Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function.

Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.

Positive Impact of a New Compressive Garment in Patients with Genital Lymphedema: OLYMPY Study.

Purpose: Genital lymphedema is a chronic debilitating condition associated with highly impaired health-related quality of life (QoL). This prospective multicenter study evaluated the use of a new compressive garment in patients with secondary and primary genital lymphedema. Methods: Thirty-two patients prospectively enrolled were advised to wear the compressive garment for 12 weeks (day and night). The primary endpoint was change in patient-reported QoL at 12 weeks via the patient global impression of change (PGI-C) instrument. Secondary outcomes included change in other QoL measures at 12 weeks (visual analog scale, Lymphedema Quality of Life Inventory [LyQLI], and EQ-5D questionnaires), lymphedema severity (genital lymphedema score [GLS]), and physician assessment (Clinical Global Impression-Improvement [CGI-I]). Safety and tolerability were also assessed. Results: After 12 weeks, improvement was reported in 78.6% of patients (PGI-C). Physician assessment (CGI-I) indicated clinical improvement in 82.8% of patients. Patient assessment of lymphedema symptoms showed a significant decrease in discomfort (p = 0.02) and swelling (p = 0.01). Significant declines in the mean global GLS (p < 0.0001), and in the proportion of patients reporting heaviness, tightness, swelling, or urinary dysfunction (p < 0.05 for all), were also observed. LyQLI scores decreased (indicating improved QoL) in each of the physical, psychosocial (p = 0.05), and practical domains. The compressive garment was well tolerated with high compliance, and adverse events (due to swelling or discomfort) led to permanent discontinuation in only three patients. Conclusion: The use of a new genital compression garment over 12 weeks improves the QoL and clinical measures in patients with genital lymphedema (ClinicalTrials.gov ID: NCT04602559; Registration: October 20, 2020).

Somatic TEK variant with intraarticular venous malformation and knee hemarthrosis treated with rapamycin.

BACKGROUND: Venous malformations (VMs) are the most common vascular anomalies and have been associated with somatic variants in TEK. Current treatment of VM joint component might be challenging due to the size or location of some lesions or ineffective with recurrence of malformed veins. Targeted molecular therapies after identification of genetic defects might be an alternative. METHODS: We report a case with intraarticular bleeding due to VM with a TEK pathogenic somatic variant treated with rapamycin. RESULTS: A 26-year-old female patient was evaluated for right calf pain secondary to venous malformation of the right inferior limb with an intraarticular component in the right knee. Hemarthrosis and degenerative chondropathy of the knee were evidenced at MRA. Molecular diagnosis evidenced a pathogenic somatic TEK variant. Rapamycin was introduced to stop bleeding, with good tolerance and efficacy. CONCLUSION: The TEK receptor signals through the PI3K/AKT/mTOR pathway and TEK mutations have been linked to AKT activation. As rapamycin acts against angiogenesis and reduces phosphorylated-AKT levels, targeted molecular therapy should be discussed as first-line therapy in patients with proven molecular diagnosis and diffuse VM inaccessible to conventional treatment.

Acute effects of graduated and progressive compression stockings on leg vein cross-sectional area and viscoelasticity in patients with chronic venous disease.

