A HGF Mutation in the Familial Case of Primary Lymphedema: A Report.

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.

Surgical Treatment for Primary Lymphedema: A Systematic Review of the Literature.

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.

Effectiveness of lymphaticovenular anastomosis for adult-onset primary lower limb lymphedema: A retrospective study.

BACKGROUND: Surgical treatments such as lymphaticovenular anastomosis (LVA) are widely used in addition to conservative treatment of secondary lymphedema. However, their indications and effectiveness for primary lymphedema are unclear. This study aims to objectively demonstrate the effectiveness of LVA for adult-onset primary lymphedema from various perspectives. METHODS: We retrospectively examined patients with primary lower limb lymphedema who underwent LVA between January 2018 and December 2021 and were 21 or older. Treatment effects were evaluated using lymphoscintigraphy, questionnaires, body mass index, extracellular fluid ratio, and lymphedema index preoperatively and 6 months postoperatively. The LVA was performed under general anesthesia. RESULTS: We evaluated 11 patients (11 lower limbs). Out of seven patients with complete obstruction preoperatively, all presented partial obstruction according to the Taiwan Lymphoscintigraphy Staging classification with a significant decrease in the score. Significant improvements were observed in clinical symptoms ("hardness") and in quality of life ("appearance" and "ease of wearing compression garments") assessments. A significant change was observed in the extracellular water ratio but not in lower extremity lymphedema index (LELindex). CONCLUSION: LVA was suggested as one of the potential treatment options for patients with adult-onset primary lymphedema in whom lymphatic flow was confirmed by lymphoscintigraphy. In addition to clinical symptoms and physical examination, the evaluation of adult-onset primary lymphedema should include the patient's quality of life.

Evaluation of Primary Lymphedema with Intranodal Lymphangiography.

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.

Current Concepts in the Management of Primary Lymphedema.

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.

Lymphatic contractile dysfunction in mouse models of Cantú Syndrome with KATP channel gain-of-function.

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.

Case Report: The compound heterozygotes variants in FLT4 causes autosomal recessive hereditary lymphedema in a Chinese family.

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.

Visualization of Organ-Specific Lymphatic Growth: An Efficient Approach to Labeling Molecular Markers in Cleared Tissues.

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.

Surgical Treatment of an Exuberant Case of Penoscrotal Elephantiasis.

Lymphedema is a manifestation of lymphatic system disturbance and deranged lymph transport, with resultant swelling, a proliferation of parenchymal and stromal elements, and excess deposition of the extracellular matrix. It may occur in any part of the body, most frequently in the limbs. Staging ranges from inconspicuous lymphatic system derangement to lymphatic elephantiasis. Surgical treatment is the preferred modality. This case report is of a 36-year-old male patient with morbid obesity with a five-year-long history of penoscrotal volume increase without any apparent trigger. Patient observation revealed a frankly enlarged scrotum involving the penis, with distortion and an increase in urinary meatus diameter. The penis was palpable but hardly observable. Neither testicle was palpable. Scrotal tissue was hardened and sclerotic. We performed surgical excision of all swollen tissue while identifying and preserving the penis and both testicles. Local advancement flaps were used to create a neoscrotum. Resurfacing of the penis was accomplished with split-thickness skin grafting harvested from a small part of healthy skin included in the excised tissue and held in place during the first week with negative pressure therapy. There are no signs of local or distant relapse, and the patient mentions a dramatic improvement in urinary flow, quality of life in terms of ambulation, everyday tasks, and self-esteem. We present a very rare clinical case of exuberant penoscrotal lymphedema in a young patient with very few risk factors. Given the extent and time of presentation, microsurgery of the lymphatics was not indicated, and thus, a Charles procedure was undertaken. Even so, patient quality of life was significantly improved, and no recurrences have been reported so far.

Lack of embryonic homozygous or adult heterozygous lymphatic phenotypes for a Sos1 mutation and lack of lymphatic embryonic phenotypes for a homozygous Cx47 mutation in mice.

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 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.

Heterozygous deletion of the VEGFC gene in 4q34.3 is associated with Milroy-like lymphedema: First prenatal case report.

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.

Pediatric Lymphedema: Study of 180 Patients Referred to a Tertiary Lymphedema Clinic.

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.

Diagnosis and Conservative Management of Primary Lymphedema Resulting From Multiple Aplastic Lymphocenters in a Dog.

