Division of Pediatric Cardiology, University of Tennessee, Le Bonheur Children's Hospital, Memphis, Tennessee.
Department of Clinical Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Pediatrics. 2022 Oct 1;150(4). doi: 10.1542/peds.2022-056336.
A 15-year-old-boy with Noonan syndrome and status post orthoptic heart transplant developed mixed mitral valve disease and underwent mechanical mitral valve replacement 6 months before presentation with acute respiratory distress. He developed massive pulmonary hemorrhage that required veno-venous extracorporeal membrane oxygenation (ECMO) support. He had a prolonged anticoagulation free ECMO course of 4 weeks, with ongoing recurrent pulmonary hemorrhage and underwent several rounds of coil embolization of aortopulmonary collaterals. ECMO course was complicated by significant nasopharyngeal bleeding that required embolization of the sphenopalatine artery. Shortly after decannulation, he developed massive gastrointestinal and peritoneal hemorrhage that was treated by embolization of the left gastric artery and a branch of the internal iliac artery. His bleeding was attributed to neo-angiogenesis. Initial treatment with propranolol was unsuccessful. Subsequent treatment with interferon α 2b demonstrated efficacy, but severe neutropenia required cessation of therapy. Because functional alterations of the rat sarcoma virus-mitogen activated protein kinase signaling pathway and protein tyrosine phosphatase nonreceptor type (PTPN11) mutations in Noonan syndrome are known to be associated with neo-angiogenesis, we used the mitogen-activated protein kinase inhibitor selumetinib as a gene-targeted therapy with the hope of controlling bleeding and inhibiting neo-angiogenesis. After initiation of selumetinib, bleeding stopped and allowed the patient to be discharged from the hospital on dipyridamole as antiplatelet prophylaxis for his mechanical mitral valve. He had no further bleeding episodes through 1 year after hospital discharge.
一名 15 岁男孩患有努南综合征，曾接受过眼科心脏移植手术，因混合性二尖瓣疾病在出现急性呼吸窘迫症前 6 个月接受了机械二尖瓣置换术。他发生了大量肺出血，需要静脉-静脉体外膜肺氧合（ECMO）支持。他接受了长达 4 周的无抗凝 ECMO 治疗，期间持续发生复发性肺出血，并进行了几次升主动脉-肺动脉侧支循环的线圈栓塞。ECMO 治疗期间出现严重的鼻咽出血，需要进行蝶腭动脉栓塞。脱机后不久，他发生了大量胃肠道和腹膜出血，通过栓塞胃左动脉和髂内动脉的一支分支进行了治疗。他的出血归因于新生血管形成。最初使用普萘洛尔治疗无效。随后使用干扰素 α 2b 治疗显示出疗效，但严重的中性粒细胞减少症需要停止治疗。因为已知大鼠肉瘤病毒-有丝分裂原激活蛋白激酶信号通路的功能改变和努南综合征中的蛋白酪氨酸磷酸酶非受体型（PTPN11）突变与新生血管形成有关，我们使用丝裂原激活蛋白激酶抑制剂 selumetinib 作为基因靶向治疗，希望能够控制出血并抑制新生血管形成。开始使用 selumetinib 后，出血停止，使患者在出院时停用双嘧达莫作为机械二尖瓣的抗血小板预防。出院后 1 年，他没有再发生出血事件。
