Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly

Abstract

Central conducting lymphatic anomaly (CCLA) is a heterogenous disorder caused by disruption of central lymphatic flow that may result in dilation or leakage of central lymphatic channels. There is also a paucity of known genetic diagnoses associated with CCLA. We hypothesized that specific genetic syndromes would have distinct lymphatic patterns and this would allow us to more precisely define CCLA. As a first step toward "precision lymphology", we defined the genetic conditions associated with CCLA by performing a retrospective cohort study. Individuals receiving care through the Jill and Mark Fishman Center for Lymphatic Disorders at the Children's Hospital of Philadelphia between 2016 and 2019 were included if they had a lymphangiogram and clinical genetic testing performed and consented to a clinical registry. In our cohort of 115 participants, 26% received a molecular diagnosis from standard genetic evaluation. The most common genetic etiologies were germline and mosaic RASopathies, chromosomal abnormalities including Trisomy 21 and 22q11.2 deletion syndrome, and PIEZO1-related lymphatic dysplasia. Next, we analyzed the dynamic contrast magnetic resonance lymphangiograms and found that individuals with germline and mosaic RASopathies, mosaic KRASopathies, PIEZO1-related lymphatic dysplasia, and Trisomy 21 had distinct central lymphatic flow phenotypes. Our research expands the genetic conditions associated with CCLA and genotype-lymphatic phenotype correlations. Future descriptions of CCLA should include both genotype (if known) and phenotype to provide more information about disease (gene-CCLA). This should be considered for updated classifications of CCLA by the International Society of Vascular Anomalies.

Fig. 1. CONSORT diagram.

Flowchart shows the inclusion and exclusion of the study participants and subsequent categorization.

Fig. 2. The clinical phenotype of participants in the confirmed category.

A RASopathies. B Mosaic KRAS-opathy. C FOXC2-related Lymphedema Distichiasis syndrome. D Trisomy 21. E 22q11.2 deletion syndrome. F PIEZO1-related Generalized Lymphatic Dysplasia. G Metabolic Disease including Andersen disease and Gaucher’s Disease Type III. Protein losing protein losing enteropathy.

Fig. 3. Representative imaging findings based on genotype.

T2 space and dynamic contrast MR lymphangiography from seven different genotypes illustrating lymphatic conduction abnormalities. A Mosaic BRAF (p.Val600Glu). T2 space shows significant edema in the intercostal, mesentery and liver lymphatics (left panel) (arrows) that correlates with abnormal perfusion patterns on intrahepatic DCMRL (right). Also note the abnormal lymphatic thoracic vessels with the absence of a normal thoracic duct. B Mosaic KRAS (p.Gly12Asp) There is edema on T2 space within the mediastinum and lungs (arrows). Patient also with cystic right kidney (asterisk). Intrahepatic DCMRL demonstrates correlation with mediastinal, pulmonary, and supraclavicular edema with perfusion of dilated lymphatic structures. Of note, this patient has a central thoracic duct (arrow heads), but it was not patent to the venous circulation on US contrast imaging. C Noonan syndrome (PTPN11 p.Gln510His). T2 space imaging demonstrating mediastinal and intercostal edema predominately. With intranodal DCMRL these areas correlate with abnormal perfusion (arrows). Again, note there is no central thoracic duct, but persistent pulmonary and intercostal perfusion. D Trisomy 21. T2 space imaging with edema in the supraclavicular (and superior mediastinal lymphatics (arrows)). On intrahepatic DCMRL there is retrograde flow into retroperitoneal lymphatics, intercostal, mediastinal, pulmonary, and supraclavicular perfusion (arrows). There is a patent thoracic duct that courses to the left venous angle (arrowhead). E PIEZO1. T2 space shows bilateral pleural effusions, pulmonary, and retroperitoneal edema (arrows). Intrahepatic DCMRL shows extensive flow to the hepatic capsular lymphatics with extension into the mediastinum and pulmonary lymphatics (arrows). There is also retrograde flow into the retroperitoneal lumbar and mesenteric lymphatics. There is a small thoracic duct seen coursing to the left venous angle (arrow head), patent on follow up imaging. F Gaucher’s Disease Type III. T2 space notable for ascites. Intrahepatic DCMRL shows retrograde perfusion to retroperitoneal lumbar lymphatics and mesentery (arrows). The thoracic duct is mildly dilated and tortuous as it courses to the left venous angle (arrowhead). G Andersen disease. T2 space imaging with significant ascites, pleural effusions, and anasarca (arrows). With intranodal DCMRL, there is extensive dermal perfusion and dilated retroperitoneal lymphatics. A thoracic duct is present and mildly dilated and tortuous (arrowhead).