Pascarella Antonia, Limongelli Giuseppe, De Falco Alessandro, Minale Elia Marco Paolo, Di Nardo Giangiacomo, Di Marco Giovanni Maria, Zito Marinosci Geremia, Olimpico Giorgia, Siani Paolo, De Brasi Daniele
Unit of Chronic and Multifactorial Diseases, Santobono-Pausilipon Children's Hospital, 80129 Naples, Italy.
Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Monaldi Hospital, 81031 Naples, Italy.
Children (Basel). 2024 Oct 31;11(11):1342. doi: 10.3390/children11111342.
RASopathies are a group of genetic syndromes caused by germline mutations in genes involved in the RAS/Mitogen-Activated Protein Kinase signaling pathway, which regulates cellular proliferation, differentiation, and angiogenesis. Despite their involvement at different levels of this pathway, RASopathies share overlapping clinical phenotypes. Noonan syndrome is the most prevalent RASopathy, with an estimated incidence of 1 in 2500 live births, and it is typically inherited in an autosomal dominant manner, with 50% of cases involving gain-of-function mutations in the PTPN11 gene. De novo mutations are common, accounting for 60% of cases. The phenotype of Noonan syndrome includes characteristic facial and physical features, congenital cardiac defects, lymphatic and cerebrovascular anomalies, renal malformations, hematological abnormalities, developmental issues, and an increased risk of cancer. Severe congenital cardiac defects and lymphatic abnormalities significantly impact prognosis, contributing to increased morbidity and mortality. Recent therapeutic advancements have introduced trametinib, an MEK1/2 inhibitor, for treating Noonan syndrome patients with severe cardiac and lymphatic complications. To assess its efficacy, here, we present a case of a newborn with Noonan syndrome who exhibited refractory chylothorax, ventricular hypertrophy, and pulmonary stenosis who was treated with trametinib. The patient demonstrated significant improvement in chylothorax and left ventricular hypertrophy, though pulmonary stenosis persisted. This case further confirms trametinib's potential as a therapeutic option for severe Noonan syndrome complications, emphasizing the need for further clinical trials to optimize treatment protocols and evaluate long-term outcomes.
RASopathies是一组由RAS/丝裂原活化蛋白激酶信号通路相关基因的种系突变引起的遗传综合征，该信号通路调节细胞增殖、分化和血管生成。尽管它们在该通路的不同水平发挥作用，但RASopathies具有重叠的临床表型。努南综合征是最常见的RASopathy，估计发病率为1/2500活产，通常以常染色体显性方式遗传，50%的病例涉及PTPN11基因的功能获得性突变。新发突变很常见，占病例的60%。努南综合征的表型包括特征性的面部和身体特征、先天性心脏缺陷、淋巴和脑血管异常、肾脏畸形、血液学异常、发育问题以及患癌风险增加。严重的先天性心脏缺陷和淋巴异常显著影响预后，导致发病率和死亡率增加。最近的治疗进展引入了曲美替尼，一种MEK1/2抑制剂，用于治疗患有严重心脏和淋巴并发症的努南综合征患者。为了评估其疗效，在此，我们报告一例患有努南综合征的新生儿病例，该患儿表现为难治性乳糜胸、心室肥大和肺动脉狭窄，接受了曲美替尼治疗。患者的乳糜胸和左心室肥大有显著改善，尽管肺动脉狭窄仍然存在。该病例进一步证实了曲美替尼作为严重努南综合征并发症治疗选择的潜力，强调需要进一步进行临床试验以优化治疗方案并评估长期结果。
