Primary Lymphedema Research Articles

Effects of Short-Term Educational Hospitalization with Multidisciplinary Approach for Lymphedema on Limb Circumference and Quality of Life.

Background: Lymphedema is an intractable disease requiring lifelong treatment. Daily self-care by the patient is essential; however, establishing care is often difficult. Our hospital offers a short-term educational hospitalization program that involves intensive, multidisciplinary intervention to develop self-care. This study aimed to evaluate the effectiveness of this program. Methods and Results: Among the patients diagnosed with primary or secondary lymphedema who underwent educational hospitalization, 31 cases (33 limbs) were included in this study. The upper extremity lymphedema (UEL) index and lower extremity lymphedema (LEL) index were used for objective evaluation, and the Lymphedema Quality of Life Questionnaire was used for subjective evaluation. The therapeutic effects of educational hospitalization were examined before admission, at discharge, and at 6 months postdischarge. The UEL/LEL index significantly decreased for both the upper and lower limbs after educational hospitalization. In addition, the UEL/LEL index change rate from prehospitalization to 6 months postdischarge was compared between the continued and discontinued exercise groups; the former index showed significantly more improvement than the latter. Comparing the quality of life (QOL) assessments pre- and posthospitalization, statistically significant improvements were observed in all categories, including function, appearance, symptoms, and psychological state. Conclusions: Short-term educational hospitalization led to a sustained reduction in the circumference of lymphedema-affected limbs and an improvement in the QOL. The multidisciplinary approach resulted in improved self-efficacy and established daily self-care.

Chylous Reflux in Pediatric Primary Lymphedema of the Lower Limbs and Genitalia: A Retrospective Study of 167 Patients.

Background: Chylous reflux (CR) in primary lymphedema (PL) of the lower extremities is rare and requires particular diagnostic procedures. This study aimed to determine clinical and lymphoscintigraphic traits for efficient screening. Methods and Results: Pediatric patients with PL of lower extremities treated in our institution between January 2020 and December 2023 were reviewed. The medical history, lymphoscintigraphy, non-contrast MR lymphography, and direct lymphangiography were analyzed. Lymphoscintigraphic visual patterns were classified to detect CR. Patients with CR showed significantly higher proportions of childhood symptom onset (65.63% vs. 25.19%, p < 0.01), genital lymphedema (62.50% vs. 19.26%, p < 0.01), and proximal-to-distal swelling (31.25% vs. 8.89%, p < 0.01). Eight patients without skin lesions had milk discharge after acupuncture or skin breakdown. Pattern 4 shows diffused dermal backflow of the leg and an absence of superficial lymphatic drainage, or normal initial cephalad flow with subsequent reflux of tracer into the affected limb. CR showed significantly higher percentages of pattern 4 (87.50% vs. 12.59%, p < 0.01), normal/widened iliac lymphatics (78.13% vs. 11.11%, p < 0.01), and thigh/calf outlining (87.50% vs. 29.63%, p < 0.01). Genital swelling preceding limb swelling and genital radioactivity were more common in the CR group. Conclusions: CR tends to occur in childhood initially, begin centrally and progress distally, and involve genitals prior to lower extremities. Milk discharge after acupuncture or skin breakdown is important for screening CR without chylous vesicles. The patterns with typical "profiling of the leg" and normal or widened iliac lymphatic trunks strongly correlate with CR. Genital lymphedema with increased radioactivity indicates CR.

EDITORIAL: RETURNING THE CENTRAL LYMPHATIC SYSTEM TO THE CENTER OF LYMPHOLOGY

After the introduction of conventional oil contrast lymphography and the founding of the discipline of lymphology, great impetus was given to investigating central lymphatic system and its disorders along with lymphatic involvement and specifically lymphostasis in common diseases of major organs such as the liver (cirrhosis) and heart (heart failure). Gradually interest shifted to more peripheral disorders such as limb lymphedema and its treatment by physical and surgical measures. At the same time, basic lymphology turned to the study of isolated ex vivo and in vitro, including lymphatic endothelial models and more recently, molecular lymphology focusing on lymphatic growth and modulating factors, genes and proteins underlying primary lymphedema, and more potential biomarkers of lymphatic disease have gained prominence. However, it has been advances in lymphatic imaging, namely lymphoscintigraphy with SPECT-CT high resolution 3-D pictures and magnetic resonance imaging (contrast and non-contrast) of the peripheral and particularly central lymphatic system by more invasive means combined with endovascular interventional techniques to treat complex and life-threatening lymphatic disorders that has returned the central lymphatic system to the center of lymphology, where the journey began.