OBJECTIVE: To determine the effects of graduated and progressive elastic compression stockings (ECS) on postural diameter changes and viscoelasticity of leg veins in healthy controls and in limbs with chronic venous disease (CVD). METHODS: In 57 patients whose legs presented with C1s, C3, or C5 CEAP classes of chronic venous disease and were treated primarily with compression, and 54 healthy controls matched for age and body mass index, we recorded interface pressures (IFP) at 9 reference leg levels. Cross-sectional areas of the small saphenous vein (SSV) and a deep calf vein (DCV) were measured with B-mode ultrasound with patients supine and standing, recording the force (PF) applied on the ultrasound probe to collapse each vein with progressive ECS, and with and without graduated 15 to 20 mm Hg and 20 to 36 mm Hg elastic stockings. We chose these veins because they were free of detectable lesion and could be investigated at the same level (mid-height of the calf), and their compression by the ultrasound probe was not hampered by bone structures. RESULTS: IFP decreased from ankle to knee with graduated 15 to 20 and 20 to 36 mm Hg, but increased with progressive ECS, and were 8.4 to 13.8 mm Hg lower for C1s than for control or C3 and C5 limbs. Without ECS, the SSV median [lower-upper quartile] cross-sectional area was 4.9 mm2 [3.6-7.1 mm2] and 7.1 mm2 [3.0-9.9 mm2] in C3 and C5 limbs versus 2.9 mm2 [1.8-5.2 mm2] and 3.8 mm2 [2.1-5.4 mm2] in controls (P < .01), respectively, while supine and standing. It remained greater in C3 and C5 than in C1s and control limbs wearing any ESC. Wearing compression, especially with progressive ECS, decreased the SSV and DCV cross-sectional area only with patients supine, thus decreasing postural changes, which remained highly diverse between individuals. The SSV cross-sectional area versus PF function traced a hysteresis loop of which the area, related to viscosity, was greater in C3 and C5 limbs than controls, even with graduated 15 to 20 or 20 to 36 mm Hg ECS. Progressive ECS decreased vein viscosity in the supine position, whereas 20 to 36 mm Hg and progressive ECS increased distensibility in the standing position. CONCLUSIONS: ECS decrease the cross-sectional area of SSV and DCV with patients supine, but not upright. C1s limbs show distinctive features, especially regarding IFP. Graduated 20 to 36 mm Hg and progressive stockings lower viscosity and increase distensibility of the SSV.

"I Cry. I Simply Cry." An Ethnography of a Lymphedema Summer Camp.

Background: The aim of this study was to explore how self-management is taught, learnt, and experienced during a 3-day educational Lymphedema Camp for parents of children with lymphedema. Methods: Participants (professionals, parents, and children) were observed during camp activities and interviewed informally and formally in focus groups. The embodied nature of the experience expressed by professionals, parents, and researchers became the analytical focus for understanding the felt tensions in the teaching and learning of self-management to families. Findings: The affective sensibilities associated with the uncertainties involved in teaching and learning self-management skills were palpable given that: young people are now expected to take up strict time-consuming self-management regimens (often via the support of a parent) where "evidence-based" outcomes are uncertain or may not match the outcomes wanted by a young person (varying in age and therefore ability or willingness to engage); or where there are tensions within the family; and the variety of different professionals involved means that techniques varied but where these professionals also lacked the necessary skills training to guide them in how to teach self-management. An analytical focus on the distress, doubt, fear, loneliness, guilt, and moralism felt by professionals, parents, and the researchers supports us to identify the character of the problems associated with performing best practice care guidance where there is a lack of practical support or resources for how self-management in this population should be achieved. Conclusion: To avoid these issues more training and research are needed on "how" to self-manage and stop victim-blaming that generates tensions and drives a wedge between the carer and the cared-for. When systemic problems get located with individuals (professionals, parents, or children), this directs our attention and understanding away from systems of care that lack coordination, may be under-resourced, and where effective training is absent.

Development of Self-Efficacy Tools for Parents and Professionals Caring for Children and Young People with Lymphedema (ILF Parent SE and ILF Professional SE).

Background: Self-management is a key aspect of lymphedema treatment and self-efficacy is a key factor linked to long-term adherence to treatment. The study aimed to generate self-efficacy scales to support the care of children and adolescents with lymphedema to support self-management. Methods and Results: Parents of children with lymphedema and the professionals caring for them were recruited during a lymphedema educational camp. Six individual semistructured focus groups were undertaken in Italian, French, and English (three for parents and three for professionals) with simultaneous translation. Scale item generation was developed using interpretative phenomenological analysis and adopted Bandura's self-efficacy concept. Two self-efficacy tools were developed from research with 26 parents and 14 professionals. The parental tool (ILF parent SE) has 6 domains and 44 items: school; home and leisure; understanding the condition and treatment, and managing child and parent emotions. The professional tool (ILF Professional SE) has 4 domains and 21 items. This scale has two parts; the first indicates the level of professional autonomy in decision making, and the second covers assessment and treatment, patient understanding, and managing emotional reactions. Both tools adopt a 0- to 100-point scale using a 10-unit interval with 0 (cannot do) through to 100 (high certainty of being able to do). Initial face validity has been undertaken. Conclusion: Self-efficacy has emerged as a complex issue faced by parents and professionals involved with children and young people with lymphedema. By being able to assess the challenges parents face in self-efficacy individualized programs can be developed that will assist families in managing this complex disease and lead to greater well-being. Increased professional self-awareness will help the development of mentorship programs to support professionals dealing daily with the stress of managing a rare disease in which the outcome may be uncertain.

