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. <Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> 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. </entry> </row> </tbody> </tgroup> </Table>

Molecular targeted treatment in infants with central conducting lymphatic anomalies

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2025年8月21日

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Vera C. van den Brink,
Lotte E. R. Kleimeier,
Erika K. S. M. Leenders,
Willemijn M. Klein,
Willem P. de Boode,
Joris Fuijkschot,
Sabine L. A. G. Vrancken

摘要

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.