Primary LYmphedema Multidisciplinary Approach in Patients Affected by Primary Lower Extremity Lymphedema.

Background: Primary lymphedema is a chronic condition caused by a developmental abnormality of the lymphatic system, leading to its malfunction. Various surgical options, including physiologic and excisional procedures, have been proposed. The aim of this study was to present a comprehensive algorithm for the treatment of primary lower extremity lymphedema: the Primary LYmphedema Multidisciplinary Approach (P-LYMA). Methods: Nineteen patients were treated following the P-LYMA protocol. Patients underwent pre- and postoperative complex decongestive therapy (CDT). A variety of physiologic and excisional procedures were performed, either independently or in combination. The primary outcome was to assess the circumferential reduction rate (CRR). The Lymphedema Quality of Life Score (LeQOLiS), reduction in the number of cellulitis episodes, and complications were recorded. Results: The mean CRR was 73 ± 20% at twelve months postoperatively. The frequency of cellulitis episodes per year decreased from a mean of 1.9 ± 0.8 preoperatively to 0.4 ± 0.6 during follow-up. Two patients experienced minor complications. The mean hospitalization time was 5 days. Patients' quality of life, as measured by the LeQOLiS, significantly improved from 70.4 ± 12 preoperatively to 24 ± 14 at twelve months postoperatively. Conclusions: The P-LYMA algorithm maximizes surgical outcomes and improves the quality of life in patients with primary lymphedema. CDT is essential for optimizing results.

GENETIC VARIANTS IN GENES CORREIATED TO THE PI3K/AKT PATHWAY: THE ROLE OF ARAP3, CDHS, KIF11 AND RELNIN PRIMARY LYMPHEDEMA

Genetic anomalies affecting lymphatic development and function can lead to lymphatic dysfunction, which could manifest as lymphedema. Understanding the signaling pathways governing lymphatics function is crucial for developing targeted diagnostic and therapeutic interventions. This study aims to characterize genetic variants in genes involved in the PI3K/AKT signaling pathway, which plays a critical role in lymphangiogenesis. 408 patients diagnosed with primary lymphedema were sequenced using a next-generation sequencing (NGS) gene panel composed of 28 diagnostic genes and 71 candidate genes. The analysis revealed six variants in genes RELN, ARAP3, CDH5, and KIF11. Five of these variants have never been reported in the literature. All these genes have been correlated to lymphatic activity and are involved in the PI3K/AKT pathway. As the PI3K/AKT signaling pathway plays an essential role in lymphangiogenesis and lymphatic function, genetic variants in genes correlated to this pathway could lead to lymphedema. Our findings underscore the potential of the PI3K/AKT pathway in lymphedema pathogenesis, supporting the role of RELN, ARAP3, CDH5, and KIF11 as diagnostic and therapeutic targets.

Quality of Life in Lymphedema Patients Treated by Microsurgical Lymphatic Vessel Transplantation-A Long-Term Follow-Up.