International Camps for Children with Lymphedema and Lymphatic Anomalies: When Education Links with Psychosocial Research.

Background: Lymphedema in children and adolescents is a rare and chronic condition. The management of their lymphedema is mainly driven by the adaptation of treatments used in adults. The aim of our study was to explore the needs and challenges the children and adolescents face during their management with the aim of finding ways to satisfy these needs and organize an hospital-based centre accordingly with an educational program. Methods and Results: Patients and their families were given the opportunity to meet other patients, their families and professionals during social activities organised annually and during two international camps. They were invited to take part in different semi structured focus groups and interviews. All patients and families described a long journey and relief when the diagnosis was obtained followed by the shock of being told that it was a chronic condition. Meeting other children with the condition was a relief. The impact of lymphedema on body shape and genitals was a source of distress. Rejection of the compression was part of journey. Lymphedema management had an impact on all the family members including siblings. Parents were responsible for their child self-management in young children which was described as demanding. It was followed by a complex transition phase to self-management. The impact was not the same according to the age the lymphedema had started. Conclusion: Acceptance and management of lymphedema is complex and invades many aspects of families' life. Self-management is demanding. Based on these results, the management of lymphedema in the centre included meeting other children and families and an educational program based on individual needs and follow-up. Clinical Trials.gov ID:NCT01922635.

Severe adverse events during sirolimus "off-label" therapy for vascular anomalies.

OBJECTIVES: Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use" for vascular anomalies. METHODS: We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow. RESULTS: We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n = 4), Gorham-Stout disease (n = 2), central conducting lymphatic anomaly (n = 1), lymphatic malformation (n = 4), tufted angioma (n = 1), kaposiform hemangioendothelioma (n = 1), and venous malformation in a patient with CLOVES syndrome (n = 1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2 years (n = 5), 2-6 years (n = 5), and older than 12 years (n = 4). SAEs occurred during the first 3 months of sirolimus therapy (n = 7), between 3 and 12 months (n = 7) and after 1 year of therapy (n = 3). The most frequent SAE was viral pneumonia (n = 8) resulting in one death due to a metapneumovirus infection in a 3 months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis. CONCLUSIONS: Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.

Noninvasive measurement of venous wall deformation induced by changes in transmural pressure shows altered viscoelasticity in patients with chronic venous disease.

OBJECTIVE: The noninvasive measurement of venous wall deformation induced by changes in transmural pressure could allow for the assessment of viscoelasticity and differentiating normal from diseased veins. METHODS: In 57 patients with limbs in the C1s (telangiectasia or reticular veins and symptoms), C3 (edema), or C5 (healed venous ulcer) CEAP (clinical, etiologic, anatomic, pathophysiologic) category of chronic venous disease and 54 matched healthy controls, we measured the changes in the cross-sectional area of the small saphenous vein and a deep calf vein in the supine and standing positions and under compression with an ultrasound probe using ultrasonography. RESULTS: The small saphenous vein, but not the deep calf vein, cross-sectional area was smaller in the limbs of the controls than in the limbs with C3 or C5 disease but was not different from that in C1s limbs. When changing from the supine to the standing position, a greater force was required to collapse the leg veins. Their cross-sectional area increased in most subjects but decreased in 31.5% of them as for the small saphenous veins and 40.5% for the deep calf vein. The small saphenous vein area vs compression force function followed a hysteresis loop, demonstrating viscoelastic features. Its area, which represents the viscosity component, was greater (P < .001) in the pooled C3 and C5 limbs (median, 2.40 N⋅mm2; lower quartile [Q1] to upper quartile [Q3], 1.65-3.88 N⋅mm2) than in the controls (median, 1.24 N⋅mm2; Q1-Q3, 0.64-2.14 N⋅mm2) and C1s limbs (median, 1.15 N⋅mm2; Q1-Q3, 0.71-2.97 N⋅mm2). The area increased (P < .0001) in the standing position in all groups. CONCLUSIONS: Postural changes in the cross-sectional area of the leg veins were highly diverse among patients with chronic venous disease and among healthy subjects and appear unsuitable for pathophysiologic characterization. In contrast, small saphenous vein viscoelasticity increased consistently in the standing position and the viscosity was greater in limbs with C3 and C5 CEAP disease than in controls.

