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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 RT­PCR. 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.

BACKGROUND: Primary lymphedema (PL) is a condition generated by an intrinsic failure in the lymphatic vessels that leads to the formation of edema of chronic character, of genetic origin, with a prevalence of 1 in 100,000 people, being more frequent in the female sex and affecting mainly the lower extremities. One of its forms, Milroy's disease (MD), which corresponds to less than 10% of all LP, is a rare, congenital entity, with autosomal dominant inheritance and variable penetrance, associated with mutations of the FLT4 gene. CLINICAL CASE: Male preterm newborn, born by cesarean section as a result of a high-risk pregnancy; parents with no family history of lymphedema. At birth he presented bilateral edema of the lower limbs, localized in the dorsum of both feet, with local changes; no other abnormalities were present. Due to the clinical presentation, PL due to MD was suspected. Multiple studies were performed, among them; soft tissue ultrasound found edema of lymphatic origin, with microcystic malformations of lymphatic vessels; findings compatible with the disease. Conservative management was provided due to the young age of the patient, with the respective multidisciplinary follow-up. CONCLUSIONS: A comprehensive clinical evaluation of the patient is essential. Given the rarity of this condition, MD should be suspected in any patient presenting bilateral lower extremity edema since birth, even without previous family history. Multidisciplinary management is essential, as well as monitoring and surveillance of the phenotypic evolution of the patient and family. [ABSTRACT FROM AUTHOR]

This is a retrospective review of surgical management for primary lymphedema.

Lymphedema is a disorder that leads to excessive swelling due to lymphatic insufficiency, resulting in the accumulation of protein-rich interstitial fluid. Primary lymphedema predominantly impacts the lower extremities and is frequently linked to hereditary factors. This condition is known to be associated with variants in several genes, such as FOXC2, FLT4, and SOX18. However, many cases remain unexplained, suggesting undiscovered gene associations. This study describes a novel mutation in the hepatocyte growth factor (HGF) gene, a previously hypothesized candidate for lymphedema pathogenesis. This mutation was identified in affected members of a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern. [ABSTRACT FROM AUTHOR]

This is a retrospective review of surgical management for primary lymphedema. Data were extracted from 55 articles from PubMed MEDLINE, Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials between the database inception and December 2022 to evaluate the outcomes of lymphaticovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT), and outcomes of soft tissue extirpative procedures such as suction-assisted lipectomy (SAL) and extensive soft tissue excision. Data from 485 patients were compiled; these were treated with LVA (n = 177), VLNT (n = 82), SAL (n = 102), and excisional procedures (n = 124). Improvement of the lower extremity lymphedema index, the quality of life (QoL), and lymphedema symptoms were reported in most studies. LVA and VLNT led to symptomatic relief and improved QoL, reaching up to 90 and 61% average circumference reduction, respectively. Cellulitis reduction was reported in 25 and 40% of LVA and VLNT papers, respectively. The extirpative procedures, used mainly in patients with advanced disease, also led to clinical improvement from the volume reduction, as well as reduced incidence of cellulitis, although with poor cosmetic results; 87.5% of these reports recommended postoperative compression garments. The overall complication rates were 1% for LVA, 13% for VLNT, 11% for SAL, and 46% for extirpative procedures. Altogether, only one paper lacked some kind of improvement. Primary lymphedema is amenable to surgical treatment; the currently performed procedures have effectively improved symptoms and QoL in this population. Complication rates are related to the invasiveness of the chosen procedure. [ABSTRACT FROM AUTHOR]

