Congenital Lymphedema Research Articles

Rictor, an mTORC2 Protein, Regulates Murine Lymphatic Valve Formation Through the AKT-FOXO1 Signaling.

Lymphatic valves are specialized structures in collecting lymphatic vessels and are crucial for preventing retrograde lymph flow. Mutations in valve-forming genes have been clinically implicated in the pathology of congenital lymphedema. Lymphatic valves form when oscillatory shear stress from lymph flow signals through the PI3K/AKT pathway to promote the transcription of valve-forming genes that trigger the growth and maintenance of lymphatic valves. Conventionally, in many cell types, AKT is phosphorylated at Ser473 by the mTORC2 (mammalian target of rapamycin complex 2). However, mTORC2 has not yet been implicated in lymphatic valve formation. In vivo and in vitro techniques were used to investigate the role of Rictor, a critical component of mTORC2, in lymphatic endothelium. Here, we showed that embryonic and postnatal lymphatic deletion of Rictor, a critical component of mTORC2, led to a significant decrease in lymphatic valves and prevented the maturation of collecting lymphatic vessels. RICTOR knockdown in human dermal lymphatic endothelial cells not only reduced the level of activated AKT and the expression of valve-forming genes under no-flow conditions but also abolished the upregulation of AKT activity and valve-forming genes in response to oscillatory shear stress. We further showed that the AKT target, FOXO1 (forkhead box protein O1), a repressor of lymphatic valve formation, had increased nuclear activity in Rictor knockout mesenteric lymphatic endothelial cells in vivo. Deletion of Foxo1 in Rictor knockout mice restored the number of valves to control levels in lymphatic vessels of the ear and mesentery. Our work identifies a novel role for RICTOR in the mechanotransduction signaling pathway, wherein it activates AKT and prevents the nuclear accumulation of the valve repressor, FOXO1, which ultimately enables the formation and maintenance of lymphatic valves.

Tuberous sclerosis associated with congenital lymphedema

Tuberous sclerosis complex is an autosomal dominant hereditary disease characterized by the formation of multiple hamartomas in various organs and tissues. Although tuberous sclerosis is considered to be a rare condition, it is among the most common genetic diseases. According to the literature, 16 cases of tuberous sclerosis associated with congenital lymphedema have been revealed from 1984 in scientific publications. Only four of these cases were described in male patients. Such combinations have not been yet described in the Russian studies. The article discusses different aspects of a rare clinical case presented by the combination of tuberous sclerosis with congenital lymphedema in a male patient aged 1 year and 6 months.

A rare clinical case of brain damage and congenital lymphedema in a boy with tuberous sclerosis with a mutation in the TSC1 gene

A rare clinical case of brain damage and congenital lymphedema in a boy with tuberous sclerosis with a mutation in the TSC1 gene

Lymphatic Vascular Permeability Determined from Direct Measurements of Solute Flux.

The permeability of the lymphatic vasculature is tightly regulated to prevent the excessive leakage of lymph into the tissues, which has profound consequences for edema, immune responses, and lipid absorption. Dysregulated lymphatic permeability is associated with several diseases, including life-threatening chylothorax and pleural effusion that occur in patients with congenital lymphedema and lymphatic malformations. Due to a growing interest in uncovering new mechanisms regulating lymphatic vascular permeability, we recently pioneered methods to quantify this aspect of lymphatic function. Here, we detail our ex vivo method to determine the permeability of mouse collecting lymphatic vessels from direct measurements of solute flux. This method is modified from a similar ex vivo assay that we described for studying the contractile function of murine collecting lymphatic vessels. Since this method also uses the mouse as a model, it enables powerful genetic tools to be combined with this physiological assay to investigate signaling pathways regulating lymphatic vascular permeability.

Congenital hypertrophy and lymphedema of the right upper limb in a child

The aim of the present study was to report a case of congenital upper limb hypertrophy associated with lymphedema in a child. An eight-year-old girl presented with a history of right upper limb oedema since birth, which was more significant in the hand. Volumetry was performed, revealing 1,838 grams in the right arm and 1,483 grams in the left arm. Intensive treatment with the Godoy method® was proposed. Treatment involved five hours per day using the RAGodoy® device, 15 minutes of cervical lymphatic therapy, and three hours of manual lymphatic therapy per day. With treatment, the volume of the right arm was reduced to 1,663 grams (reduction of 205 grams). After treatment, hypertrophy of the limb was noticed, which had been aggravated by the lymphedema. Congenital hypertrophy of the upper limb is rare in children. Its association with lymphedema has not previously been reported in the literature and could cause diagnostic difficulties.