A Study Using Visual Art Methods to Explore the Perceptions and Barriers of Self-Management in Children and Adolescents with Lymphedema.

Background: The aims of this study were to explore, using visual art methodology, how children and adolescents perceive their lymphedema and conceptualize the barriers and enablers in self-management and to explore the role of an educational camp in promoting self-efficacy. Methods: Participants (speaking English, French, and Italian) were recruited during an educational camp for children with lymphedema. Children and adolescents used different methodologies to depict living and self-managing their condition. Younger children (aged 5-12 years) drew pictures, and all children and adolescents (aged 5-18 years) were given cameras and asked to take photographs that depicted their experience of learning self-management of their condition during the camp. Rose's critical visual methodology framework was used for analysis. Results: Analysis of the data produced five categories: Normal versus altered childhood, living with lymphedema; perceptions of lymphedema and self-care in younger children; adolescents' perception of living and managing lymphedema; learning self-efficacy; and insights into cultural differences in self-care. Conclusions: The study has shown that self-management is complex. Children and adolescents face many daily challenges and frustrations in managing their condition in addition to the normal challenges of development and growth that impact on: home life, time with friends, school activities, and relationships. Children expressed a deep longing for cure and a recognition that their lives were altered by having the condition that led to limitations in sport and wearing fashionable clothes and shoes. The importance of relationships with professionals was critical as was the experience of meeting and learning with other children through the camp experience. Attempts to simplify self-management techniques would appear to be a key priority as would a greater understanding of the self-beliefs young people have of their ability to influence and control their condition and its impact on their life.

A Study to Explore the Professional Conceptualization and Challenges of Self-Management in Children and Adolescents with Lymphedema.

Background: The aim of this study was to explore the professional experience of caring for children and adolescents with lymphedema and to explore the way in which they understand and implement self-management strategies and the influence of their own self-efficacy beliefs on this process. Methods and Results: Participants were recruited during an educational camp for children with lymphedema. Three individual semistructured focus groups were undertaken in English, French, and Italian with simultaneous translation. Data were analyzed using interpretative phenomenological analysis (IPA). Analysis of the data produced three superordinate themes: professional concepts of self-management, professional practice, and redefining the cornerstone of lymphedema care. An additional seven subthemes were as follows: readiness to self-management, professional perspectives on self-management, defining success and treatment failure, emotional burden, traditional views on complex decongestive therapy, new ways to practice, and sole practitioner versus multidisciplinary teams. Conclusions: The purpose of the study was to explore the challenges professionals face when introducing self-management to children and adolescents with lymphedema and their parents and to explore their own sense of self-efficacy in approaching this. The research allowed in-depth discussion about the ways they conceptualize self-management and faced professional challenges. The research highlighted the need to define what is considered an acceptable outcome within a complex and uncertain condition and the self-management strategies that are needed to support this.

LIMPRINT: Estimation of the Prevalence of Lymphoedema/Chronic Oedema in Acute Hospital in In-Patients.

Background: To estimate the prevalence of lymphedema/chronic edema (CO) and wounds in acute hospital inpatients in five different countries. Methods and Results: A point-prevalence study was carried out during working day periods in six general hospitals in four countries (Denmark, France, United Kingdom, and Australia) and one hospital oncology inpatient unit in one other country (Ireland). The study used validated clinical tools for the assessment and collection of data. Data were collected by expert clinicians through interviews and physical examination of the patients present in the wards. A total of 1905 patients could be included and investigated among the 3041 total bed occupancy in the seven hospitals. Lymphedema/CO was present in 723 of them (38%). Main risk factors associated with CO were age, morbid obesity, and heart failure, as well as chair bound immobility and neurological deficiency. History of cellulitis was frequent in patients with CO and wounds (24.8%) and CO alone (14.1%) compared to the 1.5% prevalence in patients without CO. Conclusion: Lymphedema/CO is very frequent in patients hospitalized in hospital acute wards. It is strongly associated with obesity, venous insufficiency, and heart failure. Our results strongly suggest a hidden health care burden and cost linked to CO independently of chronic wounds.

