Vascular endothelial growth factor receptors (VEGFRs) are part of the evolutionarily conserved VEGF signalling pathways that regulate the development and maintenance of the body\'s cardiovascular and lymphovascular systems. VEGFR3, encoded by the FLT4 gene, has an indispensable and well-characterized function in development and establishment of the lymphatic system. Autosomal dominant VEGFR3 mutations, that prevent the receptor functioning as a homodimer, cause one of the major forms of hereditary primary lymphoedema; Milroy disease. Recently, we and others have shown that FLT4 variants, distinct to those observed in Milroy disease cases, predispose individuals to Tetralogy of Fallot, the most common cyanotic congenital heart disease, demonstrating a novel function for VEGFR3 in early cardiac development. Here, we examine the familiar and emerging roles of VEGFR3 in the development of both lymphovascular and cardiovascular systems, respectively, compare how distinct genetic variants in FLT4 lead to two disparate human conditions, and highlight the research still required to fully understand this multifaceted receptor.

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 reflux, 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 classification pathway/algorithm. The St George\'s classification 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 identification of new causative genes. This update brings the classification of primary lymphatic disorders in line with the International Society for the Study of Vascular Anomalies 2018 classification 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.

OBJECTIVE: Primary lymphoedema is rare and in most cases develops in the lower extremities. In some cases, conservative treatment is insufficient and can be supported by surgical procedure. The aim of this case study was to show the difference in the effectiveness of a compression wrap device and compression stockings in the treatment of primary lymphoedema.
METHODS: Before and after liposuction the patient was treated on an outpatient basis every day for three weeks. This consisted of complex decongestive therapy (CDT) including manual lymph drainage, tailored exercises, skin and nail care, compression therapy and intermittent pneumatic compression. After CDT, the patient was provided with a flat-knit compression garment. Measurements were taken at one week and at three months of wearing the compression garment. The oedema severity was measured by summary calculation method. For both healthy and swollen limbs, the sum of circumferences taken at nine fixed measuring points was determined. The difference between these sums expressed in percents was presented as a relative metric coefficient of leg lymphoedema (RMCL).
RESULTS: At the start of therapy, the difference in circumference between the healthy and swollen limb was 21.85%. After CDT (RMCL: 13.46%), the patient was provided with a flat-knit compression stocking (class 3). After one week, the RMCL was 15.92%, while after three months RCML was 20.84%. Because fluid retention was observed the patient was again treated with CDT (RMCL: 13.89%). The patient was provided with compression stocking (class 4). After one week of wearing, the RMCL was 15.77%, while after three months RMCL was 20.26%. As the results proved unsatisfactory, the patient was treated with CDT (RMCL: 13.60%) and a combination of two class 4 compression stockings was used. After one week, RMCL was 14.91%, while after three months RMCL was 19.25%. As the effects of oedema reduction were insufficient, the patient was treated again with CDT (RMCL: 13.89%) and advised to replace one of the stockings with a CirAid device (adjustable compression wrap). After one week, RMCL was 14.18% and after three months RMCL was 14.76%. The patient then qualified for liposuction (RMCL: 7.81%). At three months after surgery, the compression stocking was replaced by an adjustable compression wrap, to reduce the difference in circumference between healthy and swollen limbs (from 21.85 % to 8.68%).
CONCLUSIONS: This case study shows that in primary oedema one class of compression garment is not always sufficient, nor is the combination of two garments with varying degrees of compression. In some cases, the situation requires the use of non-elastic leg binders such as a CircAid device which, thanks to its greater stiffness, helps improve clinical outcomes.

Background: The International Lymphedema Framework developed an international study, Lymphedema Impact and Prevalence International (LIMPRINT), to estimate the prevalence and impact of chronic edema (CO) in heterogeneous populations. Methods and Results: A validation study using the LIMPRINT methodology was undertaken in Denmark. Participants with CO were identified from inpatient services and compared with those identified within a specialist lymphedema service and three primary care settings. Of 452 inpatients available for screening, CO was present in 177 (39%) and absent in 275 (61%). In addition, 723 participants were found from specialist and primary care services (LPCSs). Inpatients were significantly older and more likely to be underweight or normal weight. They were more likely to suffer from heart failure/ischaemic heart disease (44.6% vs. 23.4%, p < 0.001) and have neurological problems (18.1% vs. 10.9% p = 0.009). Patients in the inpatient group were nearly all suffering from secondary lymphedema and were less likely to have a cancer or venous diagnosis, but more likely to have immobility as the cause of CO (44.0% vs. 17.7%, p < 0.001). No inpatients had midline CO compared with 30 within LPCSs. Fewer in the inpatient group had standard CO treatment (17.1% vs. 73.5%, p < 0.001) and subjective control of swelling was worse (19.9% vs. 66.7%, p < 0.001). While the inpatient group experienced fewer acute infections, when they did so, they were more likely to be admitted to hospital for this (78.6% vs. 51.0%, p = 0.049). Conclusion: The prevalence of CO in inpatient facilities is high and those with CO have multiple comorbidities that vary according to setting. The feasibility study showed that the methodology could be adapted for use in different health systems.