Purpose: There are limited existing data on the lymphatic anatomy of patients with primary lymphedema (LED), which is caused by aberrant development of lymphatic channels. In addition, there is a paucity of contemporary studies that use groin intranodal lymphangiography (IL) to evaluate LED anatomy. The purpose of this retrospective observational study was to better delineate the disease process and anatomy of primary LED using groin IL. Materials and Methods: We identified common groin IL findings in a cohort of 17 primary LED patients performed between 1/1/2017 and 1/31/2022 at a single institution. These patients were clinically determined to have primary lymphedema and demonstrated associated findings on lower extremity MR and lymphoscintigraphy. Results: Ten patients (59%) demonstrated irregular lymph node morphology or a paucity of lymph nodes on the more symptomatic laterality. Eight patients (47%) demonstrated lymphovenous shunting from pre-existing anastomoses between the lymphatic and venous systems. Eight patients (47%) demonstrated passage of contrast past midline to the contralateral lymphatics. Finally, 12 patients (71%) failed to opacify the cisterna chyli and thoracic duct on their initial lymphangiograms. Delayed computed tomography of 3 patients showed eventual central lymphatic opacification up to the renal veins, but none of these patients showed central lymphatic opacification to the thorax. Conclusion: This descriptive, exploratory study demonstrates common central groin IL findings in primary LED to highlight patterns interventional radiologists should identify and report when addressing primary LED. [ABSTRACT FROM AUTHOR]

Primary lymphedema is a rare genetic, progressive disorder characterized by swelling due to inadequate lymphatic drainage by defective lymphatic vessels. Here we report a case of a teenage girl presenting with primary lymphedema but with erratic family history and features supportive of both a dominant and recessively inherited described mutations. [ABSTRACT FROM AUTHOR]

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 PI3KI AKTpathway. 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 o/RELN, ARAP3, CDH5, and KIF11 as diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

Lymphedema is a disorder that leads to excessive swelling due to lymphatic insufficiency, resulting in the accumulation of protein-rich interstitial fluid. Primary lymphedema predominantly impacts the lower extremities and is frequently linked to hereditary factors. This condition is known to be associated with variants in several genes, such as FOXC2, FLT4, and SOX18. However, many cases remain unexplained, suggesting undiscovered gene associations. This study describes a novel mutation in the hepatocyte growth factor (HGF) gene, a previously hypothesized candidate for lymphedema pathogenesis. This mutation was identified in affected members of a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern.

Background: Lymphedema (LE) is a chronic disease that can lead to disability. Currently, the pathogenesis of LE remains unclear, and there is a lack of serum proteins applicable for diagnosis in clinical practice. This study aimed to screen and identify the differentially expressed proteins in serum samples of limb lymphedema and normal subjects and to further explore their value in the diagnosis of LE. Methods: Nano-flow reverse phase liquid chromatography-tandem mass spectrometry (Nano RPLC-MS/MS) was used to establish the serum protein profiles of primary lymphedema (PLE), secondary lymphedema (SLE), and normal controls (NC). Differentially expressed serum proteins were screened and identified. Subsequently, enrichment analysis was performed for proteins that were up-regulated in the LE group compared to the NC group. The target protein was validated by western blot (WB) and enzyme-linked immunosorbent assay (ELISA). Both the receiver operating characteristic (ROC) curve and Spearman's correlation test were employed to evaluate the diagnostic performance of the protein and its relationship with disease severity. Results: A total of 362 serum proteins were identified, among which 241 proteins were differentially expressed among PLE, SLE, and NC subjects (p < 0.05, fold change > 1.2). The enriched pathway correlated with cornified envelope formation was selected for further analysis. Cathepsin D (CTSD), a target protein involved in the selected pathway, was found to be up-regulated in the serum of PLE and SLE patients compared to NC. The AUCs of CTSD were 0.849 and 0.880 for patients with PLE and SLE, respectively. There was a significant positive correlation between the levels of serum CTSD and disease severity in the PLE group. Conclusions: Proteomic analysis found that the levels of serum proteins related to cornified envelope formation were elevated in patients with limb lymphedema. Serum CTSD was highly expressed in patients with limb lymphedema and showed good diagnostic value. [ABSTRACT FROM AUTHOR]

Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of KATP channels. KATP overactivity results in a chronic reduction in arterial tone and hypotension, leading to other systemic cardiovascular complications. However, the underlying mechanism of lymphedema, developed by >50% of CS patients, is unknown. We investigated whether lymphatic contractile dysfunction occurs in mice expressing CS mutations in Kir6.1 (Kir6.1[V65M]) or SUR2 (SUR2[A478V], SUR2[R1154Q]). Pressure myograph tests of contractile function of popliteal lymphatic vessels over the physiological pressure range revealed significantly impaired contractile strength and reduced frequency of spontaneous contractions at all pressures in heterozygous Kir6.1[V65M] vessels, compared to control littermates. Contractile dysfunction of intact popliteal lymphatics in vivo was confirmed using near-infrared fluorescence microscopy. Homozygous SUR2[A478V] vessels exhibited profound contractile dysfunction ex vivo, but heterozygous SUR2[A478V] vessels showed essentially normal contractile function. However, further investigation of vessels from all three GoF mouse strains revealed significant disruption in contraction wave entrainment, decreased conduction speed and distance, multiple pacemaker sites, and reversing wave direction. Tests of 2-valve lymphatic vessels forced to pump against an adverse pressure gradient revealed that all CS-associated genotypes were essentially incapable of pumping under an imposed outflow load. Our results show that varying degrees of lymphatic contractile dysfunction occur in proportion to the degree of molecular GoF in Kir6.1 or SUR2. This is the first example of lymphatic contractile dysfunction caused by a smooth muscle ion channel mutation and potentially explains the susceptibility of CS patients to lymphedema. Graphical Abstract [ABSTRACT FROM AUTHOR]

Primary lymphedema is a heterogeneous group of conditions encompassing all lymphatic anomalies that result in lymphatic swelling. Primary lymphedema can be difficult to diagnose, and diagnosis is often delayed. As opposed to secondary lymphedema, primary lymphedema has an unpredictable disease course, often progressing more slowly. Primary lymphedema can be associated with various genetic syndromes or can be idiopathic. Diagnosis is often clinical, although imaging can be a helpful adjunct. The literature on treating primary lymphedema is limited, and treatment algorithms are largely based on practice patterns for secondary lymphedema. The mainstay of treatment focuses on complete decongestive therapy, including manual lymphatic drainage and compression therapy. For those who fail conservative treatment, surgical treatment can be an option. Microsurgical techniques have shown promise in primary lymphedema, with both lymphovenous bypass and vascularized lymph node transfers demonstrating improved clinical outcomes in a few studies. [ABSTRACT FROM AUTHOR]

Background: Lymphedema is a local form of tissue swelling, which is caused by excessive retention of lymph fluid in interstitial compartment caused by impaired lymphatic drainage damage. Primary lymphedema is caused by developmental lymphatic vascular abnormalities. Most cases are inherited as autosomal dominant, with incomplete penetrance and variable expression. Here we report compound heterozygotes variants in FLT4 of a Chinese family associated with primary lymphedema display autosomal recessive inheritance. Case presentation: Trio-whole-exome sequencing (Trio-WES) was performanced to analyse the underlying genetic cause of a proband with primary lymphedema in a Chinese family. Sanger sequencing was used to validate the variants in proband with primary lymphedema and members of the family with no clinical signs and symptoms. We reported compound heterozygotes for the Fms Related Receptor Tyrosine Kinase 4 (FLT4) gene detected in the proband, who carrying two different point variants. One was a missense variant (NM_182925.5; c.1504G>A, p.Glu502Lys), and the other was a recurrent variant (NM_182925.5; c.3323_3325del, p.Phe1108del). The missense variant c.1504G>A was detected in the proband, unaffected father, and unaffected paternal grandmother but not detected in unaffected paternal grandfather. The recurrent variant c.3323_3325del was detected in the proband, unaffected mother, and unaffected maternal grandfather but not detected in unaffected maternal grandmother. Our results suggests the possibility of an autosomal recessive inherited form of primary lymphedema resulting from variants of FLT4 encoding the vascular endothelial growth factor receptor-3. Conclusion: The results of the present study identifed compound heterozygotes FLT4 variants in a family with primary lymphedema which provides more information for autosomal recessive primary lymphedema caused by FLT4. [ABSTRACT FROM AUTHOR]