Genetics, diagnostics and clinical presentation of primary lymphoedema

Primary lymphoedema is ahereditary genetic disorder of the lymphatic system. These genetic disorders can result in malformation or dysfunction of the lymphatic system, which leads to an accumulation of fluid in the tissue and, thus to the formation of oedema. The most common form is peripheral lymphoedema of the lower limbs, but systemic manifestations such as intestinal lymphangiectasia, ascites, chylothorax or hydrops fetalis may also occur. The clinical presentation and the degree of lymphoedema varies depending on the causative gene and the specific gene alteration. Primary lymphoedema is divided into five categories: (1)disorders with somatic mosaicism and segmental growth abnormality, (2a) syndromal disorders, (2b) disorders with systemic involvement, (2c) congenital lymphoedema and (2d) disorders that occur after the first year of life (late onset lymphoedema). Targeted genetic diagnosis is based on the patient's clinical presentation and classification into one of the five categories. In general, the diagnosis usually starts with basic diagnostics, which include cytogenetic and molecular genetic testing. Subsequently, amolecular genetic diagnosis is made by performing single-gene analyses, gene panel examinations, exome sequencing or whole genome sequencing. This allows the identification of genetic variants or mutations that are considered to be causative for the presenting symptoms. Combined with human genetic counselling, the genetic diagnosis allows for conclusions about inheritance, the risk of recurrence and potential concomitant symptoms. In many cases, only this approach allows the definite form of primary lymphoedema to be described.

Patient with composite haemangioendothelioma containing angiosarcoma-like areas in the setting of congenital lymphoedema mimicking Stewart-Treves syndrome: a case report

BackgroundComposite haemangioendothelioma is a rare vascular neoplasm with indolent to intermediate malignant potential. Diagnosis of this disease relays on histopathological identification of at least two different morphologically distinctive vascular components in proper clinical settings. Exceedingly rare cases of this neoplasm can exhibit areas resembling high-grade angiosarcoma, which does not change the biological behaviour. Such lesions tend to occur in the setting of chronic lymphoedema and thus, can mimic Stewart-Treves syndrome, which has a much worse clinical outcome and prognosis.Case presentationWe present a case of 49 years old male suffering from chronic lymphoedema of the left lower extremity who had developed a composite haemangioendothelioma with high grade angiosarcoma-like areas mimicking the Stewart-Treves syndrome. Given the multifocality of the disease, the only potentially curable surgical treatment would be hemipelvectomy, which was refused by the patient. The patient has been followed-up, with no signs of local progression of the remaining disease, nor a distant spread outside the involved extremity for two years.ConclusionsComposite haemangioendothelioma represents a rare malignant vascular tumour, with significantly more favourable biological behaviour than angiosarcoma, even in cases where angiosarcoma-like areas are present. For that reason, composite haemangioendothelioma can be easily misdiagnosed as true angiosarcoma. The rarity of this disease unfortunately hampers the development of clinical practice guidelines and the implementation of treatment recommendations. Most of the patients with localized tumour are treated by wide surgical resection, without neo- or adjuvant radiotherapy or chemotherapy. However, in the case of this diagnosis, the watch-and-wait approach is better than mutilating procedure, highlighting the necessity of establishing of the correct diagnosis.

Respiratory distress syndrome due to pulmonary hypoplasia and neonatal congenital lymphedema

Respiratory distress syndrome due to pulmonary hypoplasia and neonatal congenital lymphedema

Prenatal diagnosis and management of Milroy syndrome: a case report

Abstract Objectives Milroy syndrome is a rare hereditary disorder characterized by congenital lymphedema, caused by mutations in the vascular endothelial growth factor receptor 3 (VEGFR3) gene. Case presentation We present a case report of a first-described mutation of a male fetus diagnosed prenatally with Milroy syndrome through amniocentesis. The fetus had bilateral lower limb edema, and genetic testing confirmed the diagnosis of Milroy syndrome. The patient was closely monitored throughout the pregnancy, and after delivery, the infant was managed with appropriate therapies, including compression garments and manual lymphatic drainage. The parents were provided with appropriate counseling and support. Conclusions This case highlights the significance of early detection and appropriate management of Milroy syndrome, which can lead to improved outcomes for affected infants.

