De Brouchoven Isabel, Lorand Juan, Bofferding Léon, Sorlin Arthur, Van Damme An, Danhaive Olivier
Division of Neonatology, Saint-Luc University Hospital, UCLouvain, Brussels, Belgium.
Division of Neonatology, Kannerklinik, Luxembourg Hospital Center, Luxembourg, Luxembourg.
Front Pediatr. 2025 Feb 18;13:1475143. doi: 10.3389/fped.2025.1475143. eCollection 2025.
Rare pathogenic variants in the and genes are the main molecular causes of Noonan syndrome (NS). Most are dominant gain-of-function variants that cause an overactivation of the RAS/MAPK signaling pathway leading to uncontrolled cell proliferation in many organs and systems. Albeit phenotypically heterogeneous, NS can be associated with severe cardiovascular and lymphatic anomalies, potentially lethal during infancy, neonatal and fetal periods. MEK inhibitors, a class of drugs targeting the final steps of the RAS/MAPK pathway and originally developed for cancer therapy, have been tested in preclinical studies as a targeted treatment for NS. These studies led to the occasional off-label use of MEK inhibitors in patients with RASopathies.
We report the case of a preterm infant with congenital pulmonary lymphangiectasis, chylothorax and hypoxic respiratory failure refractory to conventional management, who was treated with trametinib after identification of a NS class 5 variant. We performed a systematic review of the current published evidence on trametinib efficacy and safety for severe respiratory and/or cardiac manifestations in infants and children with Noonan syndrome, querying PubMed, Embase, Cochrane and Scopus databases, following the PRISMA guideline for systematic reviews, and using the Joanna Briggs Institute (JBI) Critical Appraisal tool for quality assessment of published evidence.
In our patient, a five-week trametinib course, maximum dose 0.025 mg/kg/day, led to chylothorax resolution and gradual pulmonary function improvement, allowing extubation to non-invasive support, discharge home at a corrected age of 4 months, and weaning off home oxygen therapy by 10 months. No formal clinical trial of trametinib in neonatal/pediatric Noonan syndrome has been published to our knowledge. We collected 16 published cases, and added this case for reviewing trametinib regimen, efficacy and safety. A short-term improvement of symptoms was reported in all cases, with three deaths presumably unrelated to trametinib. Moderate side effects were reported in a subset of patients. Long-term follow-up data were not available.
Trametinib is a promising drug in NS. Clinical trials are warranted to establish safety, efficacy, and standardized protocols for the use of trametinib as a rescue therapy in critically ill children and explore its potential place in the treatment of various NS comorbidities.
clinicaltrials.gov, identifier [NCT06555237].
PTPN11和KRAS基因中的罕见致病变异是努南综合征（NS）的主要分子病因。大多数是显性功能获得性变异，可导致RAS/MAPK信号通路过度激活，从而导致许多器官和系统中细胞不受控制地增殖。尽管NS在表型上具有异质性，但可伴有严重的心血管和淋巴异常，在婴儿期、新生儿期和胎儿期可能致命。MEK抑制剂是一类靶向RAS/MAPK通路最后步骤的药物，最初开发用于癌症治疗，已在临床前研究中作为NS的靶向治疗进行了测试。这些研究导致MEK抑制剂偶尔在患有RAS病的患者中被超说明书使用。
我们报告了一例早产婴儿，患有先天性肺淋巴管扩张症、乳糜胸和对传统治疗无效的低氧性呼吸衰竭，在鉴定出NS 5类变异后接受了曲美替尼治疗。我们按照系统评价的PRISMA指南，使用乔安娜·布里格斯研究所（JBI）批判性评价工具对已发表证据进行质量评估，对PubMed、Embase、Cochrane和Scopus数据库进行检索，系统回顾了目前已发表的关于曲美替尼治疗努南综合征婴幼儿严重呼吸和/或心脏表现的疗效和安全性的证据。
在我们的患者中，为期五周的曲美替尼疗程，最大剂量0.025 mg/kg/天，导致乳糜胸消退，肺功能逐渐改善，得以脱机至无创支持，在矫正年龄4个月时出院，并在10个月时停用家庭氧疗。据我们所知尚未发表曲美替尼治疗新生儿/儿童努南综合征的正式临床试验。我们收集了16例已发表的病例，并加入本病例以回顾曲美替尼治疗方案、疗效和安全性。所有病例均报告症状有短期改善，3例死亡可能与曲美替尼无关。部分患者报告有中度副作用。尚无长期随访数据。
曲美替尼在NS治疗中是一种有前景的药物。有必要开展临床试验以确定曲美替尼作为危重症儿童抢救治疗的安全性、疗效和标准化方案，并探索其在治疗各种NS合并症中的潜在地位。
clinicaltrials.gov，标识符 [NCT06555237]
