with variable clinical manifestations, is associated in most cases with the D816V mutation in KIT. 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. Activating mutations in JAK2 (JAK2 V617F) and the RAS gene family are associated with myeloproliferative diseases. We continue to screen adult patients with mastocytosis for mutations in these genes. Acquired heterozygous activating point mutations in NRAS were identified in two patients with aggressive forms of systemic mastocytosis (2/10, 20%). NRAS mutations were absent in patients with indolent disease. One indolent patient with thrombocytosis (1/14; 7%) harbored a heterozygous JAK2 V617F point mutation. Most agents in clinical trials for aggressive mastocytosis target KIT and, despite potent in vitro activity, have displayed modest clinical efficacy. Therefore, the finding of activating mutations with the potential to cooperate in disease pathogenesis has significant therapeutic implications. Pediatric onset mastocytosis usually presents as urticaria pigmentosa; and less often as diffuse cutaneous mastocytosis. While the literature indicates that disease often resolves, there has been a move to more aggressive therapy for mastocytosis early in life. We addressed the long term prognosis of pediatric-onset disease by examining 17 children with mastocytosis which we had reported on in 1989. We successfully contacted 15 of these patients and data was collected regarding their clinical status. Original bone marrow specimens were re-stained, re-examined, and correlated with disease outcome using consensus criteria. Three of five patients with persistent disease underwent repeat bone marrow biopsies. There was complete regression of disease as defined by cutaneous findings and symptoms (clinical disease severity) in 10 of 15 patients (67%). Three patients had major (20%) and two had partial regression of disease (13%). Repeat marrow examinations on three patients with persistent disease documented systemic mastocytosis based on marrow findings in one patient who had partial regression of disease and was the only patient with initial morphologic evidence of systemic disease. Of the remaining two patients, one demonstrated partial regression and the other major regression of disease; and neither had evidence of systemic mastocytosis. This study demonstrates that initial bone marrow biopsies were prognostic in that those without evidence of systemic disease experienced disease regression; and that the long term prognosis for children managed symptomatically with mastocytosis is highly encouraging. We continue to assess new clinical markers for systemic mastocytosis. As serotonin has been implicated in the genesis of clinical symptoms found in association with some chronic diseases, we determined the whole blood serotonin levels in 29 patients diagnosed with mastocytosis, and correlated these levels with multiple clinical and laboratory parameters. Patients with lower serotonin values had significantly greater rates of fatigue, migraine headaches, psychiatric symptoms, diarrhea, flushing, and abdominal and bone pain. Human chymase is a highly efficient angiotensin II-generating serine peptidase expressed by mast cells. A novel and sensitive assay was utilized to determine serum chymase levels in mastocytosis patients. Native chymase activity was detected in the serum of most subjects with systemic mastocytosis. Identification of these clinical markers in mastocytosis may help with disease classification, determining prognosis and improved treatment options.