Pharmacological inhibition of FOXO1 promotes lymphatic valve growth in a congenital lymphedema mouse model.

Mutations in many genes that regulate lymphatic valve development are associated with congenital lymphedema. Oscillatory shear stress (OSS) from lymph provides constant signals for the growth and maintenance of valve cells throughout life. The expression of valve-forming genes in lymphatic endothelial cells (LECs) is upregulated by OSS. The transcription factor FOXO1 represses lymphatic valve formation by inhibiting the expression of these genes, which makes FOXO1 a potential target for treating lymphedema. Here, we tested the ability of a FOXO1 inhibitor, AS1842856, to induce the formation of new lymphatic valves. Our quantitative RT-PCR and Western blot data showed that treatment of cultured human LECs with AS1842856 for 48h significantly increased the expression levels of valve-forming genes. To investigate the function of AS1842856 in vivo, Foxc2 +/- mice, the mouse model for lymphedema-distichiasis, were injected with AS1842856 for 2 weeks. The valve number in AS-treated Foxc2+/- mice was significantly higher than that of the vehicle-treated Foxc2+/- mice. Furthermore, since β-catenin upregulates the expression of Foxc2 and Prox1 during lymphatic valve formation, and AS1842856 treatment increased the level of active β-catenin in both cultured human LECs and in mouse mesenteric LECs in vivo, we used the mouse model with constitutive active β-catenin to rescue loss of lymphatic valves in Foxc2 +/- mice. Foxc2 +/- mice have 50% fewer lymphatic valves than control, and rescue experiments showed that the valve number was completely restored to the control level upon nuclear β-catenin activation. These findings indicate that pharmacological inhibition of FOXO1 can be explored as a viable strategy to resolve valve defects in congenital lymphedema.

Primary lymphangioma, lymphedema of the lower limb of the fetus in the practice of ultrasound

Scientifically based and experimentally confirmed data on the morphogenesis of the lymphatic system are necessary to clarify critical periods of development characterized by an increased risk of congenital anomalies of the lymphatic system in order to plan and implement effective prevention, diagnosis and correction of related abnormalities. Among the studied anomalies of lymphatic vessels, lymphangioma is most often mentioned — a congenital benign tumor consisting of many cysts of various sizes. Detection of primary fetal lymphangioma in the early stages of intrauterine development is extremely rare. The purpose of the study: to report a case of early diagnosis of congenital cystic lymphangioma and lymphedema of the left lower limb of the fetus. Congenital (primary) peripheral lymphedema, limb lymphangioma is associated with a malformation of the lymphatic system. Taking into account the fact that operative methods of correction of all types of primary lymphedema are considered unreasonable and ineffective, the main attention requires timely detection of this congenital malformation during screening studies of the fetus and the issuance of recommendations for the management of pregnancy, up to termination for medical reasons. It is necessary to raise the issue of genetic counseling of the couple and conducting the necessary genetic studies. The use of modern diagnostic methods allows for the prevention and treatment of abnormalities in the development of the lymphatic system at an earlier stage of the intrauterine period.

COMPOUND HETEROZYGOSITY FOR A VARIABLY PENETRANT VARIANT AND A VARIANT OF UNKNOWN SIGNIFICANCE IN FLT4 CAUSES FULLY PENETRANT MILROY'S LYMPHEDEMA

Milroy disease, known as primary congenital lymphedema, is characterized by chronic tissue swelling due to impaired lymphatic drainage and is inherited in an autosomal dominant manner. This study reports a rare case of Milroy disease affecting siblings from unaffected parents. A one-month-old female infant presented with swelling of the bilateral calf and the dorsum of the feet which had been present since birth. Her 14-month-old brother had a similar presentation since birth with swelling of the bilateral calf and the dorsum of the feet. Milroy disease was diagnosed based on the clinical findings of bilateral lower limb swelling and confirmed by molecular genetic testing. The patient and her family, including her brother, parents, and maternal grandfather, were genetically tested, and two novel missense mutations (NM_182925.4: c.2534T>C; p.Leu845Pro, c.4006G>A; p.Glu1336Lys) were found in the Fms-related tyrosine kinase (FLT4) gene. Mutations segregated by the parents who carried each mutation in the heterozygous state were identified in the patient and her brother. The present case report in which Milroy disease developed in all offspring of parents with a normal phenotype suggests the possibility of a compound heterozygous mutation or non-penetrance during the process of inheritance of Milroy disease.

