Insights Into Congenital Lymphatic Anomalies Underlying Fetal Effusions

Area of Science:

• Genetics
• Fetal Medicine
• Pediatric Cardiology

Background:

• Congenital lymphatic anomalies, including autosomal dominant lymphedema and generalized lymphatic dysplasia, present diagnostic challenges.
• Prenatal diagnosis of fetal effusions can indicate underlying genetic conditions.

Purpose of the Study:

• To describe pregnancies with fetal autosomal dominant lymphedema and generalized lymphatic dysplasia diagnosed via prenatal exome or genome sequencing.
• To deepen the understanding of congenital lymphatic anomalies by analyzing fetal features and parental symptoms.

Main Methods:

• Prospective enrollment of pregnancies with fetal effusions (nuchal translucency ≥ 3.5 mm, cystic hygroma, pleural effusion, pericardial effusion, ascites, skin edema) from 2017-2024.
• Exome or genome sequencing performed on affected fetuses.
• Review of medical records for personal/family history, ultrasound findings, and pregnancy outcomes.

Main Results:

• Eight of 303 pregnancies (3%) with fetal effusions received a molecular diagnosis of autosomal dominant lymphedema or generalized lymphatic dysplasia.
• Fetal effusions were detected from the first to third trimesters.
• Four fetuses inherited variants from a parent, with three parents exhibiting milder symptoms; heterozygous PIEZO1 variants correlated with more favorable perinatal outcomes.

Conclusions:

• Autosomal dominant lymphedema and generalized lymphatic dysplasia manifest with diverse fetal effusions throughout gestation.
• These conditions are often inherited from parents with less severe clinical presentations.
• Findings enhance understanding of in utero congenital lymphatic anomalies and inform recurrence risk assessment.