Lymphedema is a chronic condition characterized by the accumulation of lymph fluid in the upper or lower extremities, leading to swelling, discomfort, and disability in everyday life. While various treatment modalities exist, microsurgical lymphatic vessel transplantation (LVT) has emerged as a promising option. However, there is little to no long-term follow-up data regarding patients' improvement in quality of life for this surgical technique. The present study conducts an investigation of the long-term health-related quality of life (HRQoL) over more than 20 years in patients with lymphedema treated with LVT and accomplishes this by utilizing an adapted SF-12 survey. A retrospective analysis was conducted on patients who underwent LVT between 1 January 1983 and 1 October 2010 at LMU Clinic Munich (n = 35). Quality of life scores were assessed preoperatively and today in terms of physiological conditions, psychological conditions, and burden of therapy using a SF-12 survey adapted to the symptoms and impairments that chronic lymphedemas are known to cause. Our findings demonstrate a significant improvement in HRQoL following LVT, with notable enhancements in physiological and psychological conditions such as burden of therapy. Physiological conditions showed a significant positive change of 3.2648 (p < 0.01). Psychological conditions improved significantly by a factor of 2.0882 (p < 0.01). Additionally, the burden of therapy improved significantly by 1.5883 points (p < 0.01). Previous studies have already shown a significant improvement of HRQoL within the first postoperative years for patients treated by LVT. This study also demonstrates significant long-term improvement after LVT, thus underlining the effectiveness of using LVT to improve the quality of live for patients with both primary and secondary lymphedema long-term.

Transcriptional, developmental, and functional parallels of lymphatic and venous smooth muscle.

Lymphatic muscle cells (LMCs) are indispensable for lymphatic vessel contraction and their aberrant recruitment or absence is associated with both primary and secondary lymphedema. Despite their critical role in lymphatic vessel function, the transcriptomic and developmental basis that confer the unique contractile properties to LMCs are largely undefined. In this study, we employed single-cell RNA sequencing (scRNAseq), lineage tracing and in vivo imaging to investigate the basis for the hybrid cardiomyocyte and blood vascular smooth muscle cell (SMC) characteristics that have been described for LMCs. Using scRNAseq, the transcriptomes of LMC and venous SMCs from the murine hindlimb exhibited more similarities than differences, although both were markedly distinct from that of arteriole SMCs in the same tissue. Functionally, both lymphatic vessels and blood vessels in the murine hindlimb displayed pulsatile contractility. However, despite expressing genes that overlap with the venous SMC transcriptome, through lineage tracing we show that LMCs do not originate from Myh11+ SMC progenitors. Previous studies have shown that LMCs express cardiac-related genes, whereas in our study we found that arteriole SMCs, but not LMCs, expressed cardiac-related genes. Through lineage tracing, we demonstrate that a subpopulation of LMCs and SMCs originate from WT1+ mesodermal progenitors, which are known to give rise to SMCs. LMCs, however, do not derive from Nkx2.5+ cardiomyocyte progenitors. Overall, our findings suggest that venous SMCs and LMCs and may derive from a related mesodermal progenitor and adopt a similar gene expression program that enable their contractile properties.

The Possible Role of Lymphaticovenous and Lymph Node to Vein Anastomosis for Improvement of Milroy Disease Related Congenital Chylothorax and Lower Extremity Lymphedema.

Primary lymphedema is characterized by lymphatic dysplasia in which one variant is Milroy's disease. The association with congenital chylothorax is even rarer with poor outcome. This is the first report to utilize peripheral lymphovenous anastomosis (LVA) and lymph node to vein anastomosis (LNVA) for the management of such condition. Retrospective chart review of patients with Milroy's disease with complication of chylothorax between 2019 till 2023 was performed. Clinical assessment and radiological investigations were reviewed. Six patients with mean age of 12±3.9 years and disease duration of 10.5±2.8 years were reviewed. Three had ISL stage 3 while others had stage 2 late disease. All had bilateral lower extremity lymphedema and chylothorax with history of chest tube drainage. After LVA and LNVA, significant reduction in extremity volume was noted (p=0.028) along with near complete resolution of chylothorax was noted during the long-term follow-up (32 ±17.9 months). Milroy's disease complicated with chylothorax remains to be challenging. This is the first report utilizing peripheral bypass (LVA and LNVA) which resulted in improvement of both lower extremity lymphedema and chylothorax. The utility of this approach represents a promising modality in the management of this devastating condition.

Polymorphism of angiogenesis regulation factor genes (VEGF/VEGFR), and extracellular matrix remodeling genes (MMP/TIMP), and the levels of their products in extracellular tissues of patients with primary and secondary lymphedema.