Organ-specific lymphatics are essential for the maintenance of healthy organ function and lymphatic dysfunction can lead to the development of various diseases. However, the precise role of those lymphatic structures remains unknown, mainly due to inefficient visualization techniques. Here, we present an efficient approach to visualizing organ-specific lymphatic growth. We used a modified CUBIC protocol to clear mouse organs and combined it with whole-mount immunostaining to visualize lymphatic structures. We acquired images using upright, stereo and confocal microscopy and quantified them with AngioTool, a tool for the quantification of vascular networks. Using our approach, we then characterized the organ-specific lymphatic vasculature of the Flt4kd/+ mouse model, showing symptoms of lymphatic dysfunction. Our approach enabled us to visualize the lymphatic vasculature of organs and to analyze and quantify structural changes. We detected morphologically altered lymphatic vessels in all investigated organs of Flt4kd/+ mice, including the lungs, small intestine, heart and uterus, but no lymphatic structures in the skin. Quantifications showed that these mice have fewer and dilated lymphatic vessels in the small intestine and the lungs. Our results demonstrate that our approach can be used to investigate the importance of organ-specific lymphatics under both physiological and pathophysiological conditions. [ABSTRACT FROM AUTHOR]

Deleterious variants in the vascular endothelial growth factor C (VEGFC) gene have been recently associated with Milroy‐like primary lymphedema, an autosomal dominant disorder, characterized mainly by swelling of the lower limbs due to functional impairment of the lymphatic vessels. To date, only 26 patients with congenital lymphedema harboring VEGFC pathogenic variants were documented. Here, we describe the first prenatal case of a fetus with Milroy‐like disease. Fetal ultrasound showed bilateral foot swelling. Chromosomal microarray analysis revealed a 137‐kb copy number loss in 4q34.3 including only VEGFC gene in the propositus fetus. Segregation analysis showed that the deletion was inherited from the affected mother and grandmother. Taken together, our study highlights the important role of microarray analysis to detect subtle chromosomal imbalances in the prenatal setting and contributes to delineate the fetal phenotype of VEGFC‐related primary congenital lymphedema. [ABSTRACT FROM AUTHOR]

Lymphedema is a hot issue that has attracted wide attention in the field of rehabilitation medicine in recent years. The complex decongestive therapy of lymphedema including manual lymphatic drainage(MLD) as the key technology is developing rapidly all over the country.We report a rare case of aggravated primary lymphedema in the contralateral limb and trunk after radical mastectomy. The patient achieved remission through MLD treatment. By reviewing the diagnosis and treatment of this case, we can deepen the understanding of the complexity of the pathogenesis of lymphedema and provide reference for individualized diagnosis and treatment of lymphedema.

Background: Lymphedema is due to dysfunction of the lymphatic system. It can be primary or secondary. Pediatric lymphedema is more often primary and is a chronic disease with a heavy burden on quality of life. Methods: Medical records of patients under 18 years of age referred between 1996 and 2021 to the specialized lymphedema clinic at the Sainte-Justine University Hospital Center were reviewed. Demographic data, sex, age at presentation, location of the lymphedema, clinical features, genetic testing, symptoms, complications, investigations, and treatment were collected. Results: Of 180 referred patients, lymphedema was confirmed in 151, and 137 were primary lymphedema. Median age of apparition of primary lymphedema was 7.00 years and was significantly lower in boys than in girls. Primary congenital lymphedema was more frequent in boys (51.0%, 27.3% in girls, P =.007), and onset of primary lymphedema during adolescence was more frequent in girls (53.4%, 25.0% in boys, P =.001). Lower limbs were the most impacted (88.3%). Sixty patients had genetic testing, and 38 (63.3%) of them were discovered to have a pertinent genetic mutation. The most common mutated gene was the FLT4 gene (in 9 patients). Seven patients (5.1%) had associated extensive/central lymphatic malformation and 24 (17.6%) had a polymalformative syndrome/syndromic lymphedema. Conclusions: Pediatric lymphedema is more frequent in girls, usually involves lower limb, and is most often sporadic, but often associated with a genetic mutation, and genetic testing should be performed. [ABSTRACT FROM AUTHOR]

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.

