Phenotypes J Med Genet: first published as 10.1136/jmedgenet-2019-106084 on 14 May 2020. Downloaded from REVIEW Update and audit of the St George’s classification 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 ► Additional material is ABSTRact involvement (but can be referred to as visceral or published online only. To view, Primary lymphatic anomalies may present in a myriad of central involvement), may present with pleural or please visit the journal online (http:// dx. doi. org/ 10. 1136/ ways and are highly heterogenous. Careful consideration pericardial effusions or ascites, any of which may jmedgenet- 2019- 106084). of the presentation can lead to an accurate clinical be chylous, as well as intestinal or pulmonary and/or molecular diagnosis which will assist with lymphangiectasia, protein losing enteropathy or 1 Molecular and Clinical Sciences management. The most common presentation is chylous reflux. Research Institute, St George’s lymphoedema, swelling resulting from failure of the The International Society for the Study of Vascular University of London, London, UK peripheral lymphatic system. However, there may be Anomalies (ISSVA) updated their classification for 2Dermatology & Lymphovascular internal lymphatic dysfunction, for example, chylous vascular anomalies in 2018.4 The vascular malfor- Medicine, St George’s reflux, or lymphatic malformations, including the thorax mations are subgrouped into ‘combined’, which Universities NHS Foundation or abdomen. A number of causal germline or postzygotic include more than one type of vessel, ‘simple’ (only trust, London, UK 3Lymphedema Clinic, Derby gene mutations have been discovered. Some through involving one vessel type), and those ‘associated Hospitals NHS Foundation Trust, careful phenotyping and categorisation of the patients with other anomalies’. Derby, UK based on the St George’s classification pathway/ Lymphoedema due to a presumed genetic devel- 4 Molecular and Clinical Sciences algorithm. The St George’s classification algorithm is opmental fault in the structure or function of lymph Research Institute, St George’s, aimed at providing an accurate diagnosis for patients University of London, London, conducting pathways is called primary lymph- 5 UK with lymphoedema based on age of onset, areas oedema. Some developmental faults can lead to 5SW Thames Regional Genetics affected by swelling and associated clinical features. overt structural defects of the lymph conducting Service, St George’s Hospital, This has enabled the identification of new causative pathways and are called lymphatic malformations. London, UK genes. This update brings the classification of primary Such malformations if interfering with lymph lymphatic disorders in line with the International Society drainage cause lymphoedema (truncal malforma- Correspondence to for the Study of Vascular Anomalies 2018 classification Professor Sahar Mansour, SW tions) but some lymphatic malformations remain for vascular anomalies. The St George’s algorithm Thames Regional Genetics as isolated anomalies with no connection to main http://jmg.bmj.com/ Service, St George’s Hospital, considers combined vascular malformations and primary lymph drainage pathways and do not cause lymph- London SW17 0RE, UK; 6 lymphatic anomalies. It divides the types of primary oedema (non- truncal malformations). A primary smansour@ sgul. ac. uk lymphatic anomalies into lymphatic malformations and lymphatic anomaly is an umbrella term referring to Received 10 June 2019 primary lymphoedema. It further divides the primary all lymphatic abnormalities arising from a develop- Revised 30 December 2019 lymphoedema into syndromic, generalised lymphatic mental fault. Accepted 10 March 2020 dysplasia with internal/systemic involvement, congenital- For a long time, the diagnosis of primary lymph- Published Online First 14 May onset lymphoedema and late- onset lymphoedema. An on September 27, 2021 by guest. Protected copyright. 2020 oedema was based largely on the age of presenta- audit and update of the algorithm has revealed where tion of the swelling, congenital, pubertal and late new genes have been discovered and that a molecular onset, with limited differentiation between the diagnosis was possible in 26% of all patients overall and phenotypes. The discovery of the first causal gene, 41% of those tested. vascular endothelial growth factor receptor 3 for Milroy disease, indicated that a molecular diag- nosis was possible.7 The first St George’s classifi- INTRODUCTION cation algorithm of primary lymphoedema and The lymphatic system is a network of vessels other primary lymphatic disorders was an attempt important for whole