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

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. 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. 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. 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.

Treatment of Primary Congenital Lymphedema Via the Godoy Method: A Case Report of 17-year Follow-up

The present research aimed to report the treatment of primary congenital lymphedema using the Godoy method with a 17-year follow-up period. A 2-month-old male patient with bilateral primary congenital lymphedema of the lower limbs was sent to the Clinica Godoy-Brazil for specialized treatment. The physical examination revealed bilateral lower limb edema affecting the feet and middle third of the legs. The patient was made to use hand-crafted stockings made of grosgrain fabric. When the child reached 10 years of age, mechanical lymphatic therapy was conducted. A considerable reduction in the edema was achieved but with periods of improvement and worsening. In the last 4 years of the 17 years of treatment, the limbs have remained within or near the range of normality. The present findings demonstrate that the Godoy method is effective in controlling edema in cases of primary congenital lymphedema. When the family has difficulties, others who take care of the child should get involved to ensure the treatment of this type of lymphedema.

Primary Idiopathic Congenital Lymphedema Presenting as Swelling of Dorsum of Both Feet – A Case Report

Lymphedema is a debilitating, progressive disease causing major healthcare problem. This condition is broadly classified as primary and secondary lymphedema. Congenital subtype is a rare form of primary lymphedema. Proper history taking and appropriate investigations can rule out the other differentials of lymphedema. Early diagnosis is essential for early treatment which may halt the progression and alleviate symptoms. Lymphoscintigraphy is an important but simple imaging modality which helps to diagnose and grade lymphedema initially as well as in follow up. An interesting case of primary idiopathic congenital lymphedema presenting with dorsum of feet swellings is reported here highlighting the importance of lymphoscintigraphy. Bangladesh J. Nuclear Med. 25(1): 41-44, 2022

Microdeletion of 16q24.1–q24.2—A unique etiology of Lymphedema–Distichiasis syndrome and neurodevelopmental disorder

Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema–Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants in FOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1–q24.2. This report extends the phenotype of both 16q24.1–q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3′‐UTR part of FOXC2.

EP456: Heterozygous deletion of the VEGFC gene in 4q34.3 is associated with Milroy-Like lymphedema: First prenatal case report

Primary or congenital lymphedema occurs rarely on idiopathic or developmental abnormalities in the lymphatic system, especially hypoplasia or aplasia of lymphatics. Milroy disease (MIM #153100), an autosomal dominant congenital lymphedema, characterized by peripheral edema mainly of the lower extremities, is resulted from pathogenic variants in the vascular endothelial growth factor receptor 3 (VEGFR3) gene (MIM *136352). However, missense VEGFR3 variants were only identified in approximately 70% of the patients diagnosed with Milroy disease suggesting genetic heterogeneity of the condition. Recently, pathogenic variants in VEGFC gene (MIM *601528), encoding one of the VEGFR3 ligands, were associated with autosomal dominant Milroy-like primary lymphedema (MIM #615907), a rare autosomal dominant disorder, characterized by congenital isolated lymphedema. Hitherto, only twenty-six postnatal cases in six families world-wide with primary lymphedema harboring VEGFC single point pathogenic variants were recorded (Table 1). No prenatal cases as well as VEGFC deletions were reported. We report the three-generation family with Milroy-like disease. The proband is a 24+4-week female fetus. Ultrasonography at 23+5 weeks of gestation showed fetal edema of the feet, prefrontal edema and facial dysmorphism including broad nasal bridge, short philtrum, and full lower lip. The fetus’s mother was a 22-year-old female with occasional swelling of lower legs and ankles during pregnancy or warm weather. Dysplastic, upslanting and yellowish toenails were also observed. The fetus’s grandmother was a 40-year-old female and had a family history of lymphedema. Family history dates back to the fetus’s great-grandmother, maternal grand-aunt and two maternal cousins, they were all affected by edema. Congenital lymphedema of her feet progressed to legs but below the knees. Moreover, she also exhibited bilateral edema of the dorsi of both hands. Dysplastic and upslanting toenails, varicose, prominent veins and hyperkeratosis were also noted. Lymphoscintigraphy showed symmetrical tracer uptake, with a discrete reduction in uptake of tracer within the right groin lymph nodes. 180K aCGH analysis showed a 137 kb interstitial microdeletion within 4q34.3 region encompassing only VEGFC gene. Segregation analysis showed that the deletion was of maternal in origin. The fetus’s grandmother also carried the 4q34.3 deletion.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) To the best of our knowledge, this is the first prenatal report of VEGFC deletion. Our results reinforce that VEGFC haploinsufficiency is associated with primary Milroy-like lymphedema with incomplete penetrance, inter- and intra-familial variable expressivity, and contribute to add knowledge to the current literature with the description of the prenatal phenotype of Milroy-like disease. Our report also suggests that molecular VEGFC analysis should also be performed in VEGFR3-negative patients with congenital lymphedema.