We have studied the lymphatic phenotypes of 2 mutations, known to cause abnormalities of lymphatics in humans, in mice. The Cx47 R260C mutation (variably penetrant in humans heterozygous for it and causing limb lymphedema) had an adult mouse phenotype of hyperplasia and increased lymph nodes only in homozygous condition but we did not find any anatomical phenotype in day 16.5 homozygous embryos. Mice harboring the Sos1 mutation E846K (causing Noonan's 4 in man which occasionally shows lymphatic dysplasia) had no adult heterozygous phenotype in lymphatic vessel appearance and drainage (homozygotes are early embryonic lethals) while day 16.5 heterozygous embryos also had no detectable anatomical phenotype. [ABSTRACT FROM AUTHOR]

Primary lymphedema is a heterogeneous group of conditions encompassing all lymphatic anomalies that result in lymphatic swelling. Primary lymphedema can be difficult to diagnose, and diagnosis is often delayed. As opposed to secondary lymphedema, primary lymphedema has an unpredictable disease course, often progressing more slowly. Primary lymphedema can be associated with various genetic syndromes or can be idiopathic. Diagnosis is often clinical, although imaging can be a helpful adjunct. The literature on treating primary lymphedema is limited, and treatment algorithms are largely based on practice patterns for secondary lymphedema. The mainstay of treatment focuses on complete decongestive therapy, including manual lymphatic drainage and compression therapy. For those who fail conservative treatment, surgical treatment can be an option. Microsurgical techniques have shown promise in primary lymphedema, with both lymphovenous bypass and vascularized lymph node transfers demonstrating improved clinical outcomes in a few studies.

Organ-specific lymphatics are essential for the maintenance of healthy organ function and lymphatic dysfunction can lead to the development of various diseases. However, the precise role of those lymphatic structures remains unknown, mainly due to inefficient visualization techniques. Here, we present an efficient approach to visualizing organ-specific lymphatic growth. We used a modified CUBIC protocol to clear mouse organs and combined it with whole-mount immunostaining to visualize lymphatic structures. We acquired images using upright, stereo and confocal microscopy and quantified them with AngioTool, a tool for the quantification of vascular networks. Using our approach, we then characterized the organ-specific lymphatic vasculature of the Flt4kd/+ mouse model, showing symptoms of lymphatic dysfunction. Our approach enabled us to visualize the lymphatic vasculature of organs and to analyze and quantify structural changes. We detected morphologically altered lymphatic vessels in all investigated organs of Flt4kd/+ mice, including the lungs, small intestine, heart and uterus, but no lymphatic structures in the skin. Quantifications showed that these mice have fewer and dilated lymphatic vessels in the small intestine and the lungs. Our results demonstrate that our approach can be used to investigate the importance of organ-specific lymphatics under both physiological and pathophysiological conditions.

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Among the reasons of primary lymphedema development, a certain role belongs to genetic factors. The specific molecular products participate in remodeling of blood and lymphatic vascular networks. Vascular endothelial growth factors (VEGFs) are key regulators of endothelial functions of the cells, which are responsible for lympho- and vasculogenesis. Moreover, matrix metalloproteinases (ММР) may act as regulators of both lymphangiogenesis, and angiogenesis. Since the regulatory regions of VEGFA gene, as well as of ММР genes are polymorphic, one may suggest, that their different expression level, determined by these polymorphisms, could be associated with development of swellings typical for lymphedema.We have analyzed gene polymorphisms in two regulatory regions of vascular endothelial growth factor-A VEGF-A (rs 699947 and rs 3025039), and matrix metalloproteinase genes MMP2 (rs 2438650), MMP3 (rs 3025058), MMP9 (rs 3918242), and their combinations in the patients with primary lymphedema.A group of patients with primary lymphedema included 72 subjects (55 women and 17 men) at the age of 18 to 81 years. Control group included 526 inhabitants of Novosibirsk (153 men, 373 women) without chronic diseases, comparable for age with lymphedema patients. We have performed typing of regulatory regions in VEGF (rs 699947, rs 3025039), ММР2 (rs 2438650), ММР3 (rs 3025058), ММР9 genes (rs 3918242). Fifteen complex genotypes have been revealed that were positively associated with disease. Analysis of the gene network topology has outlined the main intergenic interactions upon primary lymphedema development. MMP2 -1306 CC, MMP9 -1562CC and VEGF +936CC arrange the basic knots in the gene network (53% of total interactions). A number of significantly different complex genotypes was revealed at patients with primary lymphedema with normal body mass index (BMI < 25) and obesity (BMI < 30). Hence, frequency of complex genotype VEGF +936 CC: MMP3 -1171 5А6А:MMP9 -1562 CC in the patients with obesity is increased more 5.5-fold compared to the patients with normal BMI.The data obtained may presume a certain value of the analyzed gene polymorphisms in pathogenesis of primary lymphedema. Topological analysis of gene networks allows to study the structural and functional organization of gene-gene interactions for development of approaches to individyal preventive maintenance and therapy of the disease.

