Neonate With Hydrops Fetalis, Chylothorax, and an FLT4 Variant: A Favorable Outcome

Congenital chylothorax is the most common cause of pleural effusion in newborns and may progress to nonimmune hydrops fetalis (NIHF).FLT4 encodes vascular endothelial growth factor receptor 3 (VEGFR-3), a receptor tyrosine kinase critical for lymphangiogenesis; pathogenic variants can impair VEGFR-3 signaling and disrupt lymphatic development.Although FLT4 has been implicated in congenital chylothorax, favorable postnatal outcomes with conservative management alone have not been well described.We present the case of a male infant born at 34 + 1 weeks' gestation with prenatal hydrops fetalis, polyhydramnios, ascites, and bilateral pleural effusions.Chest tubes drained fluid with triglycerides reaching 625 mg/dL after feeds were initiated, consistent with chylothorax.Infectious, metabolic, immunemediated, and anatomic evaluations were unremarkable.Trio whole-exome sequencing revealed a maternally inherited heterozygous FLT4 c.3824G>T (p.Ser1275Ile) substitution, classified as a variant of uncertain significance.Several features suggest possible clinical significance, including absence from population databases, damaging in silico predictions, location within the tyrosine kinase domain, and prior reports of the same variant presenting with severe prenatal lymphatic disease.The mother carried the same heterozygous variant with no known history of lymphedema or peripheral edema, consistent with incomplete penetrance.After approximately six weeks on medium-chain triglyceride formula, the chylothorax resolved, and the infant was transitioned to breast milk and discharged on day of life 75 on room air without dietary restrictions.This case suggests that a favorable neonatal outcome may be achievable with conservative management in certain neonates with NIHF and congenital chylothorax harboring FLT4 variants, pending further genotype-phenotype characterization.