Lymphoedema is the build-up of lymphatic fluid leading to swelling in the tissues. Most commonly it affects the peripheries. Diagnosis is based on clinical assessment and imaging with lymphoscintigraphy. Treatment is supportive with compression garments, massage, good skin hygiene and prompt use of antibiotics to avoid the complication of cellulitis. Most commonly, lymphoedema occurs as a result of damage to the lymphatic system following surgery, trauma, radiation or infection. However, it can be primary, often associated with a genetic defect that causes disruption to the development of the lymphatic system. Common genetic conditions associated with lymphoedema include Turner syndrome and Noonan syndrome; however, there are numerous others that can be classified based on their clinical presentation and associated features. Herein we discuss how to diagnose and classify the known primary lymphoedema conditions and how best to investigate and manage this group of patients.

BACKGROUND: Lymphoedema may cause complex problems that can strongly influence patients\' health-related quality of life (HRQoL). The main purpose of this study was to investigate the impact of lymphoedema on HRQoL in patients with varying forms of lymphoedema.
METHODS: The Lymphoedema Quality of Life Inventory (LyQLI), measuring three domains, physical, psychosocial and practical, and the Short Form 36 Health Survey Questionnaire (SF-36), measuring eight health domains, were sent to 200 lymphoedema patients. Out of those who answered both questionnaires, 88 patients had lymphoedema secondary to cancer treatment and they additionally received the Functional Assessment of Cancer Therapy Scale-General (FACT-G). The relation between continuous variables and the three domains were analysed by Spearman\'s correlation coefficients, and Kruskal-Wallis test was used to analyse categorical variables.
RESULTS: Altogether 129 patients completed the LyQLI and SF-36 and 79 of them also completed FACT-G. Twenty per cent had a high mean score (≥2.0) in at least one domain of the LyQLI, thus having a low HRQoL. Lower HRQoL was found in the practical domain of LyQLI in patients with lower limb lymphoedema compared to patient with lymphoedema in upper limb or head/neck (p = 0.002) and in patients working part-time compared to patients working full-time (p = 0.005). The impact on HRQoL tended to decrease with age, with a significant correlation in the psychosocial domain (rs = 0.194, p = 0.028). Compared with the general Swedish population, patients with lymphoedema scored significantly lower in general health (p = 0.006), vitality (p = 0.002) and social functioning (p = 0.025) assessed by the SF-36. From a cancer-specific view, HRQoL was similar to other Swedish studies using the FACT-G.
CONCLUSIONS: This study indicates that about 20% of the patients with lymphoedema had major impact on their HRQoL. More effort and research is needed to identify, understand and support groups of patients with severe lymphoedema-related problems.

Primary lymphoedema is a complex condition that causes tissue swelling, usually in one or more of the limbs, but lymphatic drainage of the head, trunk or deeper organs may also be affected. It can manifest in swelling at any time from birth meaning there are a number of children affected by this condition. While it is rare in childhood there are too few professionals experienced in diagnosis and treatment, which results in delays in identification and referral to appropriate services for diagnosis and treatment. The Children\'s Lymphoedema Special Interest Group (CLSIG) was formed in 2010 by a group of lymphoedema specialists in a bid to raise awareness, improve service provision, and enhance practitioner knowledge. One of the aims of the group was to deliver a \'fun day\' (Lymphaletics) for children with lymphoedema and their families to encourage physical activity and social interaction with children who have similar problems, and to provide a source of parent-to-parent support. This article discusses the issues for children and their families, and the aims and format of the event.

Primary lymphoedema includes some diseases whose genetic anomaly is detected and others whose pathology is unknown. In this article, we report a lymphatic thrombus found in a limb with lymphoedema during lymphatico-venous anastomosis (LVA). A 32-year-old man was aware of oedema in his left calcar pedis 3 years previously, which appeared without any trigger. Indocyanine green lymphography indicated lymphatic stasis in the left calf and thigh region, and we performed LVA for the patient. During the operation, we found yellow vessels, which were thought to be lymphatic vessels filled with a yellow solid substance, just beneath the superficial fascia at the left ankle. Pathological examination of the thrombi revealed hyaline material mixed with cell components. The cells were categorised as lymphatic endothelial cells, as they were positive for podoplanin. There was no evidence of malignancy. Causes of idiopathic lymphatic thrombus such as this may be one of the causes of so-called primary lymphoedema, and evaluation of such cases may be the first step towards elucidating the mechanisms involved in the development of primary lymphoedema.