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., Competing Interests: The authors declare no conflict of interest., (Copyright © AUTHORS.)

Clinicians and scientists at St George's University Hospital have collaborated to develop a classification algorithm for primary lymphatic anomalies. Instruction is offered on how to apply the algorithm in clinical practice to refine the diagnosis of primary lymphedema and guide on genetic testing and management. It can also be used to interpret mutation testing results of uncertain significance. The algorithm has evolved as more genes have been discovered, and it remains a "work in progress" as further discoveries are made. This transformational approach has revolutionized the understanding and classification of primary lymphatic anomalies. [ABSTRACT FROM AUTHOR]

Abstract Background Milroy‐like disease is the diagnostic definition used for patients with phenotypes that resemble classic Milroy disease (MD) but are negative to genetic testing for FLT4. In this study, we aimed at performing a genetic characterization and biochemical analysis of VEGF‐C variations found in a female proband born with congenital edema consistent with Milroy‐like disease. Methods The proband underwent next‐generation sequencing‐based genetic testing for a panel of genes associated with known forms of hereditary lymphedema. Segregation analysis was performed on family members by direct sequencing. In vitro studies were performed to evaluate the role of a novel identified variant. Results Two VEGF‐C variations were found in the proband, a novel p.(Ser65Arg) and a pathogenic c.148‐3_148‐2delCA, of paternal and maternal origin, respectively. Functional characterization of the p.(Ser65Arg) variation in vitro showed alterations in VEGF‐C processing. Conclusions Our findings reveal an interesting case in which biallelic variants in VEGF‐C are found in a patient with Milroy‐like lymphedema. These data expand our understanding of the etiology of congenital Milroy‐like lymphedema.

Abstract Background When managing patients with cancer, lymphedema of the lower limbs (LLL) is commonly reported as secondary to the surgical excision and/or irradiation of lymph nodes (LNs). In the framework of lymphoscintigraphic imaging performed to evaluate secondary LLL, some lympho-nodal presentations have been observed that could not be explained by the applied treatments, suggesting that these LLL might be primary. Therefore, all our lymphoscintigraphic examinations that were performed in patients for LLL after surgery for gynecological or urological cancer were retrospectively analyzed in order to evaluate the frequency in which these LLL might not be secondary (either completely or partially) but primary in origin. Methods Lymphoscintigraphies performed in 33 patients who underwent LN dissection (limited to the intra-abdominal LN) with or without radiotherapy for histologically confirmed ovarian cancer (n = 6), uterine cancer (n = 14 with cervical cancer and n = 7 with endometrial cancer), or prostate cancer (n = 6) were compared to lymphoscintigraphies obtained in primary LLL. Results In 12 (33% of the) patients (3 men plus 9 women, 4 with cervical cancer and 5 with endometrial cancer), scintigraphy of the lower limbs revealed lympho-nodal presentation that did not match with the expected consequences of the surgical and/or radiological treatments and were either suggestive or typical of primary lymphedema. Conclusions This retrospective analysis of a limited but well-defined series of patients suggests that the appearance of LLL might not be related to cancer treatment(s) but that these LLL may represent the development of a primary lymphatic disease latent prior to the therapeutic interventions.