Cells of various organs and systems perform their functions and intercellular interactions not in an inert environment, but in the microenvironment of tissue fluids. Violations of the normal drainage of tissue fluids accompany lymphedema. An important mechanism of angiogenesis and vasculogenesis regulation in tissue fluids is the production and reception of vascular endothelial growth factors in combination with the regulation of matrix metalloproteinases. The aim of the work was to perform: a comparative analysis of some polymorphisms of vascular endothelial growth factor and their receptors and the genes encoding matrix metalloproteinases in two forms of lymphedema; an analysis of the relationship of these genes' polymorphisms with the levels of vascular endothelial growth factor and matrix metalloproteinases and their inhibitors in serum and affected tissues. Polymorphism of VEGF (rs699947, rs3025039), KDR (rs10020464, rs11133360), NRP2 (rs849530, rs849563, rs16837641), matrix metalloproteinases MMP2 (rs2438650), MMP3 (rs3025058), MMP9 (rs3918242), Timp1 (rs6609533) and their combinations were analyzed by the Restriction Fragment Length Polymorphism method and TaqMan RT-PCR. The serum and tissue fluid levels were determined using the ELISA test system. Changes in the frequency distribution of MMP2 genotypes in primary and MMP3 in secondary lymphedema are shown. Significant frequency differences in NRP2 genotypes were revealed by comparing primary and secondary lymphedema. Features of the distribution of complex genotypes in primary and secondary lymphedema were revealed. The correlation analysis revealed the interdependence of the concentrations of the MMP, TIMP and VEGF products and differences in the structure of the correlation matrices of patients with both forms of lymphedema. It was shown that, in primary lymphedema, genotypes associated with low MMP2 and TIMP2 in serum and tissue fluid are detected, while in secondary lymphedema, other associations of the production levels with combined genetic traits are observed.

LYMPHOSCORE (Lymphoscintigraphy Scoring Reliability) Reliability of a New Qualitative and Semiquantitative Lymphoscintigraphy Scoring System for Primary Lymphedema.

Primary lymphedema (PLE) is a rare chronic disorder. Extremity lymphoscintigraphy offers access for dynamic and functional information on peripheral lymphatics and lymph nodes. We aimed to assess intraobserver and interobserver reliability of a new lymphoscintigraphy quantitative and qualitative scoring system in a homogeneous population of adult patients followed for PLE of the lower limb(s). This is a monocentric retrospective study. Clinical files of patients who underwent a lymphoscintigraphy were reviewed for inclusion. Lymphoscintigraphies were interpreted twice by 2 observers with a washout period. To assess intraobserver and interobserver reliability for both lower limbs, Cohen κ and Gwet's AC1 reliability coefficients were calculated with 95% confidence interval and P value of the zero-reliability comparison test. To interpret reliability coefficients, we used the orders of magnitude reported by Landis and Koch. One hundred forty-four patients (288 limbs) with PLE were included. For intraobserver reliability, agreement range was 0.87-1 with an almost perfect agreement in all staging items of the score for both limbs with the lower limit of the 95% confidence interval ≥80%. Interobserver reliability was overall strong or almost perfect, ranging from 0.67 to 0.97. This new scoring system demonstrated excellent intraobserver reliability and a very good interobserver reliability. Lymphoscintigraphy, when performed in a referral center and interpreted by trained nuclear medicine physicians, is a reliable means of investigation in patients with PLE of the lower limbs. This reproducibility advocates for further use of lymphoscintigraphy in multicentric cohorts of PLE patients.

Comparing complex decongestive therapy in patients with lymphedema of different causes by measuring: extremity volume, quality of life, and functionality.