An Auto-Adjustable Night Garment to Control Early Rebound Effect of Edema Volume After Intensive Phase of Decongestive Lymphedema Therapy.

BACKGROUND: Lymphedema of the arm and/or hand is a well-established complication of breast cancer therapy. The objective of the study was to determine the interest of auto-adjustable MOBIDERM® Autofit night arm sleeve in controlling edema rebound effect in breast cancer-related lymphedema patients just after a successful intensive phase of decongestive lymphedema therapy (DLT). MATERIALS AND METHODS: This is a subgroup analysis of MARILYN Study, conducted on 40 patients after completion of intensive DLT. Patients were randomized in Night-user group (fitted with MOBIDERM Autofit device) or No night-user group (no night compression). For subgroups analysis, patients were defined as high responders (HR) if their lymphedema volume reduction during DLT was ≥35% or as low responders (LR) if it was below 35%. RESULTS: In HR subgroups (n = 16), the mean lymphedema volume variation between Day 0 and 30 was 28.4 mL in the night-user group versus 181.4 mL in the no night-user group. When adjusted to the loss of volume during DLT, 89% of the DLT benefit is maintained in HR night-user versus 54% in no night-user group. Between LR (24 patients), this mean volume variation was by 65.1 mL versus 54.9 mL in night-user and no night-user groups respectively between Day 0 and 30. CONCLUSION: Wearing MOBIDERM Autofit, on top of the day time hosiery, appears a promising way to control the early rebound effect during the maintenance phase especially in DLT-HR.

Validation of lower limb segmental volumetry with hand-held, self-positioning three-dimensional laser scanner against water displacement.

BACKGROUND: Measurement of limb volume is helpful for the evaluation and follow-up of edema, especially in patients with chronic venous insufficiency (CVI) or lymphedema. Water displacement (WD) is the reference method for limb volumetry but is not really suitable for clinical routine. Indirect volumetry based on circumference measurements as well as the more expansive but automatic optoelectronic techniques do not allow detailed measurement at the extremity of the limb. METHODS: We used a self-positioning laser scanner with dynamic referencing for acquisition and real-time three-dimensional (3D) reconstruction of the lower limb volume in 30 patients with CVI, 30 patients with lymphedema, and 30 healthy controls. Two independent observers performed either one or two laser scans, whose results were tested for intra- and interobserver reproducibility and compared with WD volumetry by Lin's concordance correlation coefficient and Bland and Altman graphic analysis. RESULTS: Automatic volume calculation from 3D laser scanning data failed in one patient with major lymphedema. Lin's concordance correlation coefficient was 0.99 and 0.98, respectively, for intraobserver no. 1 and no. 2, 0.98 for interobserver reproducibility, and 0.98 and 0.96, respectively, for observer no. 1 and observer no. 2 vs WD comparison. The 3D laser scanning yielded 1.99% precision. Accuracy was 3.12% for observer no. 1 and 2.71% for observer no. 2, laser scanning values being 90 mL higher than WD, which could be attributed to the different posture during measurement. CONCLUSIONS: Three-dimensional laser scanning is accurate and reproducible, and appears suitable for the evaluation of limb volume in patients with CVI or lymphedema.

Evaluation of lower limb vein biomechanical properties and the effects of compression stockings, with an instrumented ultrasound probe.

We present a new approach for the evaluation of the biomechanical properties of lower limb veins based on the simultaneous measurements of the vein cross-sectional area with B-mode ultrasound imaging and of the force exerted on the skin by the ultrasound probe. Ongoing clinical trials allowed us to identify a behavioral model of lower limb veins without and with compression stockings.