A 6-week-old 7.4-kg (16.3-lb) sexually intact male Great Dane with a history of severe peripheral edema within the head, neck, limbs, and tail since birth was referred for further evaluation. A whole-body computed tomography examination documented severe subcutaneous edema multifocally associated with numerous hypoplastic and aplastic lymphocenters, particularly the left axillary, iliosacral, inguinal, and popliteal lymphocenters bilaterally. A congenital anomaly of the lymphatic system resulting in lymphedema was strongly suspected. The dog was managed with a combination of low-fat diet, rutin, and furosemide initially. In addition, the owner used a combination of compression socks and therapeutic massage several times daily along with carprofen and gabapentin for pain and inflammation. The patient was hospitalized to receive supportive care several times over a 2-year period for treatment of fever associated with cellulitis resulting in secondary wounds and infections. To the author's knowledge, this report represents the first case of presumed congenital lymphedema diagnosed with computed tomography and successful long-term medical management without surgical intervention.

The Combination of Lymph Node Transfer and Excisional Procedures in Bilateral Lower Extremity Lymphedema: Clinical Outcomes and Quality of Life Assessment with Long-Term Follow-Up.

BACKGROUND: Bilateral lower extremity lymphedema is a rare and invalidating condition that poses a great challenge to the scientific community, and deeply affects the quality of life (QoL) of affected patients. A combined protocol consisting of lymph node transfer and a reductive method have never been reported for the treatment of this condition, except for small case series with brief follow-up periods. METHODS: This retrospective study analyzed data of 29 patients, mean age 51 ± 17.1 years, who had been diagnosed with bilateral lower extremity lymphedema. Gastroepiploic vascularized lymph node transfer was performed in all the patients, and an excisional procedure was associated according to the clinical stage. Clinical history, circumferential limb measurements, complications, episodes of cellulitis, and responses to the Lymphedema Quality of Life Questionnaire were analyzed. RESULTS: The mean follow-up was 38.4 ± 11.8 months. A significant reduction in the episodes of cellulitis per year was observed (p < 0.001). In our series, BMI and duration of symptoms were significantly related to the development of cellulitis during the postoperative period, p = 0.006 and p = 0.020, respectively. The LYMQoL questionnaire showed a significant quality of life improvement from 3.4 ± 0.9 to 6.2 ± 0.8 (p < 0.05). CONCLUSIONS: An integrated approach is essential for the treatment of bilateral lower extremity lymphedema: reductive and reconstructive methods are complementary to achieve a successful outcome. Timely treatment and BMI reduction are relevant in order to decrease the number of episodes of cellulitis. An attentive follow-up is necessary to identify recurrence and treat affected patients in time.

Heparin-induced thrombocytopenia and thrombosis in primary lymphedema patients who underwent vascularized lymph node transplantations.

BACKGROUND: Heparin-induced thrombocytopenia and thrombosis (HITT) may result in microsurgical flap failure. This study investigated the outcomes of HITT in primary lymphedema patients who underwent vascularized lymph node transplantations (VLNT). METHODS: Between 2012 and 2019, primary lymphedema patients who underwent VLNTs were retrospectively included. The 4Ts score was used to categorize patients into HITT (scores of 5-7) and non-HITT (score < 5) groups. Outcome evaluations included the re-exploration rate, success rate, circumferential differences, cellulitis episodes, and Lymphedema Specific Quality of Life Questionnaire (LYMQoL) scores. RESULTS: Twenty-six and 15 patients with 31 and 16 VLNTs were included in the HITT and non-HITT groups, respectively. The HITT group had significantly greater first, second and third re-exploration rates of 38.7% (12/31), 25.7% (8/31), and 6.5% (2/31) than the non-HITT group (6.3%, 0%, and 0%, all p < 0.01), respectively. The platelet counts significantly decreased by 21.0% in the HITT group compared with the non-HITT group (14%) on postoperative Day one (p < 0.01) with a cutoff value of 17% and AUC = 0.88. CONCLUSIONS: HITT may cause a high re-exploration rate of VLNTs in primary lymphedema patients. The 17% reduction in platelets on postoperative day one was an early sign for detecting HITT.

Additional Lymphaticovenular Anastomosis on the Posterior Side for Treatment of Primary Lower Extremity Lymphedema.