We have created a human chromosomal map of the location of known and candidate genes involved in primary lymphedema (PLE). This should facilitate further discovery and provide a basis for understanding microdeletions which cause lymphedema. [ABSTRACT FROM AUTHOR]

Background: Milroy‐like disease is the diagnostic definition used for patients with phenotypes that resemble classic Milroy disease (MD) but are negative to genetic testing for FLT4. In this study, we aimed at performing a genetic characterization and biochemical analysis of VEGF‐C variations found in a female proband born with congenital edema consistent with Milroy‐like disease. Methods: The proband underwent next‐generation sequencing‐based genetic testing for a panel of genes associated with known forms of hereditary lymphedema. Segregation analysis was performed on family members by direct sequencing. In vitro studies were performed to evaluate the role of a novel identified variant. Results: Two VEGF‐C variations were found in the proband, a novel p.(Ser65Arg) and a pathogenic c.148‐3_148‐2delCA, of paternal and maternal origin, respectively. Functional characterization of the p.(Ser65Arg) variation in vitro showed alterations in VEGF‐C processing. Conclusions: Our findings reveal an interesting case in which biallelic variants in VEGF‐C are found in a patient with Milroy‐like lymphedema. These data expand our understanding of the etiology of congenital Milroy‐like lymphedema. [ABSTRACT FROM AUTHOR]

Background: Lymphedema may impact patients' health-related quality of life (HRQoL). The purpose of this study was to evaluate HRQoL after two different treatments to the 12-month follow-up point. Methods and Results: Study participants were patients with moderate lymphedema in the upper or lower limb who attended a Swedish rehabilitation program (RP) undergoing conservative treatment, or those with severe, chronic lymphedema dominated by excess adipose tissue, who underwent liposuction (LS) combined with controlled compression therapy (CCT) in Australia, Scotland, or Sweden. The patients completed the Lymphedema Quality of Life Inventory (LyQLI) before intervention and after 1, 3, 6, and 12 months. Mean values and standard deviations were calculated for total limb volume and excess limb volume. Mean values were also calculated for the three LyQLI domains (physical, psychosocial, and practical). To detect and analyze differences in LyQLI responses in the three domains, the Wilcoxon signed rank test was performed. In the RP, 18 eligible patients completed the LyQLI. The results show improvements in HRQoL in physical (p = 0.003) and psychosocial domains (p = 0.002) at 1 month after the RP, with results remaining steady for 12 months for the physical domain (p = 0.024). Fifty-seven eligible LS patients completed the LyQLI. The results show improvements in HRQoL in all three domains (p < 0.001), with results remaining steady up to the 12-month follow-up (p < 0.001). The total volume in affected limb and the excess volume decreased significantly in both patient groups 1 month after intervention (p < 0.001). Conclusions: Treatment with a conservative RP in moderate lymphedema or with LS combined with CCT in severe lymphedema improves HRQoL. [ABSTRACT FROM AUTHOR]

A 21-year-old single female with a large swelling of the vulva's left labia majora was diagnosed with a case of primary lymphedema of the left lower limb and external genitalia. The giant labial swelling was excised, and the patient experiences no complications or recurrence for 7 months postoperatively. Following the surgical excision of the swelling, the left labia majora and minora were reconstructed successfully. The excised mass weighed 6.3 kg and measured 40 cm x 35 cm x 30 cm. There were no complications postoperatively, and the patient has not experienced recurrence during the 7-month follow-up period. The patient returned to her normal life. Level of evidence: Level V, therapeutic study. [ABSTRACT FROM AUTHOR]