This study aimed to investigate the effects of complex decongestive therapy (CDT) applied to the lower extremities of patients with lymphedema of different causes on the extremity volume, quality of life (QoL), and functionality. The study included 90 patients, of whom 28 had primary lymphedema, 30 had secondary lymphedema, 18 had phlebolymphedema, and 14 had lipolymphedema. A total of 137 extremities were treated with CDT. The patients who received CDT for 5 days a week for 3 weeks (15 sessions in total) were included in the sample. Extremity volume was measured using a tape measure. The lymphedema QoL-Leg Questionnaire was used to evaluate QoL, and the lower extremity functional scale (LEFS) was administered to assess lower extremity functionality. The changes in QoL before and after treatment significantly differed in the primary lymphedema, phlebolymphedema, and lipolymphedema groups (p < 0.05). The post-treatment LEFS scores indicated a significant decrease in the phlebolymphedema and lipolymphedema groups compared to the pre-treatment scores (p < 0.05). The difference in appearance, which is one of the sub-parameters of QoL, significantly decreased in the comparisons performed between the groups, whereas the changes in the remaining parameters were not significant.

Frequency of Hematologic and Nonhematologic Conditions in Pediatric Patients with Vascular Anomalies: A Pediatric Health Information System Database Study

Background: Vascular anomalies (VA) are a heterogeneous group of diseases which include vascular malformations and vascular tumors. In the pediatric population, there is a sparsity of data on the frequency of associated hematologic and nonhematologic conditions as well as overall outcomes for patients. Objectives: The objective of this study was to determine the rate of certain concurrent hematologic and nonhematologic conditions in patients with VA who underwent procedures and compare those to patients who did not undergo procedures. To examine the rates of intensive care unit admissions and discharge mortality in patients who had a vascular anomaly. Methods: This is a multicenter retrospective cohort study using data from the Pediatric Health Information System. The database was queried for children 0–18 years old with a diagnosis of a VA who had inpatient encounters between January 2016 and September 2021. Results: The most common hematologic conditions were thrombocytopenia, iron deficiency anemia, and venous thrombosis. The most common nonhematologic condition was electrolyte imbalances. Intensive care unit admissions were highest among patients with other congenital malformations of the peripheral vascular system, cerebral cavernous malformations, and sporadic arteriovenous malformations. Discharge mortality was highest in patients with lymphatic malformations and primary lymphedema. Conclusions: This is the largest database study of pediatric patients with VA and their concurrent medical conditions and outcomes to date. While our study could not prove associations, we hope that our results will serve as a foundation for more extensive research regarding the impact of these identified conditions and outcomes and contribute to improved management of patients with VA.

Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema.

Primary lymphedema (PL), characterized by tissue swelling, fat accumulation, and fibrosis, results from defects in lymphatic vessels or valves caused by mutations in genes involved in development, maturation, and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor-like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodeling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability, and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR/Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2/TIE1 pathway in lymphatic function.

The mechanosensory channel PIEZO1 functions upstream of angiopoietin/TIE/FOXO1 signaling in lymphatic development.

Lymphedema is a debilitating disease with no effective cure and affects an estimated 250 million individuals worldwide. Prior studies have identified mutations in piezo-type mechanosensitive ion channel component 1 (PIEZO1), angiopoietin 2 (ANGPT2), and tyrosine kinase with Ig-like and EGF-like domains 1 (TIE1) in patients with primary lymphedema. Here, we identified crosstalk between these molecules and showed that activation of the mechanosensory channel PIEZO1 in lymphatic endothelial cells (LECs) caused rapid exocytosis of the TIE ligand ANGPT2, ectodomain shedding of TIE1 by disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), and increased TIE/PI3K/AKT signaling, followed by nuclear export of the transcription factor FOXO1. These data establish a functional network between lymphedema-associated genes and provide what we believe to be the first molecular mechanism bridging channel function with vascular signaling and intracellular events culminating in transcriptional regulation of genes expressed in LECs. Our study provides insights into the regulation of lymphatic function and molecular pathways involved in human disease.

FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms.

Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. The distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. The phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. In this study, we show that FLT4 variants identified in patients with TOF, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wild-type (WT) FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of WT human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants. Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms.

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.

