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Molecular targeted treatment in infants with central conducting lymphatic anomalies
Vera C van den Brink1, Lotte E R Kleimeier2, Erika K S M Leenders3
1Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands. Vera.vandenBrink@radboudumc.nl.
Insights
Early treatment with mTOR and/or MEK inhibitors rapidly improved outcomes in infants with central conducting lymphatic anomaly (CCLA). This approach offers a promising new therapy for this rare, life-threatening neonatal condition.
Area of Science:
- Vascular malformations
- Lymphatic system development
- Neonatal medicine
Background:
- Central conducting lymphatic anomaly (CCLA) is a rare neonatal condition with high morbidity and mortality.
- Existing treatments for CCLA have limited efficacy.
- Targeted therapies like MEK and mTOR inhibitors show promise for vascular anomalies driven by specific signaling pathways.
Purpose of the Study:
- To describe the clinical presentation, imaging findings, genetic basis, and treatment outcomes of infants with neonatal-onset CCLA.
- To evaluate the efficacy and safety of early treatment with mTOR and/or MEK inhibitors in this population.
Main Methods:
- Retrospective case series of infants with CCLA.
- Diagnosis using dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL).
- Genetic testing for germline and somatic variants.
- Treatment with sirolimus and/or trametinib.
Main Results:
- CCLA presented with hydrops fetalis and chylothorax.
- DCMRL revealed heterogeneous lymphatic abnormalities.
- Four patients had pathogenic germline variants; three had no genetic diagnosis.
- Treatment with mTOR and/or MEK inhibitors led to substantial clinical improvement and improved lymphatic flow.
- Therapy was tapered within weeks with no relapses or severe adverse events.
Conclusions:
- Early treatment with mTOR and/or MEK inhibitors is effective and safe in infants with CCLA.
- This targeted therapy promotes functional recovery during a critical lymphatic development phase.
- Further research is warranted to confirm these findings in larger cohorts.
Abstract:
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.
