1 Gordon K, et al. J Med Genet 2020;0:1–7. doi:10.1136/jmedgenet-2019-106084 REVIEW Update and audit of the St George’s classifcation algorithm of primary lymphatic anomalies: a clinical and molecular approach to diagnosis Kristiana Gordon, 1,2 Ruth Varney, 1 Vaughan Keeley, 3 Katie Riches, 3 Steve Jeffery, 4 Malou Van Zanten, 1 Peter Mortimer, 1,2 Pia Ostergaard, 1 Sahar Mansour 1,5 Phenotypes To cite: Gordon K, Varney R, Keeley V, et al. J Med Genet Epub ahead of print: [please include Day Month Year]. doi:10.1136/ jmedgenet-2019-106084 ► Additional material is published online only. To view, please visit the journal online (http://dx.doi.org/10.1136/ jmedgenet-2019-106084). 1 Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK 2 Dermatology & Lymphovascular Medicine, St George’s Universities NHS Foundation trust, London, UK 3 Lymphedema Clinic, Derby Hospitals NHS Foundation Trust, Derby, UK 4 Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, UK 5 SW Thames Regional Genetics Service, St George’s Hospital, London, UK Correspondence to Professor Sahar Mansour, SW Thames Regional Genetics Service, St George’s Hospital, London SW17 0RE, UK; smansour@sgul.ac.uk Received 10 June 2019 Revised 30 December 2019 Accepted 10 March 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. ABSTRACT Primary lymphatic anomalies may present in a myriad of ways and are highly heterogenous. Careful consideration of the presentation can lead to an accurate clinical and/or molecular diagnosis which will assist with management. The most common presentation is lymphoedema, swelling resulting from failure of the peripheral lymphatic system. However, there may be internal lymphatic dysfunction, for example, chylous refux, or lymphatic malformations, including the thorax or abdomen. A number of causal germline or postzygotic gene mutations have been discovered. Some through careful phenotyping and categorisation of the patients based on the St George’s classifcation pathway/ algorithm. The St George’s classifcation algorithm is aimed at providing an accurate diagnosis for patients with lymphoedema based on age of onset, areas affected by swelling and associated clinical features. This has enabled the identifcation of new causative genes. This update brings the classifcation of primary lymphatic disorders in line with the International Society for the Study of Vascular Anomalies 2018 classifcation for vascular anomalies. The St George’s algorithm considers combined vascular malformations and primary lymphatic anomalies. It divides the types of primary lymphatic anomalies into lymphatic malformations and primary lymphoedema. It further divides the primary lymphoedema into syndromic, generalised lymphatic dysplasia with internal/systemic involvement, congenital- onset lymphoedema and late-onset lymphoedema. An audit and update of the algorithm has revealed where new genes have been discovered and that a molecular diagnosis was possible in 26% of all patients overall and 41% of those tested. INTRODUCTION The lymphatic system is a network of vessels important for whole body fluid homeostasis, lipid absorption and immune cell trafficking. 1 2 Lymph- oedema is caused by lymphatic dysfunction, which leads to a build-up of interstitial fluid within the tissues. This manifests with swelling of the extremi- ties, usually of the legs but may involve other regions or segments of the body such as the upper limbs, face, trunk or genital area. There is an increased risk of infection due to disturbances in immune cell traf- ficking within the segment of compromised lymph drainage. 3 Lymphatic dysfunction within the thorax and abdomen, here referred to as systemic/internal involvement (but can be referred to as visceral or central involvement), may present with pleural or pericardial effusions or ascites, any of which may be chylous, as well as intestinal or pulmonary lymphangiectasia, protein losing enteropathy or chylous reflux. The International Society for the Study of Vascular Anomalies (ISSVA) updated their classification for vascular anomalies in 2018. 4 The vascular malfor- mations are subgrouped into ‘combined’, which include more than one type of vessel, ‘simple’ (only involving one vessel type), and those ‘associated with other anomalies’. Lymphoedema due to a presumed genetic devel- opmental fault in the structure or function of lymph conducting pathways is called primary lymph- oedema. 5 Some developmental faults can lead to overt structural defects of the lymph conducting pathways and are called lymphatic malformations. Such malformations if interfering with lymph drainage cause lymphoedema (truncal malforma- tions) but some lymphatic malformations remain as isolated anomalies with no connection to main lymph drainage pathways and do not cause lymph- oedema (non-truncal malformations). 6 A primary lymphatic anomaly is an umbrella term referring to all lymphatic abnormalities arising from a develop- mental fault. For a long time, the diagnosis of primary lymph- oedema was based largely on the age of presenta- tion of the swelling, congenital, pubertal and late onset, with limited differentiation between the phenotypes. The discovery of the first causal gene, vascular endothelial growth factor receptor 3 for Milroy disease, indicated that a molecular diag- nosis was possible. 7 The first St George’s classifi- cation algorithm of primary lymphoedema and other primary lymphatic disorders was an attempt to guide a clearer categorisation of phenotypes and enable the discovery of further causal genes. 8 Age of onset remained a key criterion, but the sites affected and associated features, for example, dysmor- phology, distichiasis (aberrant eyelashes), varicose veins, vascular malformations and limb overgrowth were also considered, as was internal or systemic involvement, for example, fetal hydrops, intestinal lymphangiectasia, pleural and pericardial effusions and chylous reflux. A family history of lymphoe- dema with determination of the mode of inheri- tance was considered useful. on January 25, 2022 by guest. 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