Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

A Correction to this article was published on 03 June 2022

This article has been updated


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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: CONSORT diagram.
Fig. 2: The clinical phenotype of participants in the confirmed category.
Fig. 3: Representative imaging findings based on genotype.

Data availability

The data that support this study are available in the tables and Supplementary Tables. Additional data is not available due to privacy restrictions.

Change history


  1. Makinen T, Boon LM, Vikkula M, Alitalo K. Lymphatic malformations: genetics, mechanisms and therapeutic strategies. Circ Res. 2021;129:136–54.

    Article  Google Scholar 

  2. Ricci KW, Iacobas I. How we approach the diagnosis and management of complex lymphatic anomalies. Pediatr Blood Cancer. 2021;e28985.

  3. Clemens RK, Pfammatter T, Meier TO, Alomari AI, Amann-Vesti BR. Combined and complex vascular malformations. Vasa. 2015;44:92–105.

    Article  Google Scholar 

  4. Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, et al. Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies. Pediatrics. 2015;136:e203–14.

    Article  Google Scholar 

  5. Dori Y, Zviman MM, Itkin M. Dynamic contrast-enhanced MR lymphangiography: feasibility study in swine. Radiology. 2014;273:410–6.

    Article  Google Scholar 

  6. Dori Y. Novel lymphatic imaging techniques. Tech Vasc Interventional Radiol. 2016;19:255–61.

    Article  Google Scholar 

  7. Biko DM, Reisen B, Otero HJ, Ravishankar C, Victoria T, Glatz AC, et al. Imaging of central lymphatic abnormalities in Noonan syndrome. Pediatric Radiol. 2019;49:586–92.

    Article  Google Scholar 

  8. Mills M, van Zanten M, Borri M, Mortimer PS, Gordon K, Ostergaard P, et al. Systematic review of magnetic resonance lymphangiography from a technical perspective. J Magn Reson Imaging. 2021;53:1766–90.

    Article  Google Scholar 

  9. Li D, Wenger TL, Seiler C, March ME, Gutierrez-Uzquiza A, Kao C, et al. Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly. Hum Mol Genet. 2018;27:3233–45.

    CAS  Article  Google Scholar 

  10. Li D, March ME, Gutierrez-Uzquiza A, Kao C, Seiler C, Pinto E, et al. ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. Nat Med. 2019;25:1116–22.

    CAS  Article  Google Scholar 

  11. Li D, Sheppard SE, Peroutka C, Barnes C, Reid JR, Smith CL, et al. Expanded phenotypic spectrum of JAG1-associated diseases: Central conducting lymphatic anomaly with a pathogenic variant in JAG1. Clin Genet. 2021;99:742–3.

    CAS  Article  Google Scholar 

  12. Dori Y, Smith C, Pinto E, Snyder K, March ME, Hakonarson H, et al. Severe lymphatic disorder resolved with MEK inhibition in a patient with Noonan syndrome and SOS1 mutation. Pediatrics 2020;146:e20200167.

    Article  Google Scholar 

  13. Byrne AB, Brouillard P, Sutton DL, Kazenwadel J, Montazaribarforoushi S, Secker GA, et al. Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema. Sci Transl Med. 2022;14:eabm4869.

    CAS  Article  Google Scholar 

  14. Joyce S, Gordon K, Brice G, Ostergaard P, Nagaraja R, Short J, et al. The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. Eur J Hum Genet. 2016;24:690–6.

    CAS  Article  Google Scholar 

  15. Lissewski C, Chune V, Pantaleoni F, De Luca A, Capri Y, Brinkmann J, et al. Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications. Eur J Hum Genet. 2021;29:51–60.

    CAS  Article  Google Scholar 

  16. Traub ES, Sheppard SE, Dori Y, Burns KD, Zackai EH, Ware SM, et al. Chromosome 4q28.3q32.3 duplication in a patient with lymphatic malformations, craniosynostosis, and dysmorphic features. Clin Dysmorphol. 2021;30:89–92.

    Article  Google Scholar 

  17. Fotiou E, Martin-Almedina S, Simpson MA, Lin S, Gordon K, Brice G, et al. Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis. Nat Commun. 2015;6:8085.

    Article  Google Scholar 

  18. Biko DM, Smith CL, Otero HJ, Saul D, White AM, DeWitt A, et al. Intrahepatic dynamic contrast MR lymphangiography: initial experience with a new technique for the assessment of liver lymphatics. Eur Radio. 2019;29:5190–6.

    Article  Google Scholar 

  19. Biesecker LG, Adam MP, Alkuraya FS, Amemiya AR, Bamshad MJ, Beck AE, et al. A dyadic approach to the delineation of diagnostic entities in clinical genomics. Am J Hum Genet. 2021;108:8–15.

    CAS  Article  Google Scholar 

Download references


The authors thank the patients, their families, and the other clinicians that have helped care for the individuals in this study. We thank Lymphatic Center, CAG and CVAP team members for their insightful comments and discussion.


Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR001880 (SES). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research reported in the publication was supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania (SES), The Children’s Hospital of Philadelphia Comprehensive Vascular Anomalies Frontier Program (HH), The Children’s Hospital of Philadelphia K-readiness grant (SES), Uplifting Athletes and the Lymphangiomatosis Gorham’s Disease Alliance (SES).

Author information

Authors and Affiliations



Conceptualization: YD, SES; Data curation: ML, CS, YD, SES; Formal Analysis: ML, CS, DL, SES; Funding acquisition: YD, SES; Investigation: ML, CS, DMB, DL, NR, EP, CS, EHZ, YD, SES; Methodology: ML, SS; Project administration: ML, YD; Supervision: YD, SES; Validation: ML, CS; Visualization: ML, CS, YD, SES; Writing (original draft): ML, SES; Writing (review & editing): ML, CS, DL, HH, YD, SES.

Corresponding author

Correspondence to Sarah E. Sheppard.

Ethics declarations

Competing interests

HH and The Children’s Hospital of Philadelphia are equity holders in Nobias Therapeutics Inc., developing MEK inhibitor therapy for complex lymphatic anomalies. Other authors declare no competing interests.

Ethics approval and consent to participate

The Children’s Hospital of Philadelphia Institutional Review Board approved a registry and biorepository study (PI YD). Informed consent was obtained from all participants as required by the IRB.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, M., Smith, C.L., Biko, D.M. et al. Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly. Eur J Hum Genet (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links