Background: Lymphedema includes primary lymphedema (P-LE) and secondary lymphedema (S-LE), which is a chronic progressive disease. The former group is further classified as congenital and acquired P-LE (AP-LE); its etiology is unclear, and only a few studies on its pathophysiology exist. We hypothesized that an autoimmune disease or self-inflammatory mechanism occurs in lymphatic vessels, leading to obstruction. Methods and Results: We enrolled 46 patients with lymphedema who underwent lymphaticovenous anastomosis (LVA) from January to October 2015. Collecting lymph ducts were obtained during LVA. We performed hematoxylin/eosin staining and immunostaining for LYVE-1, IL-1β, IL-6, and TNF-α. There were no substantial histological differences between the two types of lymphedema, whereas some differences in expression of inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α, were observed. Only a few inflammatory cells could be seen around the vessels. Although no significant differences in expression of IL-1β were found between AP-LE and S-LE, TNF-α was more highly expressed in the smooth muscle layer in AP-LE patients than in S-LE patients. There were no significant morphological differences in the collecting ducts of lymphatic vessels between S-LE and P-LE. Nevertheless, higher levels of TNF-α accumulation were found in the thick smooth muscle layer of P-LE patients than in that of S-LE patients. Conclusion: TNF-α-related inflammation in collecting ducts of lymphatic vessels is an important characteristic of the pathology of P-LE. TNF-α inhibitors might improve symptoms of AP-LE. [ABSTRACT FROM AUTHOR]

Background  Investigating correlations between clinical, instrumental, and genetic features of primary lymphedema (PL) with the aim to facilitate the diagnosis, the staging, and the management of this subgroup of patients. Methods  A prospective observational study was conducted from September 2016 to May 2018, including patients with diagnosis of nonsyndromic PL. All patients underwent a lymphoscintigraphic rest-stress test, an indocyanine green (ICG) lymphographic test, and a genetic test from sputum sample. Results  A total of 20 patients were enrolled in the study and 44 limbs were examined. The totality of clinically affected limbs (32/44) showed lymphographic and lymphoscintigraphic abnormalities. Concerning clinically healthy limbs (12/44), an abnormal pattern was demonstrated in 33.3% of ICG lymphographic test and 75% of lymphoscintigraphy. Regarding lymphography findings, the most frequent pattern was the distal dermal backflow (DDB). We distinguished four grades of DDB, which correlates with clinical and lymphoscintigraphic features. Furthermore, we found a new lymphographic alteration consisting of fluorescence appearing distally to the injection site of ICG, including fingers/toes and palmar/plantar surface of the hand and of the foot. This alteration, called "print sign," seems to be typical of DDB pattern PL. Genetic test did not help us make any etiological diagnosis. Conclusion  To our knowledge, this is the first study about PL comparing clinical, ICG lymphographic, lymphoscintigraphic, and genetic findings. As expected, all clinically affected limbs showed abnormalities in ICG lymphographic and lymphoscintigraphic tests. In opposition to what has previously been reported, also clinically healthy limbs showed lymphographic and lymphoscintigraphic alterations and this could suggest the existence of a subclinical form of PL. We proposed a grading of the DDB pattern, which correlates with clinical and lymphoscintigraphic features. Furthermore, we have described a new lymphographic alteration that seems to be typical of DDB pattern PL, the "print sign." [ABSTRACT FROM AUTHOR]

Lymphaticovenular anastomosis (LVA) using supermicrosurgical techniques is effective for treating and preventing progression of lymphedema. We analyzed the influence of pregnancy on LVA in five patients from a total 2179 LVA cases. Previous studies offer conflicting reports on whether pregnancy worsens pre-existing lymphedema. This is the first report on the influence of pregnancy on lower limb lymphedema previously treated by multisite LVA (mLVA). Five patients with primary (n=4) and secondary (n=1) lower leg lymphedema were analyzed for this study. Patient age ranged from 18 to 31 (average 22.6) years old with 4 right and 1 left extremities involved. Duration of symptoms ranged from one to 19 (average 7.4) years and the periods of compression therapy were from 1 to 19 years (6.6 years). Four patients had single pregnancies and one patient was multiparous with 3 pregnancies. Final follow-up ranged from 5.8 to 18 years (average 8.9 years) after the primary mLVA. All patients had normal pregnancy, birth, and no serious complications after surgeries. Following pregnancy three patients had complete functional recovery (limb volume reduction and no compression requirement), one with functional improvement (limb volume reduction but required compression), and one with no change in symptoms (not worse and continued need for compression). There were no occurrences of infection following pregnancy. Based on this case series, it is suggested that pregnancy does not worsen the pre-existing lymphedema in patients who had previously undergone mLVA. Further studies with larger number of patients are needed to confirm these results. [ABSTRACT FROM AUTHOR]