Cellular and Molecular Mechanisms of Vascular Malformations

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Genotype-phenotype correlations in central conducting lymphatic anomaly Central conducting lymphatic anomalies (CCLA) occur when there is a disruption of central lymphatic flow resulting in complications such as non-immune fetal hydrops, chylothorax, chylous ascites, protein-losing enteropathy, other effusions, or lymphedema. The heterogeneity of CCLA complicates diagnosis, treatment, and prognostication. Understanding the molecular etiology of a patients disease can drive medical care including novel treatment strategies. However, few genetic causes have been identified for CCLA. Clinical geneticists use distinct facial features to assist in diagnosis of rare disorders. Given the recent advances in lymphatic imaging, we sought to understand if we could use features identified by dynamic contrast magnetic resonance imaging to do this in CCLA. We discovered that only about a quarter of patients with CCLA have an underlying genetic diagnosis that can be identified by routine clinical evaluation. We also demonstrated that germline RASopathies, mosaic KRASopathies, PIEZO1-related lymphatic dysplasia, and Trisomy 21 have distinct central lymphatic flow phenotypes. Natural history study of lymphatic disorders We aim to develop a prospective natural history study for patients with lymphatic anomalies to systematically evaluate the disease phenotypes and long-term outcomes. This will allow us to provide improved prognostication to families, establish screening/monitoring guidelines, determine best practices for genetic diagnosis, and explore family opinions and explore fertility for those on long term medication management. This study will allow us to identify novel end points for future clinical trials. Cellular and molecular mechanism of lymphatic disorders Previously, I demonstrated that activating variants in KRAS can drive lymphatic malformations in the zebrafish which can be treated with MEK inhibitors. We have identified multiple genetic causes of central conducting lymphatic anomaly. We will evaluate these novel potential causes to understand their effect on the cellular and molecular mechanisms driving lymphatic development.