Lymphedema and Paget’s Disease: beyond the nipple

Lymphedema praecox is a rare lymphatic vascular anomaly diagnosed before the age of 35, presenting with unilateral involvement of the lower extremities. Paget's Disease of Bone (PDB) is also a rare osteometabolic disorder characterized by an accelerated rate of bone remodeling, and diagnosis of the disease is challenging. Here, we report a 49-year-old woman with primary lymphedema since the age of 33, who presented with pain and swelling in her right leg. Although the volume of the extremity diminished after complete decongestive therapy, the pain continued. Further evaluation with X-ray, bone scan, and biochemical markers supported the diagnosis of PDB. Following the zoledronic acid infusion, the pain score improved. However, there is no published association between these two diseases. Both lymphedema and PDB are associated with vascular disease and have a genetic background. This is the first case reporting the coexistence of lymphedema and PDB in the same extremity.

The value of the dermal rim sign on nonenhanced magnetic resonance imaging for predicting dermal backflow in patients with primary lower extremity lymphedema

PurposeThe dermal rim sign (DRS) on nonenhanced magnetic resonance imaging has been shown to predict dermal backflow (DBF) in patients with secondary upper limb lymphedema. However, whether the DRS has the same effects on primary lower extremity lymphedema (PLEL) has not been clearly reported. Therefore, this study aimed to explore whether the DRS can be used to diagnose DBF on lymphoscintigraphy in patients with PLEL. MethodsA total of 94 patients who were diagnosed with PLEL were recruited for this retrospective study from January 2022 to December 2023. All the patients were divided into two groups according to the lymphoscintigraphy findings: no DBF and DBF. The magnetic resonance imaging data of the two groups were recorded and statistically compared for the following indicators: range of lymphedema involvement (left, right, whole lower limbs, only thigh, only calf and ankle), signs of lymphedema (notable thickening of skin, parallel line sign, grid sign, honeycomb sign, band sign, lymph lake sign, crescent sign, DRS), and lymphedema measurement (skin thickness, band width). The DRS is characterized by notable thickening of the skin plus the grid sign and/or honeycomb sign, plus the band sign. ResultsThe following statistically significant differences in the following indicators were found between the two groups (P < .05): notable skin thickening, parallel line sign, grid sign, honeycomb sign, band sign, DRS, skin thickness, and band width. The sensitivity, specificity, and accuracy for predicting for DBF with the DRS was 82%, 64%, and 77%, respectively. ConclusionsThis study confirmed good consistency between the DRS and DBF from the perspective of imaging. This tool is suitable for children, adolescents, and patients with contraindications to lymphoscintigraphy. The DRS has important value in assessing the severity of PLEL. The DRS is suggested for the clinical use of combined surgical treatment of PLEL.

Outcomes from a proof-of-concept specialist lymphoedema clinic in the community.

The Health and Safety Execultive lymphoedema model of care was published in 2018 highlighting the lack of dedicated lymphoedema services in Ireland. This led to the introduction of a proof-of-concept primary care specialist lymphoedema clinic. The clinic was responsible for all patients from their county. A comprehensive dataset was gathered which included the patient's history for 1 year prior to their presentation at clinic and then 6 monthly. A quality of life tool (LymQoL) and a patient satisfaction survey were completed. Completed 1-year data showed a significant reduction in GP and public health nurse visits as well as a reduction in the occurrence of cellulitis and associated hospital admissions. All areas of quality of life were improved and patient satisfaction was either excellent (89%) or very good (11%). The 1-year findings strongly support the roll-out of specialist clinics to all regional health areas.

A Novel Likely Pathogenic Variant in NOTCH1 Associated With Primary Lymphedema

Lymphedema is a chronic condition characterized by the accumulation of lymphatic fluid in interstitial and fibro-adipose tissues. Primary lymphedema that arises from intrinsic defects in the lymphatic system is a rare form of lymphedema with a variable age of onset and heterogeneous presentation. Although a number of genetic variants have been identified and matched to corresponding phenotypes, a genetic cause for lymphedema is found in less than 30% of individuals with primary lymphedema. Recently, Michelini et al proposed NOTCH1 as a candidate gene for primary lymphedema, having identified missense variants in NOTCH1 in 7 of 235 patients with primary lymphedema for whom no causative gene had previously been identified. We report the case of a young female who developed bilateral primary lower limb lymphedema and on genetic testing was found to have a previously unreported heterozygous frameshift variant in the NOTCH1 gene predicting loss of function.