Insights Into Congenital Lymphatic Anomalies Underlying Fetal Effusions

We describe a series of pregnancies with autosomal dominant lymphedema and generalized lymphatic dysplasia in the fetus diagnosed with prenatal exome or genome sequencing. We focus on specific syndromes, fetal features, and parental symptoms to deepen our understanding of congenital lymphatic anomalies.

Pregnancies with one or more fetal effusions were prospectively enrolled from 2017 to 2024 and underwent exome or genome sequencing. Fetal effusions included increased nuchal translucency ≥ 3.5 mm, cystic hygroma, pleural effusion, pericardial effusion, ascites, and/or skin edema. Records were reviewed to extract personal and family history, ultrasound findings, and pregnancy outcomes.

Among 303 pregnancies with one or more fetal effusions, eight (3%) had a molecular diagnosis of autosomal dominant lymphedema or generalized lymphatic dysplasia. Gestational age at detection of fetal effusion(s) ranged from the first through third trimesters. Four fetuses inherited the genetic variant(s) from a biological parent. Of these, one parent was asymptomatic, and three had largely milder symptoms than their fetus. Perinatal outcomes were more favorable for fetuses with heterozygous PIEZO1 variants.

Autosomal dominant lymphedema and generalized lymphatic dysplasia can present with a breadth of fetal effusions from the first through third trimesters and are frequently inherited from a biological parent with less severe symptoms. These data provide a deeper understanding of how congenital lymphatic anomalies manifest in utero and inform expectations about recurrence risk in future pregnancies.