Rare pathogenic variants in the PTPN11, KRAS, SOS1 and RAF1 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 PTPN11 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].

Congenital pulmonary lymphangiectasia (CPL) is associated with fetal pulmonary venous obstructive physiology. The precise morbidity of CPL is unknown as CPL is generally fatal in neonates. Here, we report an infant with secondary CPL in total anomalous pulmonary venous connection (TAPVC). He developed severe pulmonary hypertension (PH) after corrective surgery for TAPVC. However, cardiac catheterization showed mild left pulmonary venous obstruction (PVO), which was deemed unnecessary for re-intervention. He died at 11 months-old due to an exacerbation of PH. Autopsy revealed medial hypertrophy of the pulmonary arteries, mild left PVO, and marked dilatation and proliferation of the pulmonary lymphatics which might have been involved in the PH, although CPL was not conclusively identified based on the previous biopsy findings. We should be aware of the possibility of CPL in addition to postoperative PVO when encountering patients with fetal pulmonary venous obstructive physiology. Furthermore, a cautious approach to the interpretation of lung biopsy results is warranted.

To elaborate the clinical characteristics of congenital pulmonary lymphangiectasia in a neonate with hydrops fetalis. This could be an alert in considering it as a differential diagnosis for neonates with acute respiratory failure. We reviewed and analyzed single-center registry patients who underwent cadaveric autopsies in the Department of Pathology at Children's Hospital from January 1, 2010 to December 31, 2021. We aimed to explore the perinatal clinical manifestations associated with congenital pulmonary lymphangiectasis (CPL). Literature was reviewed to summarize the common features of CPL in pregnancy from individual cases, and to facilitate prenatal and intrapartum diagnosis prognosis, and assessment of medical emergencies. Thirty-four patients were included, and the main causes of death were intrauterine infection (n = 6), severe pneumonia (n = 11), spontaneous pneumothorax (n = 3), hemorrhagic shock (n = 2), CPL (n = 1), and other non-respiratory failure manifestations (n = 12). The manifestations of respiratory distress in CPL were different from those of intrauterine infections and respiratory failure due to parenchymal lung lesions. These include prenatal presentation of fetal edema, postnatal presentation of uncorrectable respiratory failure with severe hypoproteinemia, pneumothorax and interstitial emphysema on imaging, and poor response to treatment with surfactant-like substances. Thus, when the pregnancy tests reveal fetal edema and postnatal presentation of acute, respiratory distress, the diagnosis of CPL should be considered first, and corresponding medical care should be implemented to improve the survival rate. CPL is a rare pulmonary defect, and its perinatal clinical manifestations can often be neglected. For children with prenatal fetal edema who die after birth due to progressive respiratory distress, a timely autopsy is of utmost importance to clarify the etiology, improve understanding of CPL, and diagnose early to allow for proper prenatal and postnatal care.

Pulmonary lymphangiectasia (PL) is a rare congenital disorder of pulmonary lymphatic development. Although it was traditionally a fatal disorder of infancy, some cases in later childhood have been reported, suggesting a spectrum of severity. We present an unusual case of unilateral, congenital pulmonary lymphangiectasia. Our patient presented with neonatal respiratory distress, a chronic wet cough and recurrent episodes of bronchitis. Chest CT revealed thickening of the interlobular septae of the right lung. A lung biopsy confirmed the diagnosis of lymphangiectasia. His clinical course is characterized by chronic coughing and recurrent bronchitis but normal growth and development. This case illustrates a relatively mild presentation of unilateral PL, which, along with other reports, suggests variability in the presentation and severity of this disorder. In the absence of imaging and histological examination, mild presentations may go undiagnosed.

A Chinese male infant was born at 35 weeks weighing 2935 g to a mother with polyhydramnios and prenatal hydrops fetalis. He developed marked respiratory distress secondary to bilateral congenital chylothorax and required pleural drainage, high frequency oscillation and inhaled nitric oxide therapy. He was extubated to non-invasive ventilation by day 14. There was no bacterial or intrauterine infection, haematologic, chromosomal or cardiac disorder. He was exclusively fed medium-chain triglyceride formula. High-resolution CT showed diffuse interstitial lung disease. He received a dexamethasone course for chronic lung disease to facilitate supplemental oxygen weaning. A multidisciplinary team comprising neonatology, pulmonology, haematology, interventional radiology and thoracic surgery considered congenital pulmonary lymphangiectasia as the most likely diagnosis and advised open lung biopsy, lymphangiography or scintigraphy for diagnostic confirmation should symptoms of chylothorax recur. Fortunately, he was weaned off oxygen at 5 months of life, and tolerated human milk challenge at 6 months of life and grew well.