Molecular targeted treatment in infants with central conducting lymphatic anomalies.

UNLABELLED: Central conducting lymphatic anomaly (CCLA) is a rare and potentially life-threatening vascular malformation characterized by impaired central lymphatic flow. Hydrops fetalis and congenital hydro-/chylothorax are common neonatal presentations; however, diagnosing CCLA poses challenges and requires advanced imaging. Management typically includes supportive therapies with limited effect, such as medium-chain triglyceride (MCT) diet, octreotide or propranolol, and thoracic drainage. Upcoming treatment options with mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MEK) inhibitors have shown promising results in vascular anomalies driven by dysregulated PI3K/AKT/mTOR and RAS/RAF/MAPK signalling pathways. However, data on neonatal use remain scarce. This series describes infants (gestational age 29 + 3-40 + 4 weeks) with neonatal-onset CCLA treated with mTOR and/or MEK inhibitors (age IQR: 27-57 days), detailing clinical presentations, imaging, genetic findings, and outcomes. Genetic testing included germline and somatic variant analysis. Most patients underwent dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) for diagnosis and to guide management. Pathogenic germline variants were identified in four patients; three had no genetic diagnosis. DCMRL revealed heterogeneous phenotypes; follow-up imaging showed improved lymphatic flow. Substantial clinical improvement occurred following mTOR and/or MEK inhibitor treatment (sirolimus and/or trametinib). In most cases, therapy was tapered within weeks; no relapses occurred (mean follow-up 10.3 months). No deaths or other severe adverse events occurred during inhibitor treatment.

CONCLUSION

This series describes infants with CCLA, treated with mTOR and/or MEK inhibitors early after birth, with rapid improvement possibly reflecting treatment response leading to functional recovery during a critical developmental phase of the lymphatic system.

WHAT IS KNOWN: • Central conducting lymphatic anomalies are rare conditions associated with high morbidity and mortality, especially in neonates. • Molecular targeted therapies such as MEK inhibitors and mTOR inhibitors show promise in vascular anomalies driven by upregulated PI3K/AKT/mTOR and RAS/RAF/MAPK signalling pathways.

WHAT IS NEW: • This series offers a detailed description of the early disease course, clinical variation, and management in infants with congenital chylothorax/hydrops fetalis due to CCLA, contributing to a better understanding of this rare condition in the neonatal period. • Early treatment with low-dose mTOR and/or MEK inhibitors seems effective in infants with CCLA, potentially reducing morbidity and mortality.