The efficacy of lymphaticovenular anastomosis (LVA) for the treatment of primary lymphedema has been reported. Previous research suggested the efficacy of LVA on the anterior side of the lower limb, but no research has yet underlined the effectiveness of LVA on the posterior side. In the present study, we aimed to investigate the efficacy of LVA on the posterior side of the lower leg for treatment of primary lymphedema, i.e., whether further improvement of primary lower extremity lymphedema could be expected by performing LVA on the posterior side of the lower limb in addition to the LVA on the anterior side, which is usually performed. Forty-five patients with primary lower extremity lymphedema who underwent LVA twice between March 2018 and September 2020 were retrospectively investigated. Patients were classified into two groups: those who underwent LVA on the posterior side in the second operation (PoLVA group) and those who underwent LVA on the medial and anterior sides again in the second operation (MeLVA group). All patients underwent LVA on the medial and anterior sides in the first operation, but no sufficient improvement was observed. The following factors in the second operation were compared between the two groups: skin incision length, the number of anastomoses, the diameters of the lymphatic vessels, the time required for the dissection of the lymphatic vessels and veins and the reduction in volume. LVA resulted in 227 anastomoses (106 anastomoses in the PoLVA group and 121 anastomoses in the MeLVA group) in 26 patients with primary lymphedema of the lower extremities in two surgeries. The reduction in lower extremity lymphedema index was significantly greater in the PoLVA group than that in the MeLVA group (10.5 ± 4.5 vs. 5.5 ± 3.6; p = 0.008), and the number of anastomoses in the PoLVA group was significantly lower than that in the MeLVA group (3.5 ± 0.6 vs. 4.6 ± 1.0; p = 0.038). LVA on the posterior side subsequent to LVA on the medial and anterior sides resulted in the further improvement of primary lower extremity lymphedema with fewer numbers of anastomoses.

Recurrent Left-Sided Pleural Effusions in a Patient With Chronic Lymphedema.

Chronic lymphedema can lead to several long-term complications. The causes of lymphedema can be primary, due to a genetic source, or secondary to procedures, trauma, or other conditions. Primary hereditary lymphedema, as in the case of Milroy's disease, is rare. Because of the condition's rarity, case reports mostly involve presentations to monitor for. Here we document a case of Milroy's disease in a 70-year-old woman with recurrent left lung effusions.

Factors Predicting Limb Volume Reduction Using Compression Bandaging Within Decongestive Lymphatic Therapy in Lymphedema: A Multicountry Prospective Study.

Objectives: To identify predictive factors associated with limb volume reduction using different decongestive lymphatic therapy (DLT) systems in patients with lymphoedema, over a period of up to 28 days. Methods: A multicountry (Canada, France, Germany, the United Kingdom) prospective cohort study using (DLT): skin care, exercise, compression bandaging, and manual lymphatic drainage for up to 4 weeks. Reduction in limb volume comparing DLT with (1) standard multilayer bandaging with inelastic material, and with (2) multilayer bandaging with Coban2, together with the identification of factors associated with limb volume changes. Results: Out of 264 patients with upper or lower limb lymphedema, 133 used Coban2 and 131 used standard care. Following DLT, mean limb volume reduction was 941 mL using Coban2 compared with 814 mL using standard care. A difference of 127 mL was found (95% confidence interval -275 to 529 mL, p = 0.53). Of the 176 patients with leg swelling, 166 (94.3%) had a limb volume measurement after 28 days and were included in the risk factor analysis. Of these, 132 (79.5%) were female, with overall mean age of 60.1 years (standard deviation = 14.7), with secondary lymphedema in 102/163 (62.6%). Duration of lymphedema was >10 years in 75/161 (46.6%) and 99/166 (59.7%) were International Society of Lymphology late-stage II/III, indicating longstanding and/or a high frequency of patients with advanced stages of lymphedema. Ninety-one (54.8%) received Coban2 and 75 (45.2%) had standard care. Multivariable factors for a greater leg volume reduction were large initial leg volume (p < 0.001), DLT treatment duration of 4 weeks compared with 2 weeks (p = 0.01), and peripheral arterial disease (p = 0.015). Conclusion: Limb volume changes were found to be similar between groups. Lack of standardization of DLT makes interpretation of effectiveness problematic. There is an urgent need for randomized-controlled trials. Despite this, severe lymphedema with a large limb volume responded well to DLT in this study.

Right Upper Extremity Idiopathic Primary Lymphedema in a 2-Year-Old Child.

Lymphedema of an extremity at birth can be an alarming finding. Our patient presented with difficulty breathing and productive cough and was found to have primary lymphedema of the right upper extremity since birth. Further testing was mostly unremarkable except for imaging that revealed many splenic lesions.

The St George's Classification Algorithm of Primary Lymphatic Anomalies.

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.