Lymphedema in Mexico: A Clinical and Epidemiological Overview

Background: There is insufficient clear epidemiological and clinical knowledge about lymphedema patient’s population in Mexico, this limits its investigation. The objective of this study is to present basic lymphedema epidemiological data and its clinical characteristics based on the analysis of lymphedema patients’ data collected from a specialized rehabilitation clinic in Mexico.
 Methods: This is a cohort study developed between 2015 and 2021. The study was carried ou in a private clinic specialized in oncological and peripheral vascular patients’ rehabilitation. Clinical assessments and interviews were performed to collect each case’s clinical history, considering its medical characteristics, physical activity and functionality and socio-demographic information, classified in a matrix, and later statistically evaluated.
 Results: Among 446 lymphedema patients, gender distribution was represented by 81% female and 19% male with a mean age of 50.5 years (±44.5). The population was categorized into the following three different study groups according to diagnosis: Cancer-Related Lymphedema (CRL), Non-Cancer-Related Secondary Lymphedema (NCRSL) and Primary Lymphedema. 60.08% of the patients had CRL; 25.11% had NCRSL and 14.79% had Primary Lymphedema. Among the patients with CRL, 81% of them corresponded to breast cancer diagnosis, the rest were associated to 19 different cancer diagnoses. The most prevalent diagnosis was breast CRL 48.6%; phlebolymphedema 19.4%; congenital and praecox lymphedema 14.1%; lipo-lymphedema 4.8%. The BMI of 64% of the patients ranged in overweight and obesity. 37.6% of patients reported that had experienced pain in limbs affected by lymphedema and 45% of all patients reported some disability to perform one or more activities associated to their limb volume or limb discomfort. 82% of patients had no physical activity or performed less physical activity than what is suggested to their population group’s recommendation.
 Conclusion: This study stablishes a precedent on reporting the broadest available epidemiological and clinical data of lymphedema in Mexico. Further studies are needed to report with a higher precision the epidemiological, clinical, and demographical data about each etiological group for a better understanding of lymphedema in Mexico and Latin America.

Grosgrain Stockings in the Treatment of Primary Congenital Lymphedema

Aim: The aim of the present study was to evaluate grosgrain c stockings in the reduction and maintenance of the results of treatment for lymphedema. Method: A prospective clinical trial was performed with 45 patients who made use of grosgrain stockings as monotherapy for the treatment of lower limb lymphedema with the analysis of the volumetric reduction using bioimpedance at the Clinica Godoy-Brazil. These stockings are hand-crafted and adapted to each patient, with adjustments made as necessary. Results: The mean reduction in volume was from 7.1 to 6.0 L (standard deviation: 1.56 L). This reduction was statistically significant (p-value < 0.0001, paired t-test). A total of 17 (18.8%) of the 90 limbs did not undergo reductions, but rather had discrete numerical increases. However, these increases were not statistically significant in this group of patients (p-value = 0.08, paired t-test). Conclusion: Grosgrain stockings are effective for the treatment of primary congenital lymphedema when used in accordance with the recommended instructions.

Redefining WILD syndrome: a primary lymphatic dysplasia with congenital multisegmental lymphoedema, cutaneous lymphovascular malformation, CD4 lymphopaenia and warts

BackgroundPrimary lymphoedema (PL) syndromes are increasingly recognised as presentations of complex genetic disease, with at least 20 identified causative genes. Recognition of clinical patterns is key to diagnosis, research and...