body fluid homeostasis, lipid to guide a clearer categorisation of phenotypes and 8 absorption and immune cell trafficking.1 2 Lymph- enable the discovery of further causal genes. Age of oedema is caused by lymphatic dysfunction, which onset remained a key criterion, but the sites affected leads to a build-up of interstitial fluid within the and associated features, for example, dysmor- tissues. This manifests with swelling of the extremi- phology, distichiasis (aberrant eyelashes), varicose © Author(s) (or their ties, usually of the legs but may involve other regions veins, vascular malformations and limb overgrowth employer(s)) 2020. Re- use or segments of the body such as the upper limbs, were also considered, as was internal or systemic permitted under CC BY. face, trunk or genital area. There is an increased risk involvement, for example, fetal hydrops, intestinal Published by BMJ. of infection due to disturbances in immune cell traf- lymphangiectasia, pleural and pericardial effusions To cite: Gordon K, Varney R, ficking within the segment of compromised lymph and chylous reflux. A family history of lymphoe- Keeley V, et al. J Med Genet drainage.3 Lymphatic dysfunction within the thorax dema with determination of the mode of inheri- 2020;57:653–659. and abdomen, here referred to as systemic/internal tance was considered useful. Gordon K, et al. J Med Genet 2020;57:653–659. doi:10.1136/jmedgenet-2019-106084 653 Phenotypes J Med Genet: first published as 10.1136/jmedgenet-2019-106084 on 14 May 2020. Downloaded from More rigorous phenotyping facilitated the identification of Here, we present a second update of the St George’s classifi- subgroups of patients with the same broad category of primary cation algorithm to include newly discovered genes and to bring lymphatic anomaly. These cohorts were then used for molecular it in- line with the 2018 ISSVA classification for vascular anoma- studies to identify more causal genes. Once the genotype was lies.4 The results of an audit, the purpose of which was to deter- known then crosschecking of the clinical characteristics, natural mine how well the algorithm was performing as a diagnostic aid history and inheritance patterns was possible and an accurate to classify patients with primary lymphatic anomalies and guide phenotype defined. Investigations such as lymphoscintigraphy molecular testing are also presented. helped to refine the phenotype further and give insight into the mechanisms for the development of the lymphatic disorder. A 9 first update of the classification was published in 2013. METHODS The St George’s classification algorithm is intended to help St George’s classification algorithm of primary lymphatic clinicians categorise their patients and guide testing towards, anomalies where possible, a molecular diagnosis. This algorithm is criteria The St George’s classification algorithm was updated (figure 1) matching, that is, using certain key findings for classification and then applied, retrospectively, to all patients presenting to through a multistep process of history taking, examination findings, mutation testing, etc. The next step using the informa- the national multidisciplinary ‘Primary and Paediatric Lymphoe- tion gathered is to advise on natural history, prognosis and risk dema’ Clinic held at St George’s Hospital over a 1-year period. (including genetic counselling) and to guide management. While Careful phenotyping was undertaken both on clinical grounds a molecular diagnosis should provide the most specific and accu- and after selective investigations, for example, lymphoscintig- rate diagnosis, it can be seen particularly with the postzygotic raphy. Where possible and appropriate, targeted genetic testing mosaic disorders that one genotype can be clinically very heter- was performed (this was prior to the introduction of a lymph- ogenous so there will probably always be a place for good clinical oedema gene panel in our unit) for some of the genes listed in phenotyping supported by investigation to guide management. table 1. http://jmg.bmj.com/ on September 27, 2021 by guest. Protected copyright. Figure 1 St George’s classification algorithm for primary lymphatic anomalies. The five main groupings (colour coded) with their various clinical subtypes of disease. Primary lymphoedema is the major clinical feature in the green, pink and purple sections. Text in red indicates the suggested genetic test and/ or differential diagnosis for the subgroup, however, the indicated genes do not explain the cause of disease in all patients in each grouping. For example, only 70% of patients with Milroy disease are explained by mutations in FLT4/VEGFR3.33 FH,