A110-18 EPHB4 Variant Identified in Pediatric Interstitial Lung Disease Leads to Diagnosis of Unrecognized Familial Lymphatic Disorders: A Case Illustrating the Clinical Impact of Genomic Testing

Abstract Clinical whole-genome and exome sequencing are increasingly integrated into pulmonary practice and are transforming the evaluation of unexplained interstitial and lymphatic lung disease. We report a case in which establishing a genetic diagnosis in a child with unexplained interstitial lung disease (ILD) clarified the etiology of disease in her mother and informed management for both individuals. A 7-year-old girl presented with a chronic cough and recurrent pneumonia. Pregnancy was notable for bilateral fetal pleural effusions treated with a thoracoamniotic shunt. After birth, she required prolonged mechanical ventilation, repeated pleural drainage, and home oxygen until 5 months of age. At age four, persistent wet cough and recurrent left lower lobe pneumonias prompted evaluation by a pediatric pulmonologist. Chest CT demonstrated asymmetric interlobular septal thickening (right left) and ground-glass opacities. Dynamic MR Lymphangiography revealed markedly dilated central lymphatic channels, intercostal reflux, and congested interstitial and periportal lymphatic structures, consistent with a primary lymphatic developmental disorder. Clinical whole exome sequencing identified a heterozygous maternally inherited EPHB4 variant: c.2216GA (p.Arg739Gln). EPHB4 encodes an Ephrin receptor essential for normal lymphatic branching and growth via the PI3K/mTOR pathway. Pathogenic missense variants in this gene, including Arg739Gln, lead to a loss of EPHB4 phosphorylation activity and have been previously associated with autosomal dominant central conducting lymphatic anomaly (CCLA)- one of several lymphatic malformations characterized by abnormal central lymphatic flow, resulting in dilatation, obstruction, or leakage. The patient’s mother had a history of recurrent pleural effusions beginning in adulthood. A prior lung biopsy had been interpreted as “consistent with lymphangioleiomyomatosis”, though clinical features were discordant. Identification of the EPHB4 variant prompted revisiting the family history, which identified two additional maternal family members with varicose veins, a feature reported in carriers of pathogenic EPHB4 variants. Following genetic diagnosis, to counter the dysregulated PI3K/mTOR signaling downstream of EPHB4, the mother started the mTOR pathway inhibitor sirolimus (target trough 5 ng/mL). Sirolimus was started for the child but discontinued due to medication refusal in the context of autism spectrum disorder; subsequent follow-up attempts were unsuccessful. This case demonstrates the variable clinical spectrum of EPHB4-related lymphatic malformation and supports routine consideration of genomic evaluation in pediatric ILD with lymphatic features, highlighting actionable consequences for affected relatives. Establishing a genetic diagnosis can uncover unrecognized familial cases and guide targeted management with the potential to improve outcomes. This abstract is funded by: This project was supported by the Boston Children’s Hospital Children’s